KDOQI US Commentary on the 2009 KDIGO Clinical Practice ...
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Transcript of KDOQI US Commentary on the 2009 KDIGO Clinical Practice ...
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VOL xx NO x MONTH 2010
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ARTICLE IN PRESS
KDOQICOMMENTARY
KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guidelinefor the Care of Kidney Transplant Recipients
Margaret Bia MD1 Deborah B Adey MD2 Roy D Bloom MD3 Laurence Chan MD4
Sanjay Kulkarni MD5 and Steven Tomlanovich MD6
In response to recently published KDIGO (Kidney Disease Improving Global Outcomes) guidelines for thecare of kidney transplant recipients (KTRs) the National Kidney Foundationrsquos Kidney Disease OutcomesQuality Initiative (KDOQI) organized a working group of transplant nephrologists and surgeons to reviewthese guidelines and comment on their relevance and applicability for US KTRs The following commentar-ies on the KDIGO guidelines represent the consensus of our work group The KDIGO transplant guidelinesconcentrated on aspects of transplant care most important to this population in the posttransplant periodsuch as immunosuppression infection malignancy and cardiovascular care Our KDOQI work groupconcurred with many of the KDIGO recommendations except in some important areas related to immunosup-pression in which decisions in the United States are largely made by transplant centers and are dependentin part on the specific patient population served Most but not all KDIGO guidelines are relevant to USpatients However implementation of many may remain a major challenge because of issues of limitation inresources needed to assist in the tasks of educating counseling and implementing and maintaining lifestylechanges Although very few of the guidelines are based on evidence that is strong enough to justify theirbeing used as the basis of policy or performance measures they offer an excellent road map to navigate thecomplex care of KTRsAm J Kidney Dis xxxxx copy 2010 by the National Kidney Foundation Inc
INDEX WORDS Kidney transplant recipients (KTRs) calcineurin inhibitor (CNI) mycophenolatecompound (MPA compound) inhibitor of mammalian target of rapamycin (mTOR inhibitor) KDIGO KDOQI
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n 2007 there were 16119 kidney transplantsperformed in the United States (10082 de-
eased donor and 6037 living donor)1 and58739 US patients living with a functioning
From the 1Yale School of Medicine New Haven CTUniversity of VermontFletcher Allen Health Care Burling-on VT 3Hospital of the University of Pennsylvania Phila-elphia PA 4University of Colorado Denver Aurora COYale School of Medicine New Haven CT and 6Universityf California San Francisco CA
Reprint requests to Kerry Willis PhD National Kidneyoundation 30 E 33rd St New York NY 10016 E-mail
errywkidneyorg
merican Journal of Kidney Diseases Vol xx No x (Month) 2010
idney allograft KDIGO (Kidney Disease Im-roving Global Outcomes) is an internationalnitiative formed to ldquoimprove the care and out-omes of kidney disease patients worldwide
Address correspondence to Margaret Bia MD Section ofephrology Department of Internal Medicine Yale Schoolf Medicine PO Box 208029 New Haven CT 06520-8029-mail margaretbiayaleeducopy 2010 by the National Kidney Foundation Inc0272-638610xx0x-0001$36000doi101053jajkd201004010
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ARTICLE IN PRESS
hrough promoting coordination collaborationnd integration of initiatives to develop andmplement clinical practice guidelinesrdquo2 To thisnd a KDIGO work group has recently pub-ished a new comprehensive set of recommenda-ions for the care of kidney transplant recipientsKTRs)3 The last clinical practice transplantuideline for US patients was published in 2000y theAmerican Society of Transplantation (AST)nd was based primarily on expert opinion Pre-ious KDIGO practice guidelines have been pub-ished for the care of patients with hepatitis Cnd chronic kidney disease (CKD)4 and CKDndashineral and bone disorders (CKD-MBD)5 Be-
ause global guidelines need to be adapted to theegional context in which they are used theational Kidney Foundationrsquos Kidney Diseaseutcomes Quality Initiative (KDOQI) programrganized a work group of transplant nephrolo-ists and surgeons to review the newest KDIGOuideline and comment on the relevance andpplicability for US KTRs
KDIGO GUIDELINE PROCESS
The KDIGO transplant guideline concentratedainly on aspects of transplant care most impor-
ant to this population in the posttransplant pe-iod such as immunosuppression infection ma-ignancy and cardiovascular care The guidelineso not address pretransplant evaluation or issueselated to patients returning to dialysis therapyith a failed allograft The target audience for
he guideline is physicians coordinators pharma-ists and other medical professionals who di-ectly or indirectly care for KTRs The KDIGOuideline was based on published evidence andraded according to the strength of the data (Fig) Because of the paucity of evidence in many
Figure 1 Rating guideline recommendations Within eas Level 1 Level 2 or Not Graded and the quality of theategory Not Graded typically was used to provide guidadequate application of evidence The most common exaounseling and referral to other clinical specialists Ungrad
tatements but are not meant to be interpreted as being strongeDIGO transplant guideline3 with permission of KDIGO
reas only 25 of recommendations were graded Furthermore evidence for only 2 of recom-endations were graded A 136 were graded 389 were graded C and 455 were graded3 The KDIGO authors make it clear that foruidelines in which the evidence was meagerhey chose to give guidance rather than remainilent They also make it clear that the guidelineas not developed for regulatory agencies this
s important to keep in mind because so few ofhe recommendations are based on evidence thats strong enough to justify their being used as theasis of policy or performance measures
KDOQI PROCESS FOR INTERPRETATION OFTHE KDIGO GUIDELINE IN THE CARE OF US
TRANSPLANT PATIENTS
Differences in target population individualatient immunologic risk prevalence of concomi-ant diseases (such as diabetes mellitus) availabil-ty of resources and systems of payment must alle considered in interpreting global recommenda-ions to specific regions The following commen-aries on the KDIGO guideline represent theonsensus of a work group convened by KDOQIo evaluate the relevance and applicability of theuideline to US patients and practices It iseyond the scope of our review to make a com-ent on each of the more than 150 KDIGO
ecommendations We chose instead to addressuidelines for which we questioned applicabilityo US KTRs as well as those that we believedeeded reinforcement or clarification Emphasiss placed not on critiquing the guidelines but onetermining their appropriateness for our USatients The relative importance of a recommen-ation relevance to US patients comparison to
mmendation the strength of recommendation is indicatedrting evidence is shown as A B C or D The additionalsed on common sense or when the topic does not allowinclude recommendations regarding monitoring intervalsommendations generally are written as simple declarative
ch recosuppo
nce bamplesed rec
r recommendations than Level 1 or 2 Adapted from the
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KDOQI Commentary 3
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xisting guidelines and ease of implementationorm the basis of these commentaries
Members of the KDOQI commentary workroup reached consensus on most commentariesnd have indicated when this was not the casee have relisted each KDIGO recommendation
y section with the grade for evidence support-ng it followed by our work grouprsquos rationalend commentary on the guideline If a guidelineecommendation statement was classified by theDIGO work group as important enough toecome a strong recommendation (category 1)he statement is highlighted by showing the guide-ine text in bold
COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
DIGORecommendations inChapter 1nduction Therapy
11 We recommend starting a combination of immu-nosuppressive medications before or at the timeof kidney transplantation (1A)
12 We recommend including induction therapy witha biologic agent as part of the initial immunosup-pressive regimen in KTRs (1A)121 We recommend that an IL2-RA [interleu-
kin-2 receptor antagonist] be the firstlineinduction therapy (1B)
122 We suggest using a lymphocyte-depletingagent rather than an IL2-RA for KTRs athigh immunologic risk (2B)
DOQIRationale andCommentary
It clearly is important to start immunosuppres-ion before or at the time of transplant Inductionherapy with a biologic agent such as interleukin
(IL-2) receptor antagonists or thymoglobulinecreases the frequency of acute rejection andow is used in up to 80 of US transplantenters However individual US transplant cen-ers determine immunosuppression protocolsased on their particular patient population or-an source experience ease of use and cost ofherapy Ethnic diversity of the population andhe number of high-risk patients vary in differentegions of the United States which explains inart variations in protocols used in differententers Applicability of the recommended
DIGO guidelines in this section must be inter- n
reted with these differences in mind The lastublished survey of immunosuppression use inS transplant centers was in the 2006 Organrocurement and Transplantation NetworkScien-
ific Registry of Transplant Recipients (OPTNRTR) Annual Report6 and reported on the usef calcineurin inhibitors (CNIs) mycophenolatecid compounds (MPA) mammalian target ofapamycin (mTOR) inhibitors and inductionherapy (Box 1)
Guidelines for induction therapy will be mostelevant not to community nephrologists but tohose working in transplant centers in whichnduction is used Not all patients need inductionherapy The cost of induction therapy is substan-ial and should be viewed in the context ofiskbenefit for a particular donorrecipient pro-le In the United States the use of lymphocyte-epleting antibodies (thymoglobulin and alemtuz-mab) for induction is increasing6 Many centersill use these agents in low-risk patients toinimize exposure to other maintenance drugs
ie steroids) It is unlikely that the current KDIGOuidelines recommending IL-2 receptor antago-
Box 1 2006 OPTNSRTR Annual Report
Induction Immunosuppressiona
78 used induction therapy composed ofŒ Thymoglobulin in 39Œ Interleukin 2 receptor antagonist in 28Œ Alemtuzumab in 9Œ Other in 2
22 did not receive induction therapy
Initial Immunosuppression (at discharge)
94 on CNI composed ofŒ 15 CsAŒ 79 Tac
87 on MPA 9 on mTOR inhibitor 26 steroid free
Maintenance Immunosuppression (1 year and beyond)
99 on CNI 87 on MPA 18 on mTOR inhibitors 20 steroid free
Abbreviations CNI calcineurin inhibitors CsA cyclo-porine MPA mycophenolic acid compounds mTORammalian target of rapamycin OPTNSRTR Organrocurement and Transplantation NetworkScientific Reg-
stry of Transplant Recipients Tac tacrolimusData source Andreoni et al6
ists as first-line induction therapy will alter US
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ransplant practices in which these decisions tendo be transplant-center specific and based onactors described previously
DIGORecommendations inChapter 2 InitialndMaintenance Immunosuppressiveedications
21 We recommend using a combination of immuno-suppressive medications as maintenance therapyincluding a CNI and an antiproliferative agentwith or without corticosteroids (1B)
22 We suggest that tacrolimus be the first-line CNIused (2A)221 We suggest that tacrolimus or CsA be
started before or at the time of transplanta-tion rather than delayed until the onset ofgraft function (2D tacrolimus 2B CsA)
23 We suggest that mycophenolate be the first-lineantiproliferative agent (2B)
24 We suggest that in patients who are at low immuno-logical risk and who receive induction therapycorticosteroids could be discontinued during thefirst week after transplantation (2B)
25 We recommend that if mTOR inhibitors areused they should not be started until graftfunction is established and surgical wounds arehealed (1B)
DOQIRationale andCommentary
Initial Immunosuppression
We agree that optimum initial maintenanceherapy includes a CNI and an antiproliferativegent and that tacrolimus is the preferred CNI forost patients The Symphony Study a largeulticenter clinical trial showed that the combi-
ation of low-dose tacrolimus mycophenolateofetil (MMF) and steroids with daclizumab
nduction provided superior efficacy without theegative impact on renal function compared withither cyclosporine or a CNI-free regimen ofow-dose sirolimus78 However in a small num-er of patients other issues such as age ethnic-ty risk of new-onset diabetes mellitus and pre-ious toxicity with tacrolimus may result in thenitial use of cyclosporine Immediate CNI useas not been shown to cause a delay in renalecovery Although many centers briefly hold orodify the CNI dose in the setting of delayed
raft function especially when using antilympho-yte-depleting induction agents treatment withhese drugs should be initiated before or at theime of discharge from the hospital and not
ithheld because of delayed graft function As m
tated mycophenolate compounds (MMF andycophenolate sodium) are used as the initial
ntiproliferative agent of choice in most USransplant centers
SteroidTherapyDiscontinuation
Steroid sparing with discontinuation withinhe first few weeks after transplant has gainedidespread acceptance in the United States withore than 25 of patients being discharged after
ransplant off steroid therapy6 Although theDOQI work group agreed that steroid therapy
ould be discontinued in low-risk patients afternduction therapy we did not think that thisuggestion should be accepted as a universaluideline for several reasons Although short-nd medium-term results in corticosteroid therapyiscontinuation protocols show equivalent pa-ient and graft survival there may be a price toay in the long term Acute rejection rates areigher in well-designed randomized clinical tri-ls of steroid withdrawal In addition the pres-nce of chronic interstitial fibrosis and tubulartrophy may be greater in corticosteroid-freeatients portending decreased long-term graftunction The heterogeneity of the US donor andecipient population may have a role in thisssue Newer transplant regimens decrease pred-isone dosage to 5 mgd Apart from less boneisease the potential metabolic benefits of corti-osteroid-free protocols versus 5 mgd seem toe less significant What is clear is that discontinu-tion of steroid therapy early after transplanteems to be associated with less risk of rejectionhan discontinuation of steroids later (1 year)t should be noted that there are no studies ofifferent times in the first year to determine whenorticosteroid therapy can be discontinued safelyn some centers steroid therapy discontinuations accomplished up to 6 months posttransplantate discontinuation of steroid therapy (1 yearosttransplant) is no longer recommended andorms the basis of KDIGO guideline 25 withhich we agree It also must be emphasized that
teroid therapy withdrawal should be performednly when there is close frequent monitoring ofhe patient
EarlyUseofmTOR Inhibitors
Sirolimus and everolimus (agents known as
TOR inhibitors) delay wound healing prolong
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KDOQI Commentary 5
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elayed graft function and are no longer used inhe early posttransplant period (KDIGO recom-endation 25) Furthermore studies show an
ncreased rejection rate with early use of theseompounds in place of CNIs The Symphonytudy showed that the highest rejection rateccurred in the arm using low-dose sirolimusith MMF and steroids78
DIGORecommendations inChapter 3ong-termMaintenance Immunosuppressiveedications
31 We suggest using the lowest planned doses ofmaintenance immunosuppressive medications by2-4 months after transplantation if there has beenno acute rejection (2C)
32 We suggest that CNIs be continued rather thanwithdrawn (2B)
32 If prednisone is being used beyond the first weekafter transplantation we suggest prednisone becontinued rather than withdrawn (2C)
DOQIRationale andCommentary
Decreasing ImmunosuppressiveDosage
Although our work group agreed with sugges-ion 31 we stress that dosing of immunosuppres-ion should at all times take into account thendividual patientrsquos risk profile balancing rejec-ion with the adverse effects of medications Inome patients this may mean higher drug dosingrug levels to account for a higher risk of rejec-ion Although most US transplant centers nowtrive for a lower dose of immunosuppressiveedication after the early posttransplant period
he transplant center should define each patientrsquosarget drug dosing based on immunologic riskhich depends on ethnicity age history of previ-us transplant and level of HLA antibodies
ContinueorWithdrawCNITherapy
Although we agreed that mTOR inhibitorshould not be used in the early posttransplanteriod78 newer clinical trials have exploredwitching from CNIs to mTOR inhibitors 3-6onths posttransplant910 Early results suggest
elative safety with improvement in renal func-ion Whether the trade-off of less nephrotoxic-ty with a different side-effect profile of mTORnhibitors will be beneficial in the long termemains to be determined The work groupelieved that suggestion 32 to continue CNI
herapy indefinitely in all patients required
ore study before it could be accepted as auideline
SteroidTherapyWithdrawal
We agree that late steroid therapy with-rawal (1 year) is inadvisable but stress thathe definition of ldquoearlyrdquo steroid discontinua-ion has not been well defined and may occurfter the first week (see commentary underhapter 2)
DIGORecommendations inChapter 4trategies toReduceDrugCosts
41 If drug costs block access to transplantation astrategy to minimize drug costs is appropriateeven if use of inferior drugs is necessary to obtainthe improved survival and quality of life benefitsof transplantation compared with dialysis (NotGraded)411 We suggest strategies that may reduce drug
costs includebull limiting use of a biologic agent for
induction to patients who are high-riskfor acute rejection (2C)
bull using ketoconazole to minimize CNIdose (2D)
bull using a nondihydropyridine CCB to mini-mize CNI dose (2C)
bull using azathioprine rather than mycophe-nolate (2B)
bull using adequately tested bioequivalent ge-neric drugs (2C)
bull using prednisone long-term (2C)
42 Do not use generic compounds that have not beencertified by an independent regulatory agency tomeet each of the following criteria when comparedto the reference compound (Not Graded)bull contains the same active ingredientbull is identical in strength dosage form and route of
administrationbull has the same use indicationsbull is bioequivalent in appropriate bioavailability
studiesbull meets the same batch requirements for identity
strength purity and qualitybull is manufactured under strict standards
43 It is important that the patient and the clinicianresponsible for the patientrsquos care be made aware ofany change in a prescribed immunosuppressivedrug including a change to a generic drug (NotGraded)
44 After switching to a generic medication that ismonitored using blood levels obtain levels andadjust the dose as often as necessary until a stable
therapeutic target is achieved (Not Graded)
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DOQIRationale andCommentary
Drug costs are becoming an increasing issue inransplantation that impacts on patient adherencend ultimately affects graft survival Currently im-unosuppressive drugs in the United States are
overed by the Centers for Medicare amp Medicaidervices (CMS) the primary insurer for manyTRs for 3 years after transplant although legisla-
ion is being considered to continue this coverageor the life of the kidney Most KTRs are usingany other medications in addition to immunosup-
ressive drugs In general the transplant commu-ity (patients health care providers and policyakers) need to embrace the concept of cost con-
ainment and the risk(s) to the patient and graft byhese measures However this needs to be balancedy who benefits and how much risk is at stake
Use of drugs that block the cytochrome P-450A system in an attempt to decrease CNIosing and costs are rarely used in the Unitedtates The concern is that inadvertent cessa-
ion of treatment with these drugs causing aignificant decrease in drug levels could resultn an acute rejection episode Therefore theork group did not think that many of the 411
uggestions should be accepted as a guidelinewitching from a mycophenolate compound ton azathioprine compound in the later posttrans-lant period may be considered in some pa-ients as another cost-saving maneuver espe-ially in view of recent US registry datahowing similar long-term survival with theserugs11 Although we agree with the sugges-ions outlined in 42 it should be recognizedhat many generic formulations have nevereen tested in transplant patients Patient con-usion with medications when a different ge-eric formulation or even different strengths ofhe same drug from different manufacturers isispensed at each refill can lead to inadvertentedication errors possibly affecting out-
omes Patient education is crucial to avoidrrors in medication administration We agreeith recommendation 44 that it is crucial toonitor patients after an immunosuppressive
osage change brand change or change to aeneric drug However it needs to be recog-ized that implementation of this guideline canecome burdensome as practices become inun-
ated with inquiries from patients payors and 5
harmacies regarding medications Transplantenters and practices that see many transplantatients bear an inordinate part of this burden
DIGORecommendations inChapter 5onitoring ImmunosuppressiveMedications
51 We recommend measuring CNI blood levels(1B) and suggest measuring at leastbull every other day during the immediate postopera-
tive period until target levels are reached (2C)bull whenever there is a change in medication or
patient status that may affect blood levels (2C)bull whenever there is a decline in kidney function that
may indicate nephrotoxicity or rejection (2C)511 We suggest monitoring CsA using 12-h
trough (C0) 2-h post-dose (C2) or abbrevi-ated AUC (2D)
512 We suggest monitoring tacrolimus using12-h trough (C0) (2C)
52 We suggest monitoring MMF levels (2D)53 We suggest monitoring mTOR inhibitor levels (2C)
DOQIRationale andCommentary
Because immunosuppressive drugs are classi-ed as narrow therapeutic agents drug-levelonitoring is a necessary tool to maximize effi-
iency and minimize toxicity The blood drugevel is not synonymous with level of immuno-uppression but may correlate imperfectly withhis effect In most US transplant centers levelsf CNI and mTOR inhibitors are monitoredPA monitoring is problematic because of the
oor correlation between trough levels and areander the curve (AUC) exposure Optimal moni-oring of MPA requires a 4- to 6-hour abbrevi-ted AUC measurement which is logisticallyifficult in the outpatient setting Although stud-es show that monitoring MPA levels in the earlyosttransplant period may be helpful in cyclospor-ne-treated patients recent evidence suggests thatuch monitoring may be less important in pa-ients on tacrolimus therapy12 With most USTRs now being started on tacrolimus as theNI of choice MPA monitoring is not routine inany US transplant centers Although one per-
on in our work group believed there may still beome value in monitoring MPA levels the otherembers questioned the value and applicability
f this practice (KDIGO suggestion 52) Cur-ently many US centers measure MPA only inhe setting of possible drug-related toxicities oride effects Although we agree with suggestion
3 to monitor mTOR inhibitor levels it should
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KDOQI Commentary 7
ARTICLE IN PRESS
e appreciated that therapeutic levels of thisgent have yet to be defined in controlled studies
DIGORecommendations inChapter 6reatment ofAcuteRejection
61 We recommend biopsy before treating acuterejection unless the biopsy will substantiallydelay treatment (1C)
62 We suggest treating subclinical and borderline acuterejection (2D)
63 We recommend corticosteroids for the initialtreatment of acute cellular rejection (1D)631 We suggest adding or restoring maintenance
prednisone in patients not on steroids whohave a rejection episode (2D)
632 We suggest using lymphocyte-depleting anti-bodies or OKT3 [muromonab-CD3] for acutecellular rejections that do not respond tocorticosteroids and for recurrent acute cellu-lar rejections (2C)
64 We suggest treating antibody-mediated acute rejec-tion with one or more of the following alternativeswith or without corticosteroids (2C)bull plasma exchangebull intravenous immunoglobulinbull anti-CD20 antibodybull lymphocyte-depleting antibody
65 For patients who have a rejection episode wesuggest adding mycophenolate if the patient is notreceiving mycophenolate or azathioprine or switch-ing azathioprine to mycophenolate (2D)
DOQIRationale andCommentary
We concur that biopsies should be performed onll KTRs suspected of having an acute rejectionrecommendation 61) Expert interpretation of theiopsy specimen by pathologists accustomed toeading kidney transplant biopsies is as importants expertise in performing the biopsy It is contro-ersial whether subclinical and borderline rejec-ions should be treated (recommendation 62 sup-orted by low evidence [2D]) Subclinical rejectionsre diagnosed in patients who have protocol biop-ies performed by design not for deterioration inidney function Recent data suggest that the riskf subclinical rejection in patients on tacrolimusnd mycophenolate compound therapy is so lowhat protocol biopsies may no longer be indi-ated13 Whether this is true in patients with highmmunologic risk or patients on minimization pro-ocols (ie steroid-free protocols or lower CNI doses)s uncertain Whether borderline rejection shoulde treated or some infiltrates may be protective also
s uncertain In most US centers steroids are used d
ost frequently as first-line treatment for acuteejection followed by lymphocyte-depleting anti-odies in steroid-resistant rejection but there maye exceptions to this approach Decision makingegarding appropriate initial treatment for acuteejection should be based on clinical and patho-ogic information Timing of the rejection episodeosttransplant type of induction agent used beforeejection degree of deterioration in kidney functiont the time of rejection and histologic grade of theejection may influence selection of the appropriatenitial antirejection therapy There is increasingecognition of the role of antibody-mediated mecha-isms in acute rejection This process requirespecial blood tests (to detect donor-specific antibod-es) and histochemical stains (immunofluorescenceor C4d) for diagnosis14 Coordination with theransplant center is critical to ensure that all appro-riate testing is performed and specific treatment isnitiated After treatment of an acute episode opti-
izing overall immunosuppression is requiredonsiderations should include changing the CNIdding a mycophenolate compound or increasinghe dose adding corticosteroids to previously ste-oid-free regimens or addingsubstituting an mTORnhibitor More than 85 of patients are alreadysing MPA agents so the number available forwitching will be relatively small
DIGORecommendations inChapter 7reatment of ChronicAllograft Injury (CAI)
71 We recommend kidney allograft biopsy for allpatients with declining kidney function of unclearcause to detect potentially reversible causes (1C)
72 For patients with CAI and histological evidence ofCNI toxicity we suggest reducing withdrawing orreplacing the CNI (2C)721 For patients with CAI eGFR 40 mLmin
173 m2 and urine total protein excretion500 mgg creatinine (or equivalent protein-uria by other measures) we suggest replac-ing the CNI with a mTOR inhibitor (2D)
DOQIRationale andCommentary
We agree with the need for kidney transplantiopsy in patients with decreasing kidney function71) and again stress the importance of expertise inathologic interpretation Important causes ofhronic allograft injury (CAI) which include rejec-ion BK nephropathy CNI toxicity or recurrentisease require special histochemical stains for
iagnosis that are not readily available in all labora-
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Bia et al8
ARTICLE IN PRESS
ories Therefore coordination with the transplantenter where these techniques are available is essen-ial For patients with CAI caused by CNI toxicityithdrawing the CNI should occur only after at-
empts at decreasing the dosage have failed Onelso must ensure that all other causes of CAI arexcluded to avoid inappropriate drug adjustmentsr missed treatment options Although our workroup thought that KDIGO suggestion 721 maye reasonable in some patients we also want tomphasize that the role of mTOR inhibitors in thereatment of CAICNI toxicity is poorly defined Its clear that switching from a CNI to an mTORnhibitor should be avoided in patients with se-erely decreased glomerular filtration rate (GFR)ndor the presence of proteinuria however the exactuidelines for when to switch are still evolving
SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
DIGORecommendations inChapter 8onitoringKidneyAllograft Function
81 We suggest measuring urine volume (2C)bull Every 1-2 hours for at least 24 hours after
transplantation (2D)
In the United States immunosuppressive protocolsused may vary from center to center based on theirparticular patient population organ source experienceand opinion of the transplant team ease of use and costof therapy Although data about the efficacy and safety ofsteroid-free regimens are still evolving it is clear that ifsteroids are to be eliminated this should be done in theearly transplant period and not late (after 1 year)Community nephrologists need to coordinate any alter-ations in immunosuppressive medications with the trans-plant center and be vigilant for potential drug interactionswith the addition of any new medications Drug monitor-ing is an essential monitoring tool throughout the post-transplant course but not always applicable to everyimmunosuppressive medication Transplant biopsies fre-quently are necessary to determine the cause of renaldysfunction and the interpretation must be performed bypathologists with resources and experience in handlingand reading the transplant biopsy specimen
bull Daily until graft function is stable (2D) c
82 We suggest measuring urine protein excretion (2C)at leastbull Once in the first month to determine a baseline
(2D)bull Every 3 months during the first year (2D)bull Annually thereafter (2D)
83 We recommend measuring serum creatinine (1B) atleastbull Daily for 7 days or until hospital discharge
whichever occurs sooner (2C)bull 2-3 times per week for weeks 2-4 (2C)bull Weekly for months 2 and 3 (2C)bull Every 2 weeks for months 4-6 (2C)bull Monthly for months 7-12 (2C)bull Every 2-3 months thereafter (2C)
831 We suggest estimating GFR whenever se-rum creatinine is measured (2D) usingbull One of several formulas validated for
adults (2C) orbull The Schwartz formula for children and
adolescents (2C)
84 We suggest including a kidney allograft ultrasoundexamination as part of the assessment of kidneyallograft dysfunction (2C)
DOQIRationale andCommentary
RoutineScreeningTestsandTimeandFrequencyofMonitoring
Regular surveillance and vigilant monitoring ofidney allograft function are important in improv-ng short- and long-term outcomes Early detectionf kidney allograft dysfunction will allow timelyiagnosis and treatment that may improve patientnd graft survival Frequency and types of routinecreening tests after kidney transplant are shown inig 2Although there is no standard protocol for therequency and type of monitoring recommenda-ions are guided by the likelihood of problemspecific to the particular transplant population Inhe early posttransplant period when rejection andomplications are the most likely testing is per-ormed more frequently Thereafter the follow-upnterval will depend in part on the patientrsquos generalondition and the development of additional prob-ems The AST recommended routine posttrans-lant 2-3 visits per week during month 1 every 1-3eeks during month 2-3 every 4-8 weeks duringonths 4-12 and every 2-4 months after therst year These early visits often are providedy the transplant physician or surgeon of theransplant center After 3-6 months monitor-ng may be performed by the transplant physi-
ian or community nephrologist15 In a recent
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KDOQI Commentary 9
ARTICLE IN PRESS
urvey of posttransplant outpatient visits inedicare beneficiaries in the United States
requency of visits to transplant centers variedy center and region most visits were toephrologists16
At each clinic visit education regardingedication adherence diet and healthy life-
tyle should be given Screening for tobaccose should be implemented before dischargend annually Although the work group did notgree that screening all adults for Epstein-Barrirus (EBV) was of value (see commentarynder Chapter 13 for EBV) screening for allther elements listed in Fig 2 including screen-ng for proteinuria is reasonable In additiono these tests monitoring for HLA antibodiesgainst the donor (donor-specific antibodies)hich is not described in the KDIGO guide-
ine is becoming more common in some USenters The optimal timing and frequency ofuch screening has yet to be determined1718
SerumCreatinineandEstimatedGFR
Serum creatinine measurement remains theost commonly used index of renal allograft
unction It is reliable for detecting acute changesn kidney function Furthermore serum creati-ine level at year 1 after transplant is a riskactor for subsequent outcomes19 and mayelp in the management of the frequency ofisits However it is less reliable for detecting
Figure 2 Routine screen-ng after kidney transplantomplete blood cell count in-ludes white blood cells hemo-lobin and platelets Screenor diabetes is by fasting bloodlucose level glucose toler-nce test or hemoglobin A1c
evel Lipid profile includes fast-ng cholesterol low-density li-oprotein cholesterol high-ensity lipoprotein cholesterolnd triglyceride levels Screensor BK polyoma virus (BKV)nd Epstein-Barr virus (EBV)se plasma nucleic acid test-
ng (NAT) EBV screen is foratients with no antibody toBV at transplant Adapted
rom the KDIGO transplantuideline3 with permission ofDIGO
ong-term changes in kidney function in the
idney transplant recipient Formulas to esti-ate GFR using serum creatinine values have
een tested in KTRs but no formula consis-ently has been shown to be superior to an-ther As with CKD considerable renal patho-ogic states can be present without dramatichanges in serum creatinine levels
In 2005 the definition of CKD was amendedo include all KTRs regardless of markers ofidney damage or GFR2021 Although the workroup agreed that CKD staging in KTRs isseful it must be noted that there is consider-ble difference in the rate of progression inhese 2 groups Progression is much slower inTRs in whom kidney half-life is longer at
very level of CKD Renal ultrasound is thereferred imaging study in KTRs (KDIGOuggestion 84)22
DIGORecommendations inChapter 9 Kidneyllograft Biopsy
91 We recommend kidney allograft biopsy whenthere is a persistent unexplained increase inserum creatinine (1C)
92 We suggest kidney allograft biopsy when serumcreatinine has not returned to baseline after treat-ment of acute rejection (2D)
93 We suggest kidney allograft biopsy every 7-10 daysduring delayed function (2C)
94 We suggest kidney allograft biopsy if expectedkidney function is not achieved within the first 1-2months after transplantation (2D)
95 We suggest kidney allograft biopsy when there is
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bull New onset of proteinuria (2C)bull Unexplained proteinuria 30 g per gram creati-
nine or 30 g per 24 hours (2C)
DOQIRationale andCommentary
Biopsy
Renal allograft biopsy is the gold standard foriagnosing the cause of a change in renal allo-raft function It is useful in all clinical situationsescribed in KDIGO suggestions 91-94 Poten-ial causes of allograft dysfunction include vol-me depletion compromised renal blood flowrinary outflow obstruction parenchymal causesuch as acute rejection (cellular andor humoral)hronic allograft nephropathy recurrent or deovo disease or BK nephropathy Patients show-ng a 20-25 increase in creatinine level aboveaseline values warrant consideration for biopsyther indications for pursuing renal allograftiopsy would be a less-than-expected responseo treatment of acute rejection The expectedesponse would be dependent on the severity ofissue injury noted on the diagnostic biopsy speci-
en Delayed graft function lasting longer than-7 days warrants biopsy with repeated biopsieserformed every 7-10 days until graft functionecovers New-onset proteinuria protein 20g creatinine or 20 g24 h also merits aidney biopsy De novo and recurrent glomerulariseases are common causes of new-onset pro-einuria Patients with de novo or recurrent glo-erular diseases should be followed up closely
y transplant nephrologists or community neph-ologists with close communication with theransplant center because treatment of some recur-ent kidney diseases may prevent or delay thenset of graft failure2324
SafetyandAccuracy
The safety of kidney transplant biopsies haseen documented and the overall risk of compli-ations is low Most biopsies are performed inhe transplant center by transplant nephrologistsommunity nephrologists also may perform bi-psies of the kidney in KTRs more than a yearosttransplant It is prudent to obtain a diagnosticltrasound before biopsy to rule out unexpectedlterations in blood flow or urinary tract obstruc-ion It is imperative that a pathologist familiar
ith the transplant process interprets the pathol-
gy in consultation with the referring nephrolo-ist using appropriate stains and other studies
MolecularMarkers
In addition to conventional histopathologicxamination several US transplant centers aresing molecular markers as well as genomic orroteomic methods to enhance our understand-ng of the mechanism of immunologic and non-mmunologic pathway of injury As an exampleolymerase chain reaction (PCR) has been usedo detect messenger RNA for IL-2 and otheriomarkers in biopsy samples Using this ap-roach IL-2 upregulated during rejection coulde detected 2 days before rejection was apparentsing histologic or clinical criteria Such PCRpproaches have been used to detect other generoducts upregulated during acute rejection suchs granzyme B perforin transforming growthactor IL-10 and IL-1525-27 These newerethods are performed almost exclusively in
ransplant centers and may become a standardethod of transplant biopsy analysis in the fu-
ure
DIGORecommendations inChapter 10ecurrentDisease
101 We suggest screening KTRs with primary kidneydisease caused by FSGS for proteinuria (2C) atleastbull Daily for 1 week (2D)bull Weekly for 4 weeks (2D)bull Every 3 months for the first year (2D) Every
year thereafter (2D)
102 We suggest screening KTRs with potentially treat-able recurrence of primary kidney disease fromIgA nephropathy MPGN anti-GBM disease orANCA-associated vasculitis for microhematuria(2C) at leastbull Once in the first month to determine a baseline
(2D)bull Every 3 months during the first year (2D)
Annually thereafter (2D)
103 During episodes of graft dysfunction in patientswith primary HUS we suggest screening forthrombotic microangiopathy (eg with plateletcount peripheral smear for blood cell morphologyplasma haptoglobin and serum lactate dehydroge-nase) (2D)
104 When screening suggests possible treatable recur-rent disease we suggest obtaining an allograftbiopsy (2C)
105 Treatment of recurrent kidney disease1051 We suggest plasma exchange if a biopsy
shows minimal change disease or FSGS
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KDOQI Commentary 11
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in those with primary FSGS as theirprimary kidney disease (2D)
1052 We suggest high-dose corticosteroids andcyclophosphamide in patients with recur-rent ANCA-associated vasculitis or anti-GBM disease (2D)
1053 We suggest using an ACE-I [ACE inhibi-tor] or an ARB for patients with recurrentglomerulonephritis and proteinuria (2C)
1054 For KTRs with primary hyperoxaluriawe suggest appropriate measures to pre-vent oxalate deposition until plasma andurine oxalate levels are normal (2C)includingbull Pyridoxine (2C)bull High calcium and low oxalate diet
(2C)bull Increased oral fluid intake to enhance
urinary dilution of oxalate (2C)bull Potassium or sodium citrate to alkalin-
ize the urine (2C)bull Orthophosphate (2C)bull Magnesium oxide (2C)bull Intensive hemodialysis to remove ox-
alate (2C)
DOQIRationale andCommentary
Recurrent disease accounts for a substantialmount of graft loss after renal transplant It isifficult to assess the percentage of grafts lost toecurrent disease because many patients presentith end-stage renal disease without benefit of aiagnostic native renal biopsy The likelihood ofecurrent disease after transplant is dependent onhe disease with certain diseases at particularlyigh risk of recurrence28
Recurrent Focal SegmentalGlomerulosclerosis
We agree with recommendation 101 regard-ng frequent and regular screening for protein-ria in patients with primary focal segmentallomerulosclerosis (FSGS) as the cause of end-tage renal disease If the patient is still produc-ng urine at the time of transplant a preoperativerine protein-creatinine ratio can be a very help-ul baseline measure of proteinuria Early detec-ion of FSGS recurrence which can present withormal light microscopy but foot-process efface-ent on electron microscopy29 provides the best
pportunity for intervention and amelioration ofisease
IgANephropathy
Recurrence rates of immunoglobulin A (IgA)
ephropathy are variable We agree with recom- b
endation 102 for screening routinely for micro-ematuria Recurrent disease is confirmed with aenal allograft biopsy Histologic recurrence ofisease is much more common than is clinicalisease recurrence There is no proven therapyor treatment of recurrent disease30
MembranoproliferativeGlomerulonephritis
Recurrence of membranoproliferative glomer-lonephritis (MPGN) is common as high as 80ith MPGN type II (dense-deposit disease) Theost common cause of MPGN type I is hepatitisndashassociated immune complex formation Wegree with the proposed regularly scheduledcreening for microhematuria and proteinuria inecommendation 102 Patients with known hepa-itis Cndashassociated MPGN pretransplant also maye screened for cryoglobulins which are associ-ted with MPGN31
HemolyticUremic Syndrome
Hemolytic uremic syndrome (HUS) typicallys divided into diarrheal associated (D) andonndashdiarrheal associated (D) D disease oc-urs mostly in children and rarely recurs post-ransplant However D HUS is more commonn adults and can recur In HUS associated with aomplement abnormality such as factor H defi-iency or factor I mutation recurrence rates cane as high as 80 Screening for evidence ofecurrence allows for an earlier diagnosis whichill require biopsy in most cases and provides
n opportunity for earlier intervention There iso comment in the guideline regarding recur-ence of thrombotic thrombocytopenic purpuraut early detection of recurrence provides anpportunity for treatment with plasmapheresisnd intravenous immune globulin (IVIG)
BiopsyandTreatment
As stated kidney biopsy and interpretation bypathologist with expertise in transplant speci-en readings is critical in the diagnosis of dis-
ase recurrence Treatment for most recurrentisease in renal transplantation is based on aombination of case reports case cohorts andetrospective reviews Recurrent diseases post-ransplant are not common enough that random-zed controlled trials can be implemented there-ore most recommendations for treatment are
ased on a consensus of opinion Despite this we
at
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gree in general with the recommendations de-ailed in 105
DIGORecommendations inChapter 11reventingDetecting andTreatingonadherence
111 Consider providing all KTRs and family memberswith education prevention and treatment mea-sures to minimize nonadherence to immunosup-pressive medications (Not Graded)
112 Consider providing KTRs at increased risk fornonadherence with increased levels of screeningfor nonadherence (Not Graded)
DOQIRationale andCommentary
Noncompliance or nonadherence to diet andedication is a common problem in KTRs Nonad-
erence to medication is associated with a high riskf acute rejection and allograft loss We agree thatarly efforts should be made to identify KTRs atncreased risk of nonadherence and that these pa-ients should be monitored closely Prevention iden-ification and treatment of nonadherence are inte-ral to the monitoring of kidney allograft functionnd long-term care of KTRs Certain subgroup ofTRs younger patients African Americans and
hose with financial hardships have an enhancedisk of nonadherence3233
In addition to identifying patients at risk it ismportant to have a system for addressing patientonadherence This requires coordinated efforts ofocial workers transplant coordinators financialounselors pharmacists primary nephrologists andhe patientrsquos family34 A combination of educa-ional behavioral and social support interventionsrovides the best results Because there is no per-ect measure of adherence consideration should beiven to multiple approaches for adherence moni-oring Similar team approaches also are importantn other areas requiring adherence such as dietxercise tobacco alcohol and drug use
DIGORecommendations inChapter 12accination
121 We recommend giving all KTRs approvedinactivated vaccines according to recommendedschedules for the general population except forHBV vaccination (1D)1211 We suggest HBV vaccination (ideally
prior to transplantation) and HBsAb titers6-12 weeks after completing the vaccina-
tion series (2D) h
12111 We suggest annual HBsAb[antibody to hepatitis B sur-face antigen] titers (2D)
12112 We suggest revaccination ifthe antibody titer falls below10 mIUmL (2D)
122 We suggest avoiding live vaccines in KTRs (2C)123 We suggest avoiding vaccinations except influ-
enza vaccination in the first 6 months followingkidney transplantation (2C)1231 We suggest resuming immunizations once
patients are receiving minimal mainte-nance doses of immunosuppressive medi-cations (2C)
1232 We recommend giving all KTRs whoare at least 1-month post-transplantinfluenza vaccination prior to the onsetof the annual influenza season regard-less of status of immunosuppression(1C)
124 We suggest giving the following vaccines to KTRswho due to age direct exposure residence ortravel to endemic areas or other epidemiologicalrisk factors are at increased risk for the specificdiseasesbull rabies (2D)bull tick-borne meningoencephalitis (2D)bull Japanese B encephalitismdashinactivated (2D)bull Meningococcus (2D)bull Pneumococcus (2D)bull Salmonella typhimdashinactivated (2D)1241 Consult an infectious disease specialist a
travel clinic or public health official forguidance on whether specific cases war-rant these vaccinations (Not Graded)
DOQIRationale andCommentary
KTRs are at particular risk of viral infectionsecause of the preferential suppression of T lympho-ytes by both induction and maintenance immuno-uppression The risk and consequence of develop-ng a viral infection warrant use of selected vaccineshe suggestions regarding which vaccines are safend which are contraindicated are based on whetherhe vaccine contains live or killed virus Live virusaccines are contraindicated in immunosuppressedTRs The KDIGO recommendations for vaccina-
ions agree with updated guidelines recently pub-ished by the AST35 Specific comments on theDIGO suggestions regarding vaccinations are
isted in the following sections
Hepatitis B
The work group did not concur with KDIGOuggestion 1211 Neither revaccination against
epatitis after transplant nor following up hepa-
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KDOQI Commentary 13
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itis B antibody titers annually is a commonractice in the United States Hepatitis B is nots prevalent in the United States as in otherarts of the world and evidence supportingcreening in all patients posttransplant is lack-ng However screening for seroconversion inatients at risk (receiving a hepatitis B corentibodyndashpositive kidney) is appropriate Theseatients may benefit from lamivudine or ente-avir therapy36
LiveVaccineandTimingofVaccine
There is no particular reason for a 6-monthag between transplant and vaccination Theheory is that vaccines are less likely to beffective in the period when immunosuppres-ion is high In the United States most individu-ls are on their baseline maintenance immuno-uppression therapy by 3 months posttransplantecisions regarding the timing of vaccines areade based on immunosuppression exposure
nd risk of infection Recipients also shouldvoid intimate contact with individuals whoave received live vaccines37 This includesvoiding close contact with children who haveeceived oral polio vaccine for 3 weeks anday include close contact with adults receiv-
ng the attenuated varicella vaccine to preventoster Immunosuppressed individuals are ad-ised to avoid contact for 7 days with individu-ls who have received live virus nasal spraysor influenza We concur with the recommenda-ion for flu vaccine but common practice inhe United States is to wait 3-6 months afterransplant before it is administered
DIGORecommendations inChapter 13 Viraliseases
131 BK POLYOMA VIRUS1311 We suggest screening all KTRs for BKV
with quantitative plasma NAT (2C) atleastbull monthly for the first 3-6 months after
transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull whenever there is an unexplained rise
in serum creatinine (2D)bull and after treatment for acute rejection
(2D)1312 We suggest reducing immunosuppressive
medications when BKV plasma NAT is
persistently greater than 10 000 cop-iesmL (107 copiesL) (2D)
132 CYTOMEGALOVIRUS1321 CMV prophylaxis We recommend that
KTRs (except when donor and recipi-ent both have negative CMV serolo-gies) receive chemoprophylaxis forCMV infection with oral ganciclovir orvalganciclovir for at least 3 monthsafter transplantation (1B) and for 6weeks after treatment with a T-cellndashdepleting antibody (1C)
1322 In patients with CMV disease we suggestweekly monitoring of CMV by NAT orpp65 antigenemia (2D)
1323 CMV treatment13231 We recommend that all pa-
tients with serious (includ-ing most patients with tissueinvasive) CMV disease betreated with intravenousganciclovir (1D)
13232 We recommend that CMVdisease in adult KTRs that isnot serious (eg episodes thatare associated with mildclinical symptoms) be treatedwith either intravenous gan-ciclovir or oral valganciclo-vir (1D)
13233 We recommend that allCMV disease in pediatricKTRs be treated with intra-venous ganciclovir (1D)
13234 We suggest continuing therapyuntil CMV is no longer detect-able by plasma NAT or pp65antigenemia (2D)
1324 We suggest reducing immunosuppressivemedication in life-threatening CMV dis-ease and CMV disease that persists in theface of treatment until CMV disease hasresolved (2D)13241 We suggest monitoring graft
function closely during CMVdisease (2D)
133 EPSTEIN-BARR VIRUS AND POST-TRANS-PLANT LYMPHOPROLIFERATIVE DISEASE1331 We suggest monitoring high-risk (donor
EBV seropositiverecipient seronegative)KTRs for EBV by NAT (2C)bull once in the first week after transplanta-
tion (2D)bull then at least monthly for the first 3-6
months after transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull and additionally after treatment for
acute rejection (2D)
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1332 We suggest that EBV-seronegative pa-tients with an increasing EBV load haveimmunosuppressive medication reduced(2D)
1333 We recommend that patients with EBVdisease including PTLD have a reduc-tion or cessation of immunosuppres-sive medication (1C)
134 HERPES SIMPLEX VIRUS 1 2 AND VARI-CELLA ZOSTER VIRUS1341 We recommend that KTRs who de-
velop a superficial HSV 1 2 infectionbe treated (1B) with an appropriateoral antiviral agent (eg acyclovir vala-cyclovir or famciclovir) until all le-sions have resolved (1D)
1342 We recommend that KTRs with sys-temic HSV 1 2 infection be treated(1B) with intravenous acyclovir and areduction in immunosuppressive medi-cation (1D)13421 We recommend that intrave-
nous acyclovir continue un-til the patient has a clinicalresponse (1B) then switch toan appropriate oral antiviralagent (eg acyclovir valacy-clovir or famciclovir) to com-plete a total treatment durationof 14-21 days (2D)
1343 We suggest using a prophylactic antiviralagent for KTRs experiencing frequentrecurrences of HSV 12 infection (2D)
1344 We recommend that primary VZV infec-tion (chicken pox) in KTRs be treated(1C) with either intravenous or oral acy-clovir or valacyclovir and a temporaryreduction in amount of immunosuppres-sive medication (2D)
135 HEPATITIS C VIRUS1351 We suggest that HCV-infected KTRs be
treated only when the benefits of treat-ment clearly outweigh the risk of allo-graft rejection due to interferon-basedtherapy (eg fibrosing cholestatic hepati-tis life-threatening vasculitis) (2D)[Based on KDIGO Hepatitis C Recom-mendation 215]
1352 We suggest monotherapy with standardinterferon for HCV-infected KTRs inwhom the benefits of antiviral treatmentclearly outweigh the risks (2D) [Basedon KDIGO Hepatitis C Recommenda-tions 224 and 442]
1353 We suggest that all conventional currentinduction and maintenance immunosup-pressive regimens can be used in HCVinfected patients (2D) [Based on KDIGO
Hepatitis C Recommendation 43]
1354 Measure ALT in HCV-infected patientsmonthly for the first 6 months and every3-6 months thereafter Perform imagingannually to look for cirrhosis and hepato-cellular carcinoma (Not Graded) [Basedon KDIGO Hepatitis C Recommendation441] (See Recommendation 193)
1355 Test HCV-infected patients at least every3-6 months for proteinuria (Not Graded)[Based on KDIGO Hepatitis C Recom-mendation 444]13551 For patients who develop new
onset proteinuria (either urineproteincreatinine ratio 1 or24-hour urine protein 1 g ontwo or more occasions) per-form an allograft biopsy withimmunofluorescence and elec-tron microscopy (Not Graded)[Based on KDIGO Hepatitis CRecommendation 444]
1356 We suggest that patients with HCV asso-ciated glomerulopathy not receive inter-feron (2D) [Based on KDIGO HepatitisC Recommendation 445]
136 HEPATITIS B VIRUS1361 We suggest that any currently available
induction and maintenance immunosup-pressive medication can be used in HBV-infected KTRs (2D)
1362 We suggest that interferon treatmentshould generally be avoided in HBVinfected KTRs (2C)
1363 We suggest that all HBsAg-positive KTRsreceive prophylaxis with tenofovir ente-cavir or lamivudine (2B)13631 Tenofovir or entecavir are pref-
erable to lamivudine to mini-mize development of potentialdrug resistance unless medica-tion cost requires that lami-vudinebe used (Not Graded)
13632 During therapy with antivi-rals measure HBV DNA andALT levels every 3 months tomonitor efficacy and to detectdrug resistance (Not Graded)
1364 We suggest treatment with adefovir ortenofovir for KTRs with lamivudine resis-tance (5 log10 copiesmL rebound ofHBV-DNA) (2D)
1365 Screen HBsAg-positive patients with cir-rhosis for hepatocellular carcinoma every12 months with liver ultrasound andalpha feto-protein (Not Graded) (SeeRecommendation 193)
1366 We suggest that patients who are negativefor HBsAg and have HBsAb titer 10mIUmL receive booster vaccination to
raise the titer to 100 mIUmL (2D)
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KDOQI Commentary 15
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137 HUMAN IMMUNODEFICIENCY VIRUS1371 If not already done screen for HIV
infection (Not Graded)1372 To determine antiretroviral therapy refer
HIV-infected KTRs to an HIV specialistwho should pay special attention to drugndashdrug interactions and appropriate dosingof medications (Not Graded)
DOQIRationale andCommentary
Viral infections are particularly problematic inransplant recipients because of the preferentialnhibition of T-lymphocyte function by both induc-ion and maintenance immunosuppression Use ofnduction immunosuppression with lymphocyte-epleting agents (thymoglobulin or alemtuzumab)s associated with a greater risk of viral infectionosttransplant In general the greater the cumula-ive exposure to immunosuppression the greaterhe risk of infectious complications The presenta-ion of viral infections can be asymptomatic vaguend nonspecific or life-threatening acute illnessany viral infections seen in KTRs are rarely seen
n immunocompetent patients and therefore do notnter into the differential diagnosis for physiciansnfamiliar with transplant recipients Close commu-ication with the transplant center is crucial inaring for the transplant population Early detectionnd institution of therapy provide the best chanceor viral eradication
BKVirus
Although the work group agreed with KDIGOuggestions for BK virus screening posttransplante did not think it was practical to require screen-
ng exclusively with quantitative plasma nucleiccid testing (NAT) because many US centers usenitial urinary screening and then test plasma onlyf urine screening results are positive Howeverhere is no disagreement that some type of screen-ng for BK virus is critical to avoid BK nephropa-hy for which there is no specific treatment when its established Complicating screening for BK vi-us is the variability in results between laboratoriesnd uncertainty about the level of viremia thathould trigger a response to decrease in immunosup-ression In the presence of viremia and increase inerum creatinine level a renal allograft biopsy isndicated to confirm the presence of BK nephropa-
hy Because BK viremia and viruria certainly can b
e detected beyond the first year it is not clear howong screening should be continued posttransplantlthough most centers screen for the first year onlyngoing clinical trials are exploring effective treat-ent for BK nephropathy3839 Decisions about
ecreases in immunosuppression currently theainstay of BK viremia management always
hould be made in consultation with the transplantenter
Cytomegalovirus
KDIGO recommendation 1321 regarding cyto-egalovirus (CMV) prophylaxis is reasonable and
pplicable to the US population Universal prophy-axis for CMV now is recommended over initiatingre-emptive treatment after CMV develops40 Aajor concern for US patients is the cost of CMV
rophylaxis with oral valgancyclovir Leukopeniaan be observed in patients using mycophenolatereparations when prophylaxis with valgancyclo-ir is used Screening for CMV is best performedsing NAT methods (1322) CMV antigenemiassays are still in use in many facilities but are nots sensitive as PCR assays41 There is no utility inhecking for serologic response to CMV with IgGr IgM titers posttransplant because the immuneesponse is not predictable Patients with CMVisease should be cared for by clinicians familiarith treating this disease It is recommended that
reatment be continued until viral load is undetect-ble followed by prophylactic doses of valgancy-lovir for an additional 3 months35
Epstein-BarrVirus
Current practice regarding EBV screening variesmong centers in the United States and many doot routinely screen for EBV posttransplant evenn recipient-negative donor-positive cases In con-rast to KDIGO recommendation 1311 routineBV screening is not recommended in AST infec-
ious disease guidelines35 In many centers EBVcreening is reserved for children who are muchore commonly EBV negative pretransplant than
dults EBV-induced posttransplant lymphoprolif-rative disorder (PTLD) affects many more pediat-ic than adult KTRs If screening is someday to beoutinely implemented in US centers details regard-ng the best method of screening and levels ofiremia above which a clinical intervention should
e triggered need to be better defined
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HerpesandVaricella
Systemic herpesvirus infections can be lifehreatening in transplant recipients and should bereated aggressively with intravenous antiviralgents as described in the KDIGO recommenda-ions Less aggressive cutaneous infection can bereated with oral antiviral agents as outlined inhe KDIGO guidelines
Varicella exposure is particularly concerning inransplant recipients The work group disputes theecommended dosing of acyclovir for varicellaxposure Acyclovir at a dose of 10 mgkg or about00 mg 4 times daily of oral acyclovir would betandard dosing We agree with the use of varicellammune globulin and emphasize the need to avoidhe varicella vaccine because it is a live virushould a transplant recipient develop a systemicaricella infection hospitalization and high-dosentravenous acyclovir therapy are warranted
Hepatitis C
Hepatitis C management posttransplant is ahallenge The KDIGO guidelines cited hereere based on the recently published KDIGOuideline for hepatitis C in CKD4 Hepatitis Cypically is not treated posttransplant because ofhe risk (50) of rejection precipitated bynterferon therapy particularly in US KTRs inhom hepatitis C commonly is genotype 1 which
s more resistant to treatment with interferon42
owever should hepatitis Cndashrelated glomerulo-ephritis develop the risk-benefit ratio may fa-or treatment in selected patients Such decisionslways should be made in consultation withepatology and infectious disease experts andhe transplant center Monitoring liver enzymeevels specifically alanine aminotransferaseALT) may reflect a change in hepatitis activityut monitoring hepatitis C viral load is not recom-ended because it does not seem to correlateith outcome Annual monitoring for hepatocel-
ular carcinoma using -fetoprotein and imagings encouraged but not often practiced
Hepatitis B
KDIGO recommendations for hepatitis B areeasonable and currently are followed in mostS centers except for recommendation 1366
see previous recommendation under vaccina-ions) KTRs with hepatitis C or hepatitis B also
hould be followed up by a hepatologist
Human ImmunodeficiencyVirus
Human immunodeficiency virus (HIV)-posi-ive individuals are now acceptable for transplantf CD4 count is 200 cellsL and viral loadVL) is undetectable3543 Transplant should beerformed at centers with expertise in managingIV-positive individuals and care should be co-rdinated carefully with HIV specialists Somentiretroviral agents in particular the proteasenhibitors have potentially serious drug interac-ions with immunosuppressive agents35
DIGORecommendations inChapter 14Othernfections
141 URINARY TRACT INFECTION1411 We suggest that all KTRs receive UTI
prophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 monthsafter transplantation (2B)
1412 For allograft pyelonephritis we suggestinitial hospitalization and treatment withintravenous antibiotics (2C)
142 PNEUMOCYSTIS JIROVECII PNEUMONIA1421 We recommend that all KTRs receive
PCP prophylaxis with daily tri-methoprimndashsulfamethoxazole for 3-6months after transplantation (1B)
1422 We suggest that all KTRs receive PCPprophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 weeksduring and after treatment for acute rejec-tion (2C)
1423 We recommend that KTRs with PCPdiagnosed by bronchial alveolar lavageandor lung biopsy be treated withhigh-dose intravenous trimethoprimndashsulfamethoxazole corticosteroids anda reduction in immunosuppressivemedication (1C)
1424 We recommend treatment with cortico-steroids for KTRs with moderate tosevere PCP (as defined by PaO2 lt70mm Hg in room air or an alveolargradient of gt35 mm Hg) (1C)
143 TUBERCULOSIS1431 We suggest that TB prophylaxis and
treatment regimens be the same in KTRsas would be used in the local generalpopulation who require therapy (2D)
1432 We recommend monitoring CNI andmTORi [mTOR inhibitor] blood levels inpatients receiving rifampin (1C)14321 Consider substituting rifabu-
tin for rifampin to minimize
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KDOQI Commentary 17
ARTICLE IN PRESS
interactions with CNIs andmTORi (Not Graded)
144 CANDIDA PROPHYLAXIS1441 We suggest oral and esophageal Candida
prophylaxis with oral clotrimazole loz-enges nystatin or fluconazole for 1-3months after transplantation and for 1month after treatment with an antilympho-cyte antibody (2C)
DOQIRationale andCommentary
UrinaryTract Infection
Urinary tract infections (UTIs) after kidneyransplant are very common and account for aarge percentage of readmissions posttransplantTIs are common because of multiple factors
ncluding the disrupted anatomy of the urinaryract with a ureteroneocystotomy incompleteladder emptying because of diabetes or pros-atic hypertrophy and impaired immune re-ponses Prophylaxis of UTIs usually is under-aken with trimethoprim-sulfamethoxazole for 6onths posttransplant although infections often
ccur despite therapy because of the develop-ent of drug resistance Although native kidney
yelonephritis does not always require hospital-zation it is recommended that all KTRs withhis diagnosis be hospitalized because the graftysfunction that usually accompanies transplantyelonephritis requires aggressive investigationnd treatment Individuals with recurrent UTIsarrant evaluation with urologic assessment Pa-
ients with recurrent UTIs may benefit fromong-term suppressive therapy
Pneumocystic Pneumonia
We agree that Pneumocystis jirovecii pneumoniaPCP) prophylaxis is important for the first 3-6onths posttransplant (1421)After the first month
very-other-day dosing of trimethoprim-sulfame-hoxazole or atovaquone is believed to be adequaterophylaxis In cases in which neither of thesegents can be used an individual may be treatedrophylactically with inhaled pentamidine OurDOQI work group emphasized that patients whoevelop PCP should be transferred to the transplantenter promptly for management and adjustmentsn immunosuppression
Tuberculosis
Monitoring for latent tuberculosis has posed a
hallenge in the immunosuppressed population be-
ause of the unreliable nature of skin testing Newerechniques involving interferon release assays aremerging as the new gold standard for detection ofatent tuberculosis4445
CandidaProphylaxis
Oral candidiasis must be screened for usingral mucosa examination on follow-up visitsn KTRs This is especially true in the earlyosttransplant period when immunosuppres-ive medication dosage is the highest Wegree with these recommendations and empha-ize that if fluconazole is used there is aotential for serious drug interactions becausef cytochrome P-450 3A4 inhibition
SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
Improvement in short-term outcomes has not trans-lated into significant improvements in long-term out-comes in KTRs The lack of significant improvement inlong-term survival may be related to post-transplantcomplications Frequent posttransplant monitoring mayimprove long-term outcomes by decreasing chronic graftfailure or death with a functioning graft Our work groupconcurred with the recommendation and schedules ofroutine screening in monitoring kidney allograft functionafter kidney transplant with a low threshold for perform-ing kidney biopsy in cases of graft dysfunction or protein-uria Expert tissue processing and interpretation of trans-plant biopsy specimens by pathologists with transplantexperience are critical Regular surveillance of the pa-tientrsquos kidney function at the transplant center or in thenephrologistrsquos office offers an opportunity to enhancepatient adherence to medication diet and healthy life-style Although CKD in KTRs progresses more slowlythan CKD in other patients the work group agreed thatthe KDIGO guidelines on CKD should be followed inKTRs
Opportunistic infections are common in KTRs al-though advances in diagnosis and treatment have led toimproved survival in KTRs with infection It is nowstandard of care to use vaccinations in KTRs as long asthe vaccine does not contain live or attenuated virus Italso is routine to screen for or use prophylaxis to preventseveral posttransplant viral infections With few excep-tions (related to EBV and BK virus screening andhepatitis B vaccination posttransplant) we concurredwith KDIGO guidelines for vaccination screening and
treatment of infection posttransplant
KD
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ARTICLE IN PRESS
COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULAR
DISEASE
DIGORecommendations inChapter 15iabetesMellitus
151 Screening for New-Onset Diabetes after Transplan-tation1511 We recommend screening all nondia-
betic KTRs with fasting plasma glu-cose oral glucose tolerance testingandor HbA1c (1C) at leastbull weekly for 4 weeks (2D)bull every 3 months for 1 year (2D)bull and annually thereafter (2D)
1512 We suggest screening for NODAT withfasting glucose oral glucose tolerancetesting andor after starting or substan-tially increasing the dose of CNIsmTORi or corticosteroids (2D)
152 Managing NODAT or Diabetes Present at Trans-plantation1521 If NODAT develops consider modifying
the immunosuppressive drug regimen toreverse or ameliorate diabetes afterweighing the risk of rejection and otherpotential adverse effects (Not Graded)
1522 Consider targeting HbA1c 70-75and avoid targeting HbA1c 60 espe-cially if hypoglycemic reactions are com-mon (Not Graded)
1523 We suggest that in patients with diabetesaspirin (65-100 mgd) use for the primaryprevention of CVD be based on patientpreferences and values balancing the riskfor ischemic events to that of bleeding(2D)
DOQIRationale andCommentary
Diabetic Screening
We agree with screening for new-onset diabetesfter transplantation (NODAT) as outlined by theDIGO work group Definitions used are similar
o those of the American Diabetes AssociationADA) The greater frequency of testing initially isustified by the high risk of NODAT in the earlyosttransplant period however ongoing screenings required because the risk of the development ofODAT continues to increase over time4647 We
lso point out that prediabetic states (impairedasting glucose level and impaired glucose toler-nce) occur even more commonly than overt diabe-es48 and may be associated with metabolic syn-rome as well as with increased cardiovascular
ortality49-51 Potential implications of these predia-
etic states emphasize the importance of perform-ng blood tests under fasting conditions For pa-ients with fasting hyperglycemia an oral glucoseolerance test or hemoglobinA1c (HbA1c) test shoulde performed Although more cumbersome to per-orm data suggest that an oral glucose toleranceest is a more sensitive indicator of NODAT inyperglycemic KTRs52 This may allow earlieretection of overt diabetes and more prompt institu-ion of treatment
DiabetesManagement
Data supporting a substantial benefit in themelioration or reversal of NODAT using immu-osuppression modification in KTRs are veryimited There was consensus in our work grouphat considering the paucity of data for reversingODAT by changing immunosuppression and
he potential risk of an adverse outcome withuch a maneuver KDIGO suggestion 1521 couldot be supported Certainly if such a step waseing considered it should be done in conjunc-ion with the transplant center Targeting an HbA1c
evel of 7-75 and avoiding levels 6 isased on data showing increased cardiovascularvents with the lower HbA1c target5354
DIGORecommendations inChapter 16ypertensionDyslipidemias TobaccoUse andbesity
161 Hypertension1611 We recommend measuring blood pres-
sure at each clinic visit (1C)1612 We suggest maintaining blood pressure at
130 mm Hg systolic and 80 mm Hgdiastolic if 18 years of age and 90th
percentile for sex age and height if 18years old (2C)
1613 To treat hypertension (Not Graded)bull Use any class of antihypertensive
agentbull Monitor closely for adverse effects
and drug-drug interactions and whenurine protein excretion 1 gd for18 years old and 600 mgm224 hfor 18 years old consider an ACE-Ior an ARB as first-line therapy
162 Dyslipidemias (These recommendations are basedon KDOQI Dyslipidemia Guidelines and are thusnot graded)1621 Measure a complete lipid profile in all
adult (18 years old) and adolescent
(puberty to 18 years old) KTRs [Based on
K
2saaottgswdCctarahtAGccKie
KDOQI Commentary 19
ARTICLE IN PRESS
KDOQI Dyslipidemia Recommendation1]bull 2-3 months after transplantationbull 2-3 months after a change in treatment
or other conditions known to causedyslipidemias
bull at least annually thereafter1622 Evaluate KTRs with dyslipidemias for
secondary causes [Based on KDOQI Dys-lipidemia Recommendation 3]16221 For KTRs with fasting triglyc-
erides 500 mgdL (565mmolL) that cannot be cor-rected by removing an under-lying cause treat withbull Adults therapeutic lifestyle
changes and a triglyceride-lowering agent [Based onKDOQI Recommendation41]
bull Adolescents therapeutic life-style changes [Based onKDOQI Recommendation51]
16222 For KTRs with elevatedLDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)treat to reduce LDL-C to100 mgdL (259mmolL) [Based on KDOQIGuideline 42]
bull Adolescents If LDL-C130 mgdL (336 mmolL) treat to reduce LDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 52]
16223 For KTRs with normalLDL-C elevated triglyceridesand elevated non-HDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)fasting triglycerides 200mgdL (226 mmolL)and non-HDL-C 130mgdL (336 mmolL)treat to reduce non-HDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 43]
bull Adolescents If LDL-C130 mgdL (336 mmolL) fasting triglycerides200 mgdL (226 mmolL) and non-HDL-C 160mgdL (414 mmolL)treat to reduce non-HDL-C
to 160 mgdL (414 i
mmolL) [Based on KDOQIGuideline 53]
163 Tobacco Use1631 Screen and counsel all KTRs including
adolescents and children for tobacco useand record the results in the medicalrecord (Not Graded)bull Screen during initial transplant hospi-
talizationbull Screen at least annually thereafter
1632 Offer treatment to all patients who usetobacco (Not Graded)
164 Obesity1641 Assess obesity at each visit (Not Graded)
bull Measure height and weight at eachvisit in adults and children
bull Calculate BMI at each visitbull Measure waist circumference when
weight and physical appearance sug-gest obesity but BMI is 35 kgm2
1642 Offer a weight-reduction program to allobese KTRs (Not Graded)
DOQIRationale andCommentary
Hypertension
The KDIGO work group adapted the KDOQI004 recommendations for target blood pres-ure in KTRs55 Self measurement is useful inssessing response to therapy and enhancesdherence56 In general we agree that the classf antihypertensive agent does not matter inhe treatment of blood pressure elevation inhis population and that attention should beiven to potential side effects of antihyperten-ive agents as well as possible interactionsith the immunosuppressive regimen (eg non-ihydropyridine calcium channel blockers andNIs) In the absence of adequate randomizedontrolled trials it is not known whether angio-ensin-converting enzyme (ACE) inhibitors andngiotensin receptor blockers (ARBs) prolongecipient or allograft survival Some but notll retrospective studies suggest a benefitowever all these studies are limited by selec-ion bias5758 Although ACE inhibitors andRBs commonly lead to some decrease inFR treatment with these drugs should be
ontinued unless serum creatinine level in-reases by 25 to 30 in keeping withDOQI recommendations55 In KTRs receiv-
ng ACE inhibitors or ARBs it is important toducate patients to maintain adequate fluid
ntake during illness to prevent a prerenal
inwa
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Bia et al20
ARTICLE IN PRESS
nsult to the allograft Similarly awareness isecessary when using diuretics in conjunctionith therapies that block the renin-angiotensin-
ldosterone-system59
Dyslipidemia
The KDIGO work group based their recom-endations for evaluation and treatment of
yperlipidemia on the KDOQI dyslipidemiauidelines for KTRs60 We agree with theseecommendations CNIs potentiate the toxicityf statins by slowing their metabolism throughhe cytochrome P-450 system This interactionccurs more commonly with cyclosporine61
han with tacrolimus Dyslipidemia especiallyypertriglyceridemia frequently complicatesTOR-inhibitor use and lipid-lowering therapy
s required in most patients using these agents
TobaccoUse
Not surprisingly tobacco use at the time ofransplant is associated with decreased patientnd graft survival as well as increased risk ofosttransplant cardiovascular disease (CVD)lthough the KDIGO work group recom-ends initial screening and intervention dur-
ng the hospitalization for transplant we be-ieve there may be benefit gained by startingounseling in the pretransplant period duringhe evaluation phase Unfortunately this doesot occur often because of time and personnelonstraints in transplant centers Ideally allransplant centers should have smoking-cessa-ion programs available to patients either in-ouse or through referral Ideally systemshould be created to continue to screen andonitor for smoking cessation at yearly inter-
als after transplant because there is a highate of relapse with this addiction As outlinedn KDIGO Table 253 although all pharmaco-ogic therapies for smoking cessation can besed in KTRs the starting dose of vareniclinehould be decreased in patients with GFR 30Lmin
Obesity
Obesity is an epidemic in the United Statesnd the proportion of obese kidney transplantandidates continues to grow In additioneight gain after transplant is very commonly
bserved Obesity in KTRs is associated with w
ncreased risks of wound complications de-ayed graft function acute rejection and NO-AT resulting in inferior patient and graftutcomes Attention to this potential complica-ion and counseling should be initiated duringhe pretransplant evaluation phase Informa-ion regarding pharmacologic therapies foreight loss in KTRs is not available and we
gree with the KDIGO work group that thera-eutic lifestyle measures should be encour-ged Data regarding steroid therapy with-rawal and weight gain are controversial Aecent double-blind randomized controlled trialxamining early steroid therapy withdrawalid not show a difference in weight gain at 5ears posttransplant compared with the cohortemaining on standard maintenance corticoste-oid therapy62
DIGORecommendations inChapter 17ardiovascularManagement
171 Consider managing CVD at least as intensively inKTRs as in the general population with appropri-ate diagnostic tests and treatments (Not Graded)
172 We suggest using aspirin (65-100 mgd) in allpatients with atherosclerotic CVD unless there arecontraindications (2B)
DOQIRationale andCommentary
Although outcomes are favorable comparedith remaining on the waiting list the risk of
ardiovascular mortality in KTRs is several-foldigher than observed in the general population63
specially in younger age groups and patientsith decreasing allograft function64 CVD is aajor cause of graft loss after the first post-
ransplant year In this context we strongly agreehat CVD should be managed in KTRs at least asntensively as in the general population Ideallyecreasing CVD risk in KTRs requires a multifac-ted and multidisciplinary approach Based onurrent practice models in the United States theransplant and nephrology community has notet been able to achieve these desirable goals65
his clearly deserves more attention becauseontrol of CVD has the potential to contributeore to long-term kidney graft survival than the
iscovery of newer drugs that decrease the ratef allograft rejection Our KDOQI working groupgreed with the use of low-dose aspirin in KTRs
ith evidence of atherosclerosis
Ko
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KDOQI Commentary 21
ARTICLE IN PRESS
SUMMARY OF COMMENTARY ONSECTION III CVD
COMMENTARY ON SECTION IV OF KDIGO
TRANSPLANT GUIDELINE MALIGNANCY
DIGORecommendations inChapter 18 Cancerf the Skin andLip
181 We recommend that KTRs especially thosewho have fair skin live in high sun-exposureclimates have occupations requiring sun expo-sure have had significant sun exposure as achild or have a history of skin cancer be toldthat their risk of skin and lip cancer is veryhigh (1C)
182 We recommend that KTRs minimize life-longsun exposure and use appropriate ultravioletlight blocking agents (1D)
183 We suggest that adult KTRs perform skin andlip self-examinations and report new lesions toa health-care provider (2D)
184 For adult KTRs we suggest that a qualified healthprofessional with experience in diagnosing skincancer perform annual skin and lip examinationon KTRs except possibly for KTRs with dark skinpigmentation (2D)
185 We suggest that patients with a history of skin orlip cancer or premalignant lesions be referred to andfollowed by a qualified health professional withexperience in diagnosing and treating skin cancer
With the decrease in acute rejection during the pastdecade in association with improved immunosuppres-sion regimens patient death now rivals chronic graftdysfunction as one of the leading causes of long-termgraft loss Because CVD is the most common cause ofpatient death in KTRs a concerted effort at minimizingrisk factors for heart disease likely will have as great oreven greater impact on optimizing patient and graftoutcomes than the discovery of new antirejection thera-pies CVD risk reduction strategies should include regularscreening for new-onset diabetes (using ADA-based defini-tions) in the posttransplant period in previously nondiabeticpatients good glycemic regulation for diabetic patients accord-ing to current ADA guidelines and lipid management andblood pressure control according to KDOQI recommenda-tions In addition promotion of a healthy lifestyle throughweight control exercise and smoking cessation should be acentral part of posttransplant counseling and care Whenimmunosuppression modification is being considered to miti-gate cardiovascular risk we recommend that this be inconjunction with the transplant center In summary we gener-ally concurred with the suggestions of the work group in thissection but based on current practice standards in the UnitedStateschallengesremainwith implementationof thisguideline
(2D) s
186 We suggest that patients with a history of skincancer be offered treatment with oral acitretin ifthere are no contraindications (2B)
DOQIRationale andCommentary
CounselingandSunscreen
We concur with recommendations 181 and82 because skin cancer is a major source oforbidity and sometimes mortality in KTRsarning patients at risk of the high danger of
kin cancer a 1C recommendation is reinforcedy a recent prospective case-control study ofrgan transplant recipients that showed that regu-ar use of broad-spectrum sunscreens that pro-ide UVA and UVB protection may prevent theevelopment of actinic keratosis invasive squa-ous cell carcinoma and to a lesser extent
asal cell carcinoma66 Most cancer-causing ra-iation is thought to come from the UVB spec-rum and newer broad-spectrum sunscreens pro-ide protection against UVA and UVB radiationounseling about sunscreen and the need for sunvoidance needs to be incorporated into routineffice visits although it may not always beuccessful In a recent study of KTRs in which1 of patients had been informed about theeed for sun protection only 46 used morehan a tube of sunscreen per year67
Dermatology Involvement
There is increased evidence to suggest thatpecialty dermatology clinics for organ trans-lant recipients improve outcome measures in-luding compliance with photoprotection andncreased awareness of skin cancer68 The re-ources required for these specialty clinics makemplementation difficult for community nephrol-gy groups that do not have direct access to aransplant center Transplant patients should bencouraged to have annual visits with their trans-lant center and if dermatology specialty clinicsre available attempt to coordinate a skin cancervaluation annually
UseofRetinoid-likeCompounds
There is a limited scientific basis for KDIGOuggestion recommendation 186 Although reti-oids now are used routinely in KTRs with aigh skin cancer burden our KDOQI work groupelieves that more data are needed before this
uggestion should be accepted as a guideline In
ldfivs
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ARTICLE IN PRESS
ow-immunologic-risk groups and particularlyifficult cases some data suggest that switchingrom CNI to sirolimus therapy may decrease thencidence of skin cancer69 however the riskersus benefit of this maneuver has not been welltudied
DIGORecommendations inChapter 19on-SkinMalignancies
191 Develop an individualized screening plan for eachKTR that takes into account the patientrsquos pastmedical and family history tobacco use compet-ing risks for death and the performance of thescreening methodology (Not Graded)
192 Screen for the following cancers as per localguidelines for the general population (Not Graded)Women cervical breast and colon cancer Menprostate and colon cancer
193 Obtain hepatic ultrasound and alpha feto-proteinevery 12 months in patients with compensatedcirrhosis (Not Graded) [See Recommendations1354 (HCV) and 1365 (HBV)]
DOQIRationale andCommentary
Screening
It is recognized that KTRs have a higher inci-ence of malignancy particularly those associatedith specific viral infections Although cancer
creening may have benefits in this higher riskopulation it should be reinforced that some meth-ds of screening have significant risks which shoulde considered on an individualized basis particu-arly in patients who have projected survival lesshan 5 years
Screening forCancer inPatientsWithHepatitis
Many patients who have underlying cirrhosisn the United States will be followed up by arofessional specializing in liver disease whoay provide additional insight into this cancer
creening recommendation Based on a recentuestionnaire of US gastroenterologists only 50creen patients for hepatocellular carcinoma70
herefore implementation of this guideline byS clinicians is unlikely to be widespread
DIGORecommendations inChapter 20anagingCancerwithReductionof
mmunosuppressiveMedication
201 We suggest consideration be given to reducingimmunosuppressive medications for KTRs with can-
cer (2C)
2011 Important factors for consideration in-clude (Not Graded)bull The stage of cancer at diagnosisbull Whether the cancer is likely to be
exacerbated by immunosuppressionbull The therapies available for the can-
cerbull Whether immunosuppressive medica-
tions interfere with ability to admin-ister the standard chemotherapy
202 For patients with Kaposi sarcoma we suggestusing mTORi along with a reduction in overallimmunosuppression (2C)
DOQIRationale andCommentary
Table 1 (Table 29 in the KDIGO report3 andxcerpted from Grulich et al71) lists cancershat are increased most in immunosuppressedTRs based on standardized incidence ratios
SIRs) which compare the incidence toatched populations Cancers with the highestIRs may be those most likely to respond to aecrease in immunosuppression Except foraposi sarcoma limited evidence is available
or a decrease in immunosuppression in theseettings A strategy to change immunosuppres-ion therapy must occur in consultation withhe transplant center Switching to sirolimusherapy and decreasing immunosuppression inatients who develop Kaposi sarcoma is basedn sound scientific rationale7273
SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
The incidence of cancer posttransplant is 2-20times higher than that in the general population andKDIGO guidelines have been written to outline stepsfor prevention and screening With few exceptions weagree with the recommendations as outlined Skincancer is common in US transplant patients andscreening and prevention are critical However imple-mentation of guidelines for doing so including theKDIGO guidelines is a challenge because of patientpreferences against the routine use of sunscreen aswell as time constraints during office visits Althoughmany posttransplant cancers are viral mediated andrelated to immunosuppression it is less clear how toalter immunosuppression after malignancy has oc-curred We agree that although age-specific screeningfor malignancy should be incorporated into care con-sideration must be given to the risk of screening inpatients with limited life spans (5 years) because of
comorbid conditions
KT
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
ommonPopu
i sarco-Hodgmelanise sm
sophaemia
estima standa10 c
ut esti
0 case
alized t
to guide treatment specifically before the
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
K
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CUcneucetcitdt
ttlhA(o
KH
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Ka
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
REFERENCES1 McCullough KP Keith DS Meyer KH et al Kidney
nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
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ml
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c2
p2
sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
ation Transpl Rev 200923191-19815 Abbud-Filho M Adams PL Alberuacute J et al A report
f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
cA
nrc
t2
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trN
hUt
Iwa
rl5
mi8
oe1
DA
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hm2
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Bia et al30
ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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ARTICLE IN PRESS
hrough promoting coordination collaborationnd integration of initiatives to develop andmplement clinical practice guidelinesrdquo2 To thisnd a KDIGO work group has recently pub-ished a new comprehensive set of recommenda-ions for the care of kidney transplant recipientsKTRs)3 The last clinical practice transplantuideline for US patients was published in 2000y theAmerican Society of Transplantation (AST)nd was based primarily on expert opinion Pre-ious KDIGO practice guidelines have been pub-ished for the care of patients with hepatitis Cnd chronic kidney disease (CKD)4 and CKDndashineral and bone disorders (CKD-MBD)5 Be-
ause global guidelines need to be adapted to theegional context in which they are used theational Kidney Foundationrsquos Kidney Diseaseutcomes Quality Initiative (KDOQI) programrganized a work group of transplant nephrolo-ists and surgeons to review the newest KDIGOuideline and comment on the relevance andpplicability for US KTRs
KDIGO GUIDELINE PROCESS
The KDIGO transplant guideline concentratedainly on aspects of transplant care most impor-
ant to this population in the posttransplant pe-iod such as immunosuppression infection ma-ignancy and cardiovascular care The guidelineso not address pretransplant evaluation or issueselated to patients returning to dialysis therapyith a failed allograft The target audience for
he guideline is physicians coordinators pharma-ists and other medical professionals who di-ectly or indirectly care for KTRs The KDIGOuideline was based on published evidence andraded according to the strength of the data (Fig) Because of the paucity of evidence in many
Figure 1 Rating guideline recommendations Within eas Level 1 Level 2 or Not Graded and the quality of theategory Not Graded typically was used to provide guidadequate application of evidence The most common exaounseling and referral to other clinical specialists Ungrad
tatements but are not meant to be interpreted as being strongeDIGO transplant guideline3 with permission of KDIGO
reas only 25 of recommendations were graded Furthermore evidence for only 2 of recom-endations were graded A 136 were graded 389 were graded C and 455 were graded3 The KDIGO authors make it clear that foruidelines in which the evidence was meagerhey chose to give guidance rather than remainilent They also make it clear that the guidelineas not developed for regulatory agencies this
s important to keep in mind because so few ofhe recommendations are based on evidence thats strong enough to justify their being used as theasis of policy or performance measures
KDOQI PROCESS FOR INTERPRETATION OFTHE KDIGO GUIDELINE IN THE CARE OF US
TRANSPLANT PATIENTS
Differences in target population individualatient immunologic risk prevalence of concomi-ant diseases (such as diabetes mellitus) availabil-ty of resources and systems of payment must alle considered in interpreting global recommenda-ions to specific regions The following commen-aries on the KDIGO guideline represent theonsensus of a work group convened by KDOQIo evaluate the relevance and applicability of theuideline to US patients and practices It iseyond the scope of our review to make a com-ent on each of the more than 150 KDIGO
ecommendations We chose instead to addressuidelines for which we questioned applicabilityo US KTRs as well as those that we believedeeded reinforcement or clarification Emphasiss placed not on critiquing the guidelines but onetermining their appropriateness for our USatients The relative importance of a recommen-ation relevance to US patients comparison to
mmendation the strength of recommendation is indicatedrting evidence is shown as A B C or D The additionalsed on common sense or when the topic does not allowinclude recommendations regarding monitoring intervalsommendations generally are written as simple declarative
ch recosuppo
nce bamplesed rec
r recommendations than Level 1 or 2 Adapted from the
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KDOQI Commentary 3
ARTICLE IN PRESS
xisting guidelines and ease of implementationorm the basis of these commentaries
Members of the KDOQI commentary workroup reached consensus on most commentariesnd have indicated when this was not the casee have relisted each KDIGO recommendation
y section with the grade for evidence support-ng it followed by our work grouprsquos rationalend commentary on the guideline If a guidelineecommendation statement was classified by theDIGO work group as important enough toecome a strong recommendation (category 1)he statement is highlighted by showing the guide-ine text in bold
COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
DIGORecommendations inChapter 1nduction Therapy
11 We recommend starting a combination of immu-nosuppressive medications before or at the timeof kidney transplantation (1A)
12 We recommend including induction therapy witha biologic agent as part of the initial immunosup-pressive regimen in KTRs (1A)121 We recommend that an IL2-RA [interleu-
kin-2 receptor antagonist] be the firstlineinduction therapy (1B)
122 We suggest using a lymphocyte-depletingagent rather than an IL2-RA for KTRs athigh immunologic risk (2B)
DOQIRationale andCommentary
It clearly is important to start immunosuppres-ion before or at the time of transplant Inductionherapy with a biologic agent such as interleukin
(IL-2) receptor antagonists or thymoglobulinecreases the frequency of acute rejection andow is used in up to 80 of US transplantenters However individual US transplant cen-ers determine immunosuppression protocolsased on their particular patient population or-an source experience ease of use and cost ofherapy Ethnic diversity of the population andhe number of high-risk patients vary in differentegions of the United States which explains inart variations in protocols used in differententers Applicability of the recommended
DIGO guidelines in this section must be inter- n
reted with these differences in mind The lastublished survey of immunosuppression use inS transplant centers was in the 2006 Organrocurement and Transplantation NetworkScien-
ific Registry of Transplant Recipients (OPTNRTR) Annual Report6 and reported on the usef calcineurin inhibitors (CNIs) mycophenolatecid compounds (MPA) mammalian target ofapamycin (mTOR) inhibitors and inductionherapy (Box 1)
Guidelines for induction therapy will be mostelevant not to community nephrologists but tohose working in transplant centers in whichnduction is used Not all patients need inductionherapy The cost of induction therapy is substan-ial and should be viewed in the context ofiskbenefit for a particular donorrecipient pro-le In the United States the use of lymphocyte-epleting antibodies (thymoglobulin and alemtuz-mab) for induction is increasing6 Many centersill use these agents in low-risk patients toinimize exposure to other maintenance drugs
ie steroids) It is unlikely that the current KDIGOuidelines recommending IL-2 receptor antago-
Box 1 2006 OPTNSRTR Annual Report
Induction Immunosuppressiona
78 used induction therapy composed ofŒ Thymoglobulin in 39Œ Interleukin 2 receptor antagonist in 28Œ Alemtuzumab in 9Œ Other in 2
22 did not receive induction therapy
Initial Immunosuppression (at discharge)
94 on CNI composed ofŒ 15 CsAŒ 79 Tac
87 on MPA 9 on mTOR inhibitor 26 steroid free
Maintenance Immunosuppression (1 year and beyond)
99 on CNI 87 on MPA 18 on mTOR inhibitors 20 steroid free
Abbreviations CNI calcineurin inhibitors CsA cyclo-porine MPA mycophenolic acid compounds mTORammalian target of rapamycin OPTNSRTR Organrocurement and Transplantation NetworkScientific Reg-
stry of Transplant Recipients Tac tacrolimusData source Andreoni et al6
ists as first-line induction therapy will alter US
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ARTICLE IN PRESS
ransplant practices in which these decisions tendo be transplant-center specific and based onactors described previously
DIGORecommendations inChapter 2 InitialndMaintenance Immunosuppressiveedications
21 We recommend using a combination of immuno-suppressive medications as maintenance therapyincluding a CNI and an antiproliferative agentwith or without corticosteroids (1B)
22 We suggest that tacrolimus be the first-line CNIused (2A)221 We suggest that tacrolimus or CsA be
started before or at the time of transplanta-tion rather than delayed until the onset ofgraft function (2D tacrolimus 2B CsA)
23 We suggest that mycophenolate be the first-lineantiproliferative agent (2B)
24 We suggest that in patients who are at low immuno-logical risk and who receive induction therapycorticosteroids could be discontinued during thefirst week after transplantation (2B)
25 We recommend that if mTOR inhibitors areused they should not be started until graftfunction is established and surgical wounds arehealed (1B)
DOQIRationale andCommentary
Initial Immunosuppression
We agree that optimum initial maintenanceherapy includes a CNI and an antiproliferativegent and that tacrolimus is the preferred CNI forost patients The Symphony Study a largeulticenter clinical trial showed that the combi-
ation of low-dose tacrolimus mycophenolateofetil (MMF) and steroids with daclizumab
nduction provided superior efficacy without theegative impact on renal function compared withither cyclosporine or a CNI-free regimen ofow-dose sirolimus78 However in a small num-er of patients other issues such as age ethnic-ty risk of new-onset diabetes mellitus and pre-ious toxicity with tacrolimus may result in thenitial use of cyclosporine Immediate CNI useas not been shown to cause a delay in renalecovery Although many centers briefly hold orodify the CNI dose in the setting of delayed
raft function especially when using antilympho-yte-depleting induction agents treatment withhese drugs should be initiated before or at theime of discharge from the hospital and not
ithheld because of delayed graft function As m
tated mycophenolate compounds (MMF andycophenolate sodium) are used as the initial
ntiproliferative agent of choice in most USransplant centers
SteroidTherapyDiscontinuation
Steroid sparing with discontinuation withinhe first few weeks after transplant has gainedidespread acceptance in the United States withore than 25 of patients being discharged after
ransplant off steroid therapy6 Although theDOQI work group agreed that steroid therapy
ould be discontinued in low-risk patients afternduction therapy we did not think that thisuggestion should be accepted as a universaluideline for several reasons Although short-nd medium-term results in corticosteroid therapyiscontinuation protocols show equivalent pa-ient and graft survival there may be a price toay in the long term Acute rejection rates areigher in well-designed randomized clinical tri-ls of steroid withdrawal In addition the pres-nce of chronic interstitial fibrosis and tubulartrophy may be greater in corticosteroid-freeatients portending decreased long-term graftunction The heterogeneity of the US donor andecipient population may have a role in thisssue Newer transplant regimens decrease pred-isone dosage to 5 mgd Apart from less boneisease the potential metabolic benefits of corti-osteroid-free protocols versus 5 mgd seem toe less significant What is clear is that discontinu-tion of steroid therapy early after transplanteems to be associated with less risk of rejectionhan discontinuation of steroids later (1 year)t should be noted that there are no studies ofifferent times in the first year to determine whenorticosteroid therapy can be discontinued safelyn some centers steroid therapy discontinuations accomplished up to 6 months posttransplantate discontinuation of steroid therapy (1 yearosttransplant) is no longer recommended andorms the basis of KDIGO guideline 25 withhich we agree It also must be emphasized that
teroid therapy withdrawal should be performednly when there is close frequent monitoring ofhe patient
EarlyUseofmTOR Inhibitors
Sirolimus and everolimus (agents known as
TOR inhibitors) delay wound healing prolong
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KDOQI Commentary 5
ARTICLE IN PRESS
elayed graft function and are no longer used inhe early posttransplant period (KDIGO recom-endation 25) Furthermore studies show an
ncreased rejection rate with early use of theseompounds in place of CNIs The Symphonytudy showed that the highest rejection rateccurred in the arm using low-dose sirolimusith MMF and steroids78
DIGORecommendations inChapter 3ong-termMaintenance Immunosuppressiveedications
31 We suggest using the lowest planned doses ofmaintenance immunosuppressive medications by2-4 months after transplantation if there has beenno acute rejection (2C)
32 We suggest that CNIs be continued rather thanwithdrawn (2B)
32 If prednisone is being used beyond the first weekafter transplantation we suggest prednisone becontinued rather than withdrawn (2C)
DOQIRationale andCommentary
Decreasing ImmunosuppressiveDosage
Although our work group agreed with sugges-ion 31 we stress that dosing of immunosuppres-ion should at all times take into account thendividual patientrsquos risk profile balancing rejec-ion with the adverse effects of medications Inome patients this may mean higher drug dosingrug levels to account for a higher risk of rejec-ion Although most US transplant centers nowtrive for a lower dose of immunosuppressiveedication after the early posttransplant period
he transplant center should define each patientrsquosarget drug dosing based on immunologic riskhich depends on ethnicity age history of previ-us transplant and level of HLA antibodies
ContinueorWithdrawCNITherapy
Although we agreed that mTOR inhibitorshould not be used in the early posttransplanteriod78 newer clinical trials have exploredwitching from CNIs to mTOR inhibitors 3-6onths posttransplant910 Early results suggest
elative safety with improvement in renal func-ion Whether the trade-off of less nephrotoxic-ty with a different side-effect profile of mTORnhibitors will be beneficial in the long termemains to be determined The work groupelieved that suggestion 32 to continue CNI
herapy indefinitely in all patients required
ore study before it could be accepted as auideline
SteroidTherapyWithdrawal
We agree that late steroid therapy with-rawal (1 year) is inadvisable but stress thathe definition of ldquoearlyrdquo steroid discontinua-ion has not been well defined and may occurfter the first week (see commentary underhapter 2)
DIGORecommendations inChapter 4trategies toReduceDrugCosts
41 If drug costs block access to transplantation astrategy to minimize drug costs is appropriateeven if use of inferior drugs is necessary to obtainthe improved survival and quality of life benefitsof transplantation compared with dialysis (NotGraded)411 We suggest strategies that may reduce drug
costs includebull limiting use of a biologic agent for
induction to patients who are high-riskfor acute rejection (2C)
bull using ketoconazole to minimize CNIdose (2D)
bull using a nondihydropyridine CCB to mini-mize CNI dose (2C)
bull using azathioprine rather than mycophe-nolate (2B)
bull using adequately tested bioequivalent ge-neric drugs (2C)
bull using prednisone long-term (2C)
42 Do not use generic compounds that have not beencertified by an independent regulatory agency tomeet each of the following criteria when comparedto the reference compound (Not Graded)bull contains the same active ingredientbull is identical in strength dosage form and route of
administrationbull has the same use indicationsbull is bioequivalent in appropriate bioavailability
studiesbull meets the same batch requirements for identity
strength purity and qualitybull is manufactured under strict standards
43 It is important that the patient and the clinicianresponsible for the patientrsquos care be made aware ofany change in a prescribed immunosuppressivedrug including a change to a generic drug (NotGraded)
44 After switching to a generic medication that ismonitored using blood levels obtain levels andadjust the dose as often as necessary until a stable
therapeutic target is achieved (Not Graded)
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ARTICLE IN PRESS
DOQIRationale andCommentary
Drug costs are becoming an increasing issue inransplantation that impacts on patient adherencend ultimately affects graft survival Currently im-unosuppressive drugs in the United States are
overed by the Centers for Medicare amp Medicaidervices (CMS) the primary insurer for manyTRs for 3 years after transplant although legisla-
ion is being considered to continue this coverageor the life of the kidney Most KTRs are usingany other medications in addition to immunosup-
ressive drugs In general the transplant commu-ity (patients health care providers and policyakers) need to embrace the concept of cost con-
ainment and the risk(s) to the patient and graft byhese measures However this needs to be balancedy who benefits and how much risk is at stake
Use of drugs that block the cytochrome P-450A system in an attempt to decrease CNIosing and costs are rarely used in the Unitedtates The concern is that inadvertent cessa-
ion of treatment with these drugs causing aignificant decrease in drug levels could resultn an acute rejection episode Therefore theork group did not think that many of the 411
uggestions should be accepted as a guidelinewitching from a mycophenolate compound ton azathioprine compound in the later posttrans-lant period may be considered in some pa-ients as another cost-saving maneuver espe-ially in view of recent US registry datahowing similar long-term survival with theserugs11 Although we agree with the sugges-ions outlined in 42 it should be recognizedhat many generic formulations have nevereen tested in transplant patients Patient con-usion with medications when a different ge-eric formulation or even different strengths ofhe same drug from different manufacturers isispensed at each refill can lead to inadvertentedication errors possibly affecting out-
omes Patient education is crucial to avoidrrors in medication administration We agreeith recommendation 44 that it is crucial toonitor patients after an immunosuppressive
osage change brand change or change to aeneric drug However it needs to be recog-ized that implementation of this guideline canecome burdensome as practices become inun-
ated with inquiries from patients payors and 5
harmacies regarding medications Transplantenters and practices that see many transplantatients bear an inordinate part of this burden
DIGORecommendations inChapter 5onitoring ImmunosuppressiveMedications
51 We recommend measuring CNI blood levels(1B) and suggest measuring at leastbull every other day during the immediate postopera-
tive period until target levels are reached (2C)bull whenever there is a change in medication or
patient status that may affect blood levels (2C)bull whenever there is a decline in kidney function that
may indicate nephrotoxicity or rejection (2C)511 We suggest monitoring CsA using 12-h
trough (C0) 2-h post-dose (C2) or abbrevi-ated AUC (2D)
512 We suggest monitoring tacrolimus using12-h trough (C0) (2C)
52 We suggest monitoring MMF levels (2D)53 We suggest monitoring mTOR inhibitor levels (2C)
DOQIRationale andCommentary
Because immunosuppressive drugs are classi-ed as narrow therapeutic agents drug-levelonitoring is a necessary tool to maximize effi-
iency and minimize toxicity The blood drugevel is not synonymous with level of immuno-uppression but may correlate imperfectly withhis effect In most US transplant centers levelsf CNI and mTOR inhibitors are monitoredPA monitoring is problematic because of the
oor correlation between trough levels and areander the curve (AUC) exposure Optimal moni-oring of MPA requires a 4- to 6-hour abbrevi-ted AUC measurement which is logisticallyifficult in the outpatient setting Although stud-es show that monitoring MPA levels in the earlyosttransplant period may be helpful in cyclospor-ne-treated patients recent evidence suggests thatuch monitoring may be less important in pa-ients on tacrolimus therapy12 With most USTRs now being started on tacrolimus as theNI of choice MPA monitoring is not routine inany US transplant centers Although one per-
on in our work group believed there may still beome value in monitoring MPA levels the otherembers questioned the value and applicability
f this practice (KDIGO suggestion 52) Cur-ently many US centers measure MPA only inhe setting of possible drug-related toxicities oride effects Although we agree with suggestion
3 to monitor mTOR inhibitor levels it should
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KDOQI Commentary 7
ARTICLE IN PRESS
e appreciated that therapeutic levels of thisgent have yet to be defined in controlled studies
DIGORecommendations inChapter 6reatment ofAcuteRejection
61 We recommend biopsy before treating acuterejection unless the biopsy will substantiallydelay treatment (1C)
62 We suggest treating subclinical and borderline acuterejection (2D)
63 We recommend corticosteroids for the initialtreatment of acute cellular rejection (1D)631 We suggest adding or restoring maintenance
prednisone in patients not on steroids whohave a rejection episode (2D)
632 We suggest using lymphocyte-depleting anti-bodies or OKT3 [muromonab-CD3] for acutecellular rejections that do not respond tocorticosteroids and for recurrent acute cellu-lar rejections (2C)
64 We suggest treating antibody-mediated acute rejec-tion with one or more of the following alternativeswith or without corticosteroids (2C)bull plasma exchangebull intravenous immunoglobulinbull anti-CD20 antibodybull lymphocyte-depleting antibody
65 For patients who have a rejection episode wesuggest adding mycophenolate if the patient is notreceiving mycophenolate or azathioprine or switch-ing azathioprine to mycophenolate (2D)
DOQIRationale andCommentary
We concur that biopsies should be performed onll KTRs suspected of having an acute rejectionrecommendation 61) Expert interpretation of theiopsy specimen by pathologists accustomed toeading kidney transplant biopsies is as importants expertise in performing the biopsy It is contro-ersial whether subclinical and borderline rejec-ions should be treated (recommendation 62 sup-orted by low evidence [2D]) Subclinical rejectionsre diagnosed in patients who have protocol biop-ies performed by design not for deterioration inidney function Recent data suggest that the riskf subclinical rejection in patients on tacrolimusnd mycophenolate compound therapy is so lowhat protocol biopsies may no longer be indi-ated13 Whether this is true in patients with highmmunologic risk or patients on minimization pro-ocols (ie steroid-free protocols or lower CNI doses)s uncertain Whether borderline rejection shoulde treated or some infiltrates may be protective also
s uncertain In most US centers steroids are used d
ost frequently as first-line treatment for acuteejection followed by lymphocyte-depleting anti-odies in steroid-resistant rejection but there maye exceptions to this approach Decision makingegarding appropriate initial treatment for acuteejection should be based on clinical and patho-ogic information Timing of the rejection episodeosttransplant type of induction agent used beforeejection degree of deterioration in kidney functiont the time of rejection and histologic grade of theejection may influence selection of the appropriatenitial antirejection therapy There is increasingecognition of the role of antibody-mediated mecha-isms in acute rejection This process requirespecial blood tests (to detect donor-specific antibod-es) and histochemical stains (immunofluorescenceor C4d) for diagnosis14 Coordination with theransplant center is critical to ensure that all appro-riate testing is performed and specific treatment isnitiated After treatment of an acute episode opti-
izing overall immunosuppression is requiredonsiderations should include changing the CNIdding a mycophenolate compound or increasinghe dose adding corticosteroids to previously ste-oid-free regimens or addingsubstituting an mTORnhibitor More than 85 of patients are alreadysing MPA agents so the number available forwitching will be relatively small
DIGORecommendations inChapter 7reatment of ChronicAllograft Injury (CAI)
71 We recommend kidney allograft biopsy for allpatients with declining kidney function of unclearcause to detect potentially reversible causes (1C)
72 For patients with CAI and histological evidence ofCNI toxicity we suggest reducing withdrawing orreplacing the CNI (2C)721 For patients with CAI eGFR 40 mLmin
173 m2 and urine total protein excretion500 mgg creatinine (or equivalent protein-uria by other measures) we suggest replac-ing the CNI with a mTOR inhibitor (2D)
DOQIRationale andCommentary
We agree with the need for kidney transplantiopsy in patients with decreasing kidney function71) and again stress the importance of expertise inathologic interpretation Important causes ofhronic allograft injury (CAI) which include rejec-ion BK nephropathy CNI toxicity or recurrentisease require special histochemical stains for
iagnosis that are not readily available in all labora-
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Bia et al8
ARTICLE IN PRESS
ories Therefore coordination with the transplantenter where these techniques are available is essen-ial For patients with CAI caused by CNI toxicityithdrawing the CNI should occur only after at-
empts at decreasing the dosage have failed Onelso must ensure that all other causes of CAI arexcluded to avoid inappropriate drug adjustmentsr missed treatment options Although our workroup thought that KDIGO suggestion 721 maye reasonable in some patients we also want tomphasize that the role of mTOR inhibitors in thereatment of CAICNI toxicity is poorly defined Its clear that switching from a CNI to an mTORnhibitor should be avoided in patients with se-erely decreased glomerular filtration rate (GFR)ndor the presence of proteinuria however the exactuidelines for when to switch are still evolving
SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
DIGORecommendations inChapter 8onitoringKidneyAllograft Function
81 We suggest measuring urine volume (2C)bull Every 1-2 hours for at least 24 hours after
transplantation (2D)
In the United States immunosuppressive protocolsused may vary from center to center based on theirparticular patient population organ source experienceand opinion of the transplant team ease of use and costof therapy Although data about the efficacy and safety ofsteroid-free regimens are still evolving it is clear that ifsteroids are to be eliminated this should be done in theearly transplant period and not late (after 1 year)Community nephrologists need to coordinate any alter-ations in immunosuppressive medications with the trans-plant center and be vigilant for potential drug interactionswith the addition of any new medications Drug monitor-ing is an essential monitoring tool throughout the post-transplant course but not always applicable to everyimmunosuppressive medication Transplant biopsies fre-quently are necessary to determine the cause of renaldysfunction and the interpretation must be performed bypathologists with resources and experience in handlingand reading the transplant biopsy specimen
bull Daily until graft function is stable (2D) c
82 We suggest measuring urine protein excretion (2C)at leastbull Once in the first month to determine a baseline
(2D)bull Every 3 months during the first year (2D)bull Annually thereafter (2D)
83 We recommend measuring serum creatinine (1B) atleastbull Daily for 7 days or until hospital discharge
whichever occurs sooner (2C)bull 2-3 times per week for weeks 2-4 (2C)bull Weekly for months 2 and 3 (2C)bull Every 2 weeks for months 4-6 (2C)bull Monthly for months 7-12 (2C)bull Every 2-3 months thereafter (2C)
831 We suggest estimating GFR whenever se-rum creatinine is measured (2D) usingbull One of several formulas validated for
adults (2C) orbull The Schwartz formula for children and
adolescents (2C)
84 We suggest including a kidney allograft ultrasoundexamination as part of the assessment of kidneyallograft dysfunction (2C)
DOQIRationale andCommentary
RoutineScreeningTestsandTimeandFrequencyofMonitoring
Regular surveillance and vigilant monitoring ofidney allograft function are important in improv-ng short- and long-term outcomes Early detectionf kidney allograft dysfunction will allow timelyiagnosis and treatment that may improve patientnd graft survival Frequency and types of routinecreening tests after kidney transplant are shown inig 2Although there is no standard protocol for therequency and type of monitoring recommenda-ions are guided by the likelihood of problemspecific to the particular transplant population Inhe early posttransplant period when rejection andomplications are the most likely testing is per-ormed more frequently Thereafter the follow-upnterval will depend in part on the patientrsquos generalondition and the development of additional prob-ems The AST recommended routine posttrans-lant 2-3 visits per week during month 1 every 1-3eeks during month 2-3 every 4-8 weeks duringonths 4-12 and every 2-4 months after therst year These early visits often are providedy the transplant physician or surgeon of theransplant center After 3-6 months monitor-ng may be performed by the transplant physi-
ian or community nephrologist15 In a recent
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KDOQI Commentary 9
ARTICLE IN PRESS
urvey of posttransplant outpatient visits inedicare beneficiaries in the United States
requency of visits to transplant centers variedy center and region most visits were toephrologists16
At each clinic visit education regardingedication adherence diet and healthy life-
tyle should be given Screening for tobaccose should be implemented before dischargend annually Although the work group did notgree that screening all adults for Epstein-Barrirus (EBV) was of value (see commentarynder Chapter 13 for EBV) screening for allther elements listed in Fig 2 including screen-ng for proteinuria is reasonable In additiono these tests monitoring for HLA antibodiesgainst the donor (donor-specific antibodies)hich is not described in the KDIGO guide-
ine is becoming more common in some USenters The optimal timing and frequency ofuch screening has yet to be determined1718
SerumCreatinineandEstimatedGFR
Serum creatinine measurement remains theost commonly used index of renal allograft
unction It is reliable for detecting acute changesn kidney function Furthermore serum creati-ine level at year 1 after transplant is a riskactor for subsequent outcomes19 and mayelp in the management of the frequency ofisits However it is less reliable for detecting
Figure 2 Routine screen-ng after kidney transplantomplete blood cell count in-ludes white blood cells hemo-lobin and platelets Screenor diabetes is by fasting bloodlucose level glucose toler-nce test or hemoglobin A1c
evel Lipid profile includes fast-ng cholesterol low-density li-oprotein cholesterol high-ensity lipoprotein cholesterolnd triglyceride levels Screensor BK polyoma virus (BKV)nd Epstein-Barr virus (EBV)se plasma nucleic acid test-
ng (NAT) EBV screen is foratients with no antibody toBV at transplant Adapted
rom the KDIGO transplantuideline3 with permission ofDIGO
ong-term changes in kidney function in the
idney transplant recipient Formulas to esti-ate GFR using serum creatinine values have
een tested in KTRs but no formula consis-ently has been shown to be superior to an-ther As with CKD considerable renal patho-ogic states can be present without dramatichanges in serum creatinine levels
In 2005 the definition of CKD was amendedo include all KTRs regardless of markers ofidney damage or GFR2021 Although the workroup agreed that CKD staging in KTRs isseful it must be noted that there is consider-ble difference in the rate of progression inhese 2 groups Progression is much slower inTRs in whom kidney half-life is longer at
very level of CKD Renal ultrasound is thereferred imaging study in KTRs (KDIGOuggestion 84)22
DIGORecommendations inChapter 9 Kidneyllograft Biopsy
91 We recommend kidney allograft biopsy whenthere is a persistent unexplained increase inserum creatinine (1C)
92 We suggest kidney allograft biopsy when serumcreatinine has not returned to baseline after treat-ment of acute rejection (2D)
93 We suggest kidney allograft biopsy every 7-10 daysduring delayed function (2C)
94 We suggest kidney allograft biopsy if expectedkidney function is not achieved within the first 1-2months after transplantation (2D)
95 We suggest kidney allograft biopsy when there is
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Bia et al10
ARTICLE IN PRESS
bull New onset of proteinuria (2C)bull Unexplained proteinuria 30 g per gram creati-
nine or 30 g per 24 hours (2C)
DOQIRationale andCommentary
Biopsy
Renal allograft biopsy is the gold standard foriagnosing the cause of a change in renal allo-raft function It is useful in all clinical situationsescribed in KDIGO suggestions 91-94 Poten-ial causes of allograft dysfunction include vol-me depletion compromised renal blood flowrinary outflow obstruction parenchymal causesuch as acute rejection (cellular andor humoral)hronic allograft nephropathy recurrent or deovo disease or BK nephropathy Patients show-ng a 20-25 increase in creatinine level aboveaseline values warrant consideration for biopsyther indications for pursuing renal allograftiopsy would be a less-than-expected responseo treatment of acute rejection The expectedesponse would be dependent on the severity ofissue injury noted on the diagnostic biopsy speci-
en Delayed graft function lasting longer than-7 days warrants biopsy with repeated biopsieserformed every 7-10 days until graft functionecovers New-onset proteinuria protein 20g creatinine or 20 g24 h also merits aidney biopsy De novo and recurrent glomerulariseases are common causes of new-onset pro-einuria Patients with de novo or recurrent glo-erular diseases should be followed up closely
y transplant nephrologists or community neph-ologists with close communication with theransplant center because treatment of some recur-ent kidney diseases may prevent or delay thenset of graft failure2324
SafetyandAccuracy
The safety of kidney transplant biopsies haseen documented and the overall risk of compli-ations is low Most biopsies are performed inhe transplant center by transplant nephrologistsommunity nephrologists also may perform bi-psies of the kidney in KTRs more than a yearosttransplant It is prudent to obtain a diagnosticltrasound before biopsy to rule out unexpectedlterations in blood flow or urinary tract obstruc-ion It is imperative that a pathologist familiar
ith the transplant process interprets the pathol-
gy in consultation with the referring nephrolo-ist using appropriate stains and other studies
MolecularMarkers
In addition to conventional histopathologicxamination several US transplant centers aresing molecular markers as well as genomic orroteomic methods to enhance our understand-ng of the mechanism of immunologic and non-mmunologic pathway of injury As an exampleolymerase chain reaction (PCR) has been usedo detect messenger RNA for IL-2 and otheriomarkers in biopsy samples Using this ap-roach IL-2 upregulated during rejection coulde detected 2 days before rejection was apparentsing histologic or clinical criteria Such PCRpproaches have been used to detect other generoducts upregulated during acute rejection suchs granzyme B perforin transforming growthactor IL-10 and IL-1525-27 These newerethods are performed almost exclusively in
ransplant centers and may become a standardethod of transplant biopsy analysis in the fu-
ure
DIGORecommendations inChapter 10ecurrentDisease
101 We suggest screening KTRs with primary kidneydisease caused by FSGS for proteinuria (2C) atleastbull Daily for 1 week (2D)bull Weekly for 4 weeks (2D)bull Every 3 months for the first year (2D) Every
year thereafter (2D)
102 We suggest screening KTRs with potentially treat-able recurrence of primary kidney disease fromIgA nephropathy MPGN anti-GBM disease orANCA-associated vasculitis for microhematuria(2C) at leastbull Once in the first month to determine a baseline
(2D)bull Every 3 months during the first year (2D)
Annually thereafter (2D)
103 During episodes of graft dysfunction in patientswith primary HUS we suggest screening forthrombotic microangiopathy (eg with plateletcount peripheral smear for blood cell morphologyplasma haptoglobin and serum lactate dehydroge-nase) (2D)
104 When screening suggests possible treatable recur-rent disease we suggest obtaining an allograftbiopsy (2C)
105 Treatment of recurrent kidney disease1051 We suggest plasma exchange if a biopsy
shows minimal change disease or FSGS
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KDOQI Commentary 11
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in those with primary FSGS as theirprimary kidney disease (2D)
1052 We suggest high-dose corticosteroids andcyclophosphamide in patients with recur-rent ANCA-associated vasculitis or anti-GBM disease (2D)
1053 We suggest using an ACE-I [ACE inhibi-tor] or an ARB for patients with recurrentglomerulonephritis and proteinuria (2C)
1054 For KTRs with primary hyperoxaluriawe suggest appropriate measures to pre-vent oxalate deposition until plasma andurine oxalate levels are normal (2C)includingbull Pyridoxine (2C)bull High calcium and low oxalate diet
(2C)bull Increased oral fluid intake to enhance
urinary dilution of oxalate (2C)bull Potassium or sodium citrate to alkalin-
ize the urine (2C)bull Orthophosphate (2C)bull Magnesium oxide (2C)bull Intensive hemodialysis to remove ox-
alate (2C)
DOQIRationale andCommentary
Recurrent disease accounts for a substantialmount of graft loss after renal transplant It isifficult to assess the percentage of grafts lost toecurrent disease because many patients presentith end-stage renal disease without benefit of aiagnostic native renal biopsy The likelihood ofecurrent disease after transplant is dependent onhe disease with certain diseases at particularlyigh risk of recurrence28
Recurrent Focal SegmentalGlomerulosclerosis
We agree with recommendation 101 regard-ng frequent and regular screening for protein-ria in patients with primary focal segmentallomerulosclerosis (FSGS) as the cause of end-tage renal disease If the patient is still produc-ng urine at the time of transplant a preoperativerine protein-creatinine ratio can be a very help-ul baseline measure of proteinuria Early detec-ion of FSGS recurrence which can present withormal light microscopy but foot-process efface-ent on electron microscopy29 provides the best
pportunity for intervention and amelioration ofisease
IgANephropathy
Recurrence rates of immunoglobulin A (IgA)
ephropathy are variable We agree with recom- b
endation 102 for screening routinely for micro-ematuria Recurrent disease is confirmed with aenal allograft biopsy Histologic recurrence ofisease is much more common than is clinicalisease recurrence There is no proven therapyor treatment of recurrent disease30
MembranoproliferativeGlomerulonephritis
Recurrence of membranoproliferative glomer-lonephritis (MPGN) is common as high as 80ith MPGN type II (dense-deposit disease) Theost common cause of MPGN type I is hepatitisndashassociated immune complex formation Wegree with the proposed regularly scheduledcreening for microhematuria and proteinuria inecommendation 102 Patients with known hepa-itis Cndashassociated MPGN pretransplant also maye screened for cryoglobulins which are associ-ted with MPGN31
HemolyticUremic Syndrome
Hemolytic uremic syndrome (HUS) typicallys divided into diarrheal associated (D) andonndashdiarrheal associated (D) D disease oc-urs mostly in children and rarely recurs post-ransplant However D HUS is more commonn adults and can recur In HUS associated with aomplement abnormality such as factor H defi-iency or factor I mutation recurrence rates cane as high as 80 Screening for evidence ofecurrence allows for an earlier diagnosis whichill require biopsy in most cases and provides
n opportunity for earlier intervention There iso comment in the guideline regarding recur-ence of thrombotic thrombocytopenic purpuraut early detection of recurrence provides anpportunity for treatment with plasmapheresisnd intravenous immune globulin (IVIG)
BiopsyandTreatment
As stated kidney biopsy and interpretation bypathologist with expertise in transplant speci-en readings is critical in the diagnosis of dis-
ase recurrence Treatment for most recurrentisease in renal transplantation is based on aombination of case reports case cohorts andetrospective reviews Recurrent diseases post-ransplant are not common enough that random-zed controlled trials can be implemented there-ore most recommendations for treatment are
ased on a consensus of opinion Despite this we
at
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gree in general with the recommendations de-ailed in 105
DIGORecommendations inChapter 11reventingDetecting andTreatingonadherence
111 Consider providing all KTRs and family memberswith education prevention and treatment mea-sures to minimize nonadherence to immunosup-pressive medications (Not Graded)
112 Consider providing KTRs at increased risk fornonadherence with increased levels of screeningfor nonadherence (Not Graded)
DOQIRationale andCommentary
Noncompliance or nonadherence to diet andedication is a common problem in KTRs Nonad-
erence to medication is associated with a high riskf acute rejection and allograft loss We agree thatarly efforts should be made to identify KTRs atncreased risk of nonadherence and that these pa-ients should be monitored closely Prevention iden-ification and treatment of nonadherence are inte-ral to the monitoring of kidney allograft functionnd long-term care of KTRs Certain subgroup ofTRs younger patients African Americans and
hose with financial hardships have an enhancedisk of nonadherence3233
In addition to identifying patients at risk it ismportant to have a system for addressing patientonadherence This requires coordinated efforts ofocial workers transplant coordinators financialounselors pharmacists primary nephrologists andhe patientrsquos family34 A combination of educa-ional behavioral and social support interventionsrovides the best results Because there is no per-ect measure of adherence consideration should beiven to multiple approaches for adherence moni-oring Similar team approaches also are importantn other areas requiring adherence such as dietxercise tobacco alcohol and drug use
DIGORecommendations inChapter 12accination
121 We recommend giving all KTRs approvedinactivated vaccines according to recommendedschedules for the general population except forHBV vaccination (1D)1211 We suggest HBV vaccination (ideally
prior to transplantation) and HBsAb titers6-12 weeks after completing the vaccina-
tion series (2D) h
12111 We suggest annual HBsAb[antibody to hepatitis B sur-face antigen] titers (2D)
12112 We suggest revaccination ifthe antibody titer falls below10 mIUmL (2D)
122 We suggest avoiding live vaccines in KTRs (2C)123 We suggest avoiding vaccinations except influ-
enza vaccination in the first 6 months followingkidney transplantation (2C)1231 We suggest resuming immunizations once
patients are receiving minimal mainte-nance doses of immunosuppressive medi-cations (2C)
1232 We recommend giving all KTRs whoare at least 1-month post-transplantinfluenza vaccination prior to the onsetof the annual influenza season regard-less of status of immunosuppression(1C)
124 We suggest giving the following vaccines to KTRswho due to age direct exposure residence ortravel to endemic areas or other epidemiologicalrisk factors are at increased risk for the specificdiseasesbull rabies (2D)bull tick-borne meningoencephalitis (2D)bull Japanese B encephalitismdashinactivated (2D)bull Meningococcus (2D)bull Pneumococcus (2D)bull Salmonella typhimdashinactivated (2D)1241 Consult an infectious disease specialist a
travel clinic or public health official forguidance on whether specific cases war-rant these vaccinations (Not Graded)
DOQIRationale andCommentary
KTRs are at particular risk of viral infectionsecause of the preferential suppression of T lympho-ytes by both induction and maintenance immuno-uppression The risk and consequence of develop-ng a viral infection warrant use of selected vaccineshe suggestions regarding which vaccines are safend which are contraindicated are based on whetherhe vaccine contains live or killed virus Live virusaccines are contraindicated in immunosuppressedTRs The KDIGO recommendations for vaccina-
ions agree with updated guidelines recently pub-ished by the AST35 Specific comments on theDIGO suggestions regarding vaccinations are
isted in the following sections
Hepatitis B
The work group did not concur with KDIGOuggestion 1211 Neither revaccination against
epatitis after transplant nor following up hepa-
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KDOQI Commentary 13
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itis B antibody titers annually is a commonractice in the United States Hepatitis B is nots prevalent in the United States as in otherarts of the world and evidence supportingcreening in all patients posttransplant is lack-ng However screening for seroconversion inatients at risk (receiving a hepatitis B corentibodyndashpositive kidney) is appropriate Theseatients may benefit from lamivudine or ente-avir therapy36
LiveVaccineandTimingofVaccine
There is no particular reason for a 6-monthag between transplant and vaccination Theheory is that vaccines are less likely to beffective in the period when immunosuppres-ion is high In the United States most individu-ls are on their baseline maintenance immuno-uppression therapy by 3 months posttransplantecisions regarding the timing of vaccines areade based on immunosuppression exposure
nd risk of infection Recipients also shouldvoid intimate contact with individuals whoave received live vaccines37 This includesvoiding close contact with children who haveeceived oral polio vaccine for 3 weeks anday include close contact with adults receiv-
ng the attenuated varicella vaccine to preventoster Immunosuppressed individuals are ad-ised to avoid contact for 7 days with individu-ls who have received live virus nasal spraysor influenza We concur with the recommenda-ion for flu vaccine but common practice inhe United States is to wait 3-6 months afterransplant before it is administered
DIGORecommendations inChapter 13 Viraliseases
131 BK POLYOMA VIRUS1311 We suggest screening all KTRs for BKV
with quantitative plasma NAT (2C) atleastbull monthly for the first 3-6 months after
transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull whenever there is an unexplained rise
in serum creatinine (2D)bull and after treatment for acute rejection
(2D)1312 We suggest reducing immunosuppressive
medications when BKV plasma NAT is
persistently greater than 10 000 cop-iesmL (107 copiesL) (2D)
132 CYTOMEGALOVIRUS1321 CMV prophylaxis We recommend that
KTRs (except when donor and recipi-ent both have negative CMV serolo-gies) receive chemoprophylaxis forCMV infection with oral ganciclovir orvalganciclovir for at least 3 monthsafter transplantation (1B) and for 6weeks after treatment with a T-cellndashdepleting antibody (1C)
1322 In patients with CMV disease we suggestweekly monitoring of CMV by NAT orpp65 antigenemia (2D)
1323 CMV treatment13231 We recommend that all pa-
tients with serious (includ-ing most patients with tissueinvasive) CMV disease betreated with intravenousganciclovir (1D)
13232 We recommend that CMVdisease in adult KTRs that isnot serious (eg episodes thatare associated with mildclinical symptoms) be treatedwith either intravenous gan-ciclovir or oral valganciclo-vir (1D)
13233 We recommend that allCMV disease in pediatricKTRs be treated with intra-venous ganciclovir (1D)
13234 We suggest continuing therapyuntil CMV is no longer detect-able by plasma NAT or pp65antigenemia (2D)
1324 We suggest reducing immunosuppressivemedication in life-threatening CMV dis-ease and CMV disease that persists in theface of treatment until CMV disease hasresolved (2D)13241 We suggest monitoring graft
function closely during CMVdisease (2D)
133 EPSTEIN-BARR VIRUS AND POST-TRANS-PLANT LYMPHOPROLIFERATIVE DISEASE1331 We suggest monitoring high-risk (donor
EBV seropositiverecipient seronegative)KTRs for EBV by NAT (2C)bull once in the first week after transplanta-
tion (2D)bull then at least monthly for the first 3-6
months after transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull and additionally after treatment for
acute rejection (2D)
Bia et al14
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1332 We suggest that EBV-seronegative pa-tients with an increasing EBV load haveimmunosuppressive medication reduced(2D)
1333 We recommend that patients with EBVdisease including PTLD have a reduc-tion or cessation of immunosuppres-sive medication (1C)
134 HERPES SIMPLEX VIRUS 1 2 AND VARI-CELLA ZOSTER VIRUS1341 We recommend that KTRs who de-
velop a superficial HSV 1 2 infectionbe treated (1B) with an appropriateoral antiviral agent (eg acyclovir vala-cyclovir or famciclovir) until all le-sions have resolved (1D)
1342 We recommend that KTRs with sys-temic HSV 1 2 infection be treated(1B) with intravenous acyclovir and areduction in immunosuppressive medi-cation (1D)13421 We recommend that intrave-
nous acyclovir continue un-til the patient has a clinicalresponse (1B) then switch toan appropriate oral antiviralagent (eg acyclovir valacy-clovir or famciclovir) to com-plete a total treatment durationof 14-21 days (2D)
1343 We suggest using a prophylactic antiviralagent for KTRs experiencing frequentrecurrences of HSV 12 infection (2D)
1344 We recommend that primary VZV infec-tion (chicken pox) in KTRs be treated(1C) with either intravenous or oral acy-clovir or valacyclovir and a temporaryreduction in amount of immunosuppres-sive medication (2D)
135 HEPATITIS C VIRUS1351 We suggest that HCV-infected KTRs be
treated only when the benefits of treat-ment clearly outweigh the risk of allo-graft rejection due to interferon-basedtherapy (eg fibrosing cholestatic hepati-tis life-threatening vasculitis) (2D)[Based on KDIGO Hepatitis C Recom-mendation 215]
1352 We suggest monotherapy with standardinterferon for HCV-infected KTRs inwhom the benefits of antiviral treatmentclearly outweigh the risks (2D) [Basedon KDIGO Hepatitis C Recommenda-tions 224 and 442]
1353 We suggest that all conventional currentinduction and maintenance immunosup-pressive regimens can be used in HCVinfected patients (2D) [Based on KDIGO
Hepatitis C Recommendation 43]
1354 Measure ALT in HCV-infected patientsmonthly for the first 6 months and every3-6 months thereafter Perform imagingannually to look for cirrhosis and hepato-cellular carcinoma (Not Graded) [Basedon KDIGO Hepatitis C Recommendation441] (See Recommendation 193)
1355 Test HCV-infected patients at least every3-6 months for proteinuria (Not Graded)[Based on KDIGO Hepatitis C Recom-mendation 444]13551 For patients who develop new
onset proteinuria (either urineproteincreatinine ratio 1 or24-hour urine protein 1 g ontwo or more occasions) per-form an allograft biopsy withimmunofluorescence and elec-tron microscopy (Not Graded)[Based on KDIGO Hepatitis CRecommendation 444]
1356 We suggest that patients with HCV asso-ciated glomerulopathy not receive inter-feron (2D) [Based on KDIGO HepatitisC Recommendation 445]
136 HEPATITIS B VIRUS1361 We suggest that any currently available
induction and maintenance immunosup-pressive medication can be used in HBV-infected KTRs (2D)
1362 We suggest that interferon treatmentshould generally be avoided in HBVinfected KTRs (2C)
1363 We suggest that all HBsAg-positive KTRsreceive prophylaxis with tenofovir ente-cavir or lamivudine (2B)13631 Tenofovir or entecavir are pref-
erable to lamivudine to mini-mize development of potentialdrug resistance unless medica-tion cost requires that lami-vudinebe used (Not Graded)
13632 During therapy with antivi-rals measure HBV DNA andALT levels every 3 months tomonitor efficacy and to detectdrug resistance (Not Graded)
1364 We suggest treatment with adefovir ortenofovir for KTRs with lamivudine resis-tance (5 log10 copiesmL rebound ofHBV-DNA) (2D)
1365 Screen HBsAg-positive patients with cir-rhosis for hepatocellular carcinoma every12 months with liver ultrasound andalpha feto-protein (Not Graded) (SeeRecommendation 193)
1366 We suggest that patients who are negativefor HBsAg and have HBsAb titer 10mIUmL receive booster vaccination to
raise the titer to 100 mIUmL (2D)
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KDOQI Commentary 15
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137 HUMAN IMMUNODEFICIENCY VIRUS1371 If not already done screen for HIV
infection (Not Graded)1372 To determine antiretroviral therapy refer
HIV-infected KTRs to an HIV specialistwho should pay special attention to drugndashdrug interactions and appropriate dosingof medications (Not Graded)
DOQIRationale andCommentary
Viral infections are particularly problematic inransplant recipients because of the preferentialnhibition of T-lymphocyte function by both induc-ion and maintenance immunosuppression Use ofnduction immunosuppression with lymphocyte-epleting agents (thymoglobulin or alemtuzumab)s associated with a greater risk of viral infectionosttransplant In general the greater the cumula-ive exposure to immunosuppression the greaterhe risk of infectious complications The presenta-ion of viral infections can be asymptomatic vaguend nonspecific or life-threatening acute illnessany viral infections seen in KTRs are rarely seen
n immunocompetent patients and therefore do notnter into the differential diagnosis for physiciansnfamiliar with transplant recipients Close commu-ication with the transplant center is crucial inaring for the transplant population Early detectionnd institution of therapy provide the best chanceor viral eradication
BKVirus
Although the work group agreed with KDIGOuggestions for BK virus screening posttransplante did not think it was practical to require screen-
ng exclusively with quantitative plasma nucleiccid testing (NAT) because many US centers usenitial urinary screening and then test plasma onlyf urine screening results are positive Howeverhere is no disagreement that some type of screen-ng for BK virus is critical to avoid BK nephropa-hy for which there is no specific treatment when its established Complicating screening for BK vi-us is the variability in results between laboratoriesnd uncertainty about the level of viremia thathould trigger a response to decrease in immunosup-ression In the presence of viremia and increase inerum creatinine level a renal allograft biopsy isndicated to confirm the presence of BK nephropa-
hy Because BK viremia and viruria certainly can b
e detected beyond the first year it is not clear howong screening should be continued posttransplantlthough most centers screen for the first year onlyngoing clinical trials are exploring effective treat-ent for BK nephropathy3839 Decisions about
ecreases in immunosuppression currently theainstay of BK viremia management always
hould be made in consultation with the transplantenter
Cytomegalovirus
KDIGO recommendation 1321 regarding cyto-egalovirus (CMV) prophylaxis is reasonable and
pplicable to the US population Universal prophy-axis for CMV now is recommended over initiatingre-emptive treatment after CMV develops40 Aajor concern for US patients is the cost of CMV
rophylaxis with oral valgancyclovir Leukopeniaan be observed in patients using mycophenolatereparations when prophylaxis with valgancyclo-ir is used Screening for CMV is best performedsing NAT methods (1322) CMV antigenemiassays are still in use in many facilities but are nots sensitive as PCR assays41 There is no utility inhecking for serologic response to CMV with IgGr IgM titers posttransplant because the immuneesponse is not predictable Patients with CMVisease should be cared for by clinicians familiarith treating this disease It is recommended that
reatment be continued until viral load is undetect-ble followed by prophylactic doses of valgancy-lovir for an additional 3 months35
Epstein-BarrVirus
Current practice regarding EBV screening variesmong centers in the United States and many doot routinely screen for EBV posttransplant evenn recipient-negative donor-positive cases In con-rast to KDIGO recommendation 1311 routineBV screening is not recommended in AST infec-
ious disease guidelines35 In many centers EBVcreening is reserved for children who are muchore commonly EBV negative pretransplant than
dults EBV-induced posttransplant lymphoprolif-rative disorder (PTLD) affects many more pediat-ic than adult KTRs If screening is someday to beoutinely implemented in US centers details regard-ng the best method of screening and levels ofiremia above which a clinical intervention should
e triggered need to be better defined
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ARTICLE IN PRESS
HerpesandVaricella
Systemic herpesvirus infections can be lifehreatening in transplant recipients and should bereated aggressively with intravenous antiviralgents as described in the KDIGO recommenda-ions Less aggressive cutaneous infection can bereated with oral antiviral agents as outlined inhe KDIGO guidelines
Varicella exposure is particularly concerning inransplant recipients The work group disputes theecommended dosing of acyclovir for varicellaxposure Acyclovir at a dose of 10 mgkg or about00 mg 4 times daily of oral acyclovir would betandard dosing We agree with the use of varicellammune globulin and emphasize the need to avoidhe varicella vaccine because it is a live virushould a transplant recipient develop a systemicaricella infection hospitalization and high-dosentravenous acyclovir therapy are warranted
Hepatitis C
Hepatitis C management posttransplant is ahallenge The KDIGO guidelines cited hereere based on the recently published KDIGOuideline for hepatitis C in CKD4 Hepatitis Cypically is not treated posttransplant because ofhe risk (50) of rejection precipitated bynterferon therapy particularly in US KTRs inhom hepatitis C commonly is genotype 1 which
s more resistant to treatment with interferon42
owever should hepatitis Cndashrelated glomerulo-ephritis develop the risk-benefit ratio may fa-or treatment in selected patients Such decisionslways should be made in consultation withepatology and infectious disease experts andhe transplant center Monitoring liver enzymeevels specifically alanine aminotransferaseALT) may reflect a change in hepatitis activityut monitoring hepatitis C viral load is not recom-ended because it does not seem to correlateith outcome Annual monitoring for hepatocel-
ular carcinoma using -fetoprotein and imagings encouraged but not often practiced
Hepatitis B
KDIGO recommendations for hepatitis B areeasonable and currently are followed in mostS centers except for recommendation 1366
see previous recommendation under vaccina-ions) KTRs with hepatitis C or hepatitis B also
hould be followed up by a hepatologist
Human ImmunodeficiencyVirus
Human immunodeficiency virus (HIV)-posi-ive individuals are now acceptable for transplantf CD4 count is 200 cellsL and viral loadVL) is undetectable3543 Transplant should beerformed at centers with expertise in managingIV-positive individuals and care should be co-rdinated carefully with HIV specialists Somentiretroviral agents in particular the proteasenhibitors have potentially serious drug interac-ions with immunosuppressive agents35
DIGORecommendations inChapter 14Othernfections
141 URINARY TRACT INFECTION1411 We suggest that all KTRs receive UTI
prophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 monthsafter transplantation (2B)
1412 For allograft pyelonephritis we suggestinitial hospitalization and treatment withintravenous antibiotics (2C)
142 PNEUMOCYSTIS JIROVECII PNEUMONIA1421 We recommend that all KTRs receive
PCP prophylaxis with daily tri-methoprimndashsulfamethoxazole for 3-6months after transplantation (1B)
1422 We suggest that all KTRs receive PCPprophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 weeksduring and after treatment for acute rejec-tion (2C)
1423 We recommend that KTRs with PCPdiagnosed by bronchial alveolar lavageandor lung biopsy be treated withhigh-dose intravenous trimethoprimndashsulfamethoxazole corticosteroids anda reduction in immunosuppressivemedication (1C)
1424 We recommend treatment with cortico-steroids for KTRs with moderate tosevere PCP (as defined by PaO2 lt70mm Hg in room air or an alveolargradient of gt35 mm Hg) (1C)
143 TUBERCULOSIS1431 We suggest that TB prophylaxis and
treatment regimens be the same in KTRsas would be used in the local generalpopulation who require therapy (2D)
1432 We recommend monitoring CNI andmTORi [mTOR inhibitor] blood levels inpatients receiving rifampin (1C)14321 Consider substituting rifabu-
tin for rifampin to minimize
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KDOQI Commentary 17
ARTICLE IN PRESS
interactions with CNIs andmTORi (Not Graded)
144 CANDIDA PROPHYLAXIS1441 We suggest oral and esophageal Candida
prophylaxis with oral clotrimazole loz-enges nystatin or fluconazole for 1-3months after transplantation and for 1month after treatment with an antilympho-cyte antibody (2C)
DOQIRationale andCommentary
UrinaryTract Infection
Urinary tract infections (UTIs) after kidneyransplant are very common and account for aarge percentage of readmissions posttransplantTIs are common because of multiple factors
ncluding the disrupted anatomy of the urinaryract with a ureteroneocystotomy incompleteladder emptying because of diabetes or pros-atic hypertrophy and impaired immune re-ponses Prophylaxis of UTIs usually is under-aken with trimethoprim-sulfamethoxazole for 6onths posttransplant although infections often
ccur despite therapy because of the develop-ent of drug resistance Although native kidney
yelonephritis does not always require hospital-zation it is recommended that all KTRs withhis diagnosis be hospitalized because the graftysfunction that usually accompanies transplantyelonephritis requires aggressive investigationnd treatment Individuals with recurrent UTIsarrant evaluation with urologic assessment Pa-
ients with recurrent UTIs may benefit fromong-term suppressive therapy
Pneumocystic Pneumonia
We agree that Pneumocystis jirovecii pneumoniaPCP) prophylaxis is important for the first 3-6onths posttransplant (1421)After the first month
very-other-day dosing of trimethoprim-sulfame-hoxazole or atovaquone is believed to be adequaterophylaxis In cases in which neither of thesegents can be used an individual may be treatedrophylactically with inhaled pentamidine OurDOQI work group emphasized that patients whoevelop PCP should be transferred to the transplantenter promptly for management and adjustmentsn immunosuppression
Tuberculosis
Monitoring for latent tuberculosis has posed a
hallenge in the immunosuppressed population be-
ause of the unreliable nature of skin testing Newerechniques involving interferon release assays aremerging as the new gold standard for detection ofatent tuberculosis4445
CandidaProphylaxis
Oral candidiasis must be screened for usingral mucosa examination on follow-up visitsn KTRs This is especially true in the earlyosttransplant period when immunosuppres-ive medication dosage is the highest Wegree with these recommendations and empha-ize that if fluconazole is used there is aotential for serious drug interactions becausef cytochrome P-450 3A4 inhibition
SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
Improvement in short-term outcomes has not trans-lated into significant improvements in long-term out-comes in KTRs The lack of significant improvement inlong-term survival may be related to post-transplantcomplications Frequent posttransplant monitoring mayimprove long-term outcomes by decreasing chronic graftfailure or death with a functioning graft Our work groupconcurred with the recommendation and schedules ofroutine screening in monitoring kidney allograft functionafter kidney transplant with a low threshold for perform-ing kidney biopsy in cases of graft dysfunction or protein-uria Expert tissue processing and interpretation of trans-plant biopsy specimens by pathologists with transplantexperience are critical Regular surveillance of the pa-tientrsquos kidney function at the transplant center or in thenephrologistrsquos office offers an opportunity to enhancepatient adherence to medication diet and healthy life-style Although CKD in KTRs progresses more slowlythan CKD in other patients the work group agreed thatthe KDIGO guidelines on CKD should be followed inKTRs
Opportunistic infections are common in KTRs al-though advances in diagnosis and treatment have led toimproved survival in KTRs with infection It is nowstandard of care to use vaccinations in KTRs as long asthe vaccine does not contain live or attenuated virus Italso is routine to screen for or use prophylaxis to preventseveral posttransplant viral infections With few excep-tions (related to EBV and BK virus screening andhepatitis B vaccination posttransplant) we concurredwith KDIGO guidelines for vaccination screening and
treatment of infection posttransplant
KD
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ARTICLE IN PRESS
COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULAR
DISEASE
DIGORecommendations inChapter 15iabetesMellitus
151 Screening for New-Onset Diabetes after Transplan-tation1511 We recommend screening all nondia-
betic KTRs with fasting plasma glu-cose oral glucose tolerance testingandor HbA1c (1C) at leastbull weekly for 4 weeks (2D)bull every 3 months for 1 year (2D)bull and annually thereafter (2D)
1512 We suggest screening for NODAT withfasting glucose oral glucose tolerancetesting andor after starting or substan-tially increasing the dose of CNIsmTORi or corticosteroids (2D)
152 Managing NODAT or Diabetes Present at Trans-plantation1521 If NODAT develops consider modifying
the immunosuppressive drug regimen toreverse or ameliorate diabetes afterweighing the risk of rejection and otherpotential adverse effects (Not Graded)
1522 Consider targeting HbA1c 70-75and avoid targeting HbA1c 60 espe-cially if hypoglycemic reactions are com-mon (Not Graded)
1523 We suggest that in patients with diabetesaspirin (65-100 mgd) use for the primaryprevention of CVD be based on patientpreferences and values balancing the riskfor ischemic events to that of bleeding(2D)
DOQIRationale andCommentary
Diabetic Screening
We agree with screening for new-onset diabetesfter transplantation (NODAT) as outlined by theDIGO work group Definitions used are similar
o those of the American Diabetes AssociationADA) The greater frequency of testing initially isustified by the high risk of NODAT in the earlyosttransplant period however ongoing screenings required because the risk of the development ofODAT continues to increase over time4647 We
lso point out that prediabetic states (impairedasting glucose level and impaired glucose toler-nce) occur even more commonly than overt diabe-es48 and may be associated with metabolic syn-rome as well as with increased cardiovascular
ortality49-51 Potential implications of these predia-
etic states emphasize the importance of perform-ng blood tests under fasting conditions For pa-ients with fasting hyperglycemia an oral glucoseolerance test or hemoglobinA1c (HbA1c) test shoulde performed Although more cumbersome to per-orm data suggest that an oral glucose toleranceest is a more sensitive indicator of NODAT inyperglycemic KTRs52 This may allow earlieretection of overt diabetes and more prompt institu-ion of treatment
DiabetesManagement
Data supporting a substantial benefit in themelioration or reversal of NODAT using immu-osuppression modification in KTRs are veryimited There was consensus in our work grouphat considering the paucity of data for reversingODAT by changing immunosuppression and
he potential risk of an adverse outcome withuch a maneuver KDIGO suggestion 1521 couldot be supported Certainly if such a step waseing considered it should be done in conjunc-ion with the transplant center Targeting an HbA1c
evel of 7-75 and avoiding levels 6 isased on data showing increased cardiovascularvents with the lower HbA1c target5354
DIGORecommendations inChapter 16ypertensionDyslipidemias TobaccoUse andbesity
161 Hypertension1611 We recommend measuring blood pres-
sure at each clinic visit (1C)1612 We suggest maintaining blood pressure at
130 mm Hg systolic and 80 mm Hgdiastolic if 18 years of age and 90th
percentile for sex age and height if 18years old (2C)
1613 To treat hypertension (Not Graded)bull Use any class of antihypertensive
agentbull Monitor closely for adverse effects
and drug-drug interactions and whenurine protein excretion 1 gd for18 years old and 600 mgm224 hfor 18 years old consider an ACE-Ior an ARB as first-line therapy
162 Dyslipidemias (These recommendations are basedon KDOQI Dyslipidemia Guidelines and are thusnot graded)1621 Measure a complete lipid profile in all
adult (18 years old) and adolescent
(puberty to 18 years old) KTRs [Based on
K
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KDOQI Commentary 19
ARTICLE IN PRESS
KDOQI Dyslipidemia Recommendation1]bull 2-3 months after transplantationbull 2-3 months after a change in treatment
or other conditions known to causedyslipidemias
bull at least annually thereafter1622 Evaluate KTRs with dyslipidemias for
secondary causes [Based on KDOQI Dys-lipidemia Recommendation 3]16221 For KTRs with fasting triglyc-
erides 500 mgdL (565mmolL) that cannot be cor-rected by removing an under-lying cause treat withbull Adults therapeutic lifestyle
changes and a triglyceride-lowering agent [Based onKDOQI Recommendation41]
bull Adolescents therapeutic life-style changes [Based onKDOQI Recommendation51]
16222 For KTRs with elevatedLDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)treat to reduce LDL-C to100 mgdL (259mmolL) [Based on KDOQIGuideline 42]
bull Adolescents If LDL-C130 mgdL (336 mmolL) treat to reduce LDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 52]
16223 For KTRs with normalLDL-C elevated triglyceridesand elevated non-HDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)fasting triglycerides 200mgdL (226 mmolL)and non-HDL-C 130mgdL (336 mmolL)treat to reduce non-HDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 43]
bull Adolescents If LDL-C130 mgdL (336 mmolL) fasting triglycerides200 mgdL (226 mmolL) and non-HDL-C 160mgdL (414 mmolL)treat to reduce non-HDL-C
to 160 mgdL (414 i
mmolL) [Based on KDOQIGuideline 53]
163 Tobacco Use1631 Screen and counsel all KTRs including
adolescents and children for tobacco useand record the results in the medicalrecord (Not Graded)bull Screen during initial transplant hospi-
talizationbull Screen at least annually thereafter
1632 Offer treatment to all patients who usetobacco (Not Graded)
164 Obesity1641 Assess obesity at each visit (Not Graded)
bull Measure height and weight at eachvisit in adults and children
bull Calculate BMI at each visitbull Measure waist circumference when
weight and physical appearance sug-gest obesity but BMI is 35 kgm2
1642 Offer a weight-reduction program to allobese KTRs (Not Graded)
DOQIRationale andCommentary
Hypertension
The KDIGO work group adapted the KDOQI004 recommendations for target blood pres-ure in KTRs55 Self measurement is useful inssessing response to therapy and enhancesdherence56 In general we agree that the classf antihypertensive agent does not matter inhe treatment of blood pressure elevation inhis population and that attention should beiven to potential side effects of antihyperten-ive agents as well as possible interactionsith the immunosuppressive regimen (eg non-ihydropyridine calcium channel blockers andNIs) In the absence of adequate randomizedontrolled trials it is not known whether angio-ensin-converting enzyme (ACE) inhibitors andngiotensin receptor blockers (ARBs) prolongecipient or allograft survival Some but notll retrospective studies suggest a benefitowever all these studies are limited by selec-ion bias5758 Although ACE inhibitors andRBs commonly lead to some decrease inFR treatment with these drugs should be
ontinued unless serum creatinine level in-reases by 25 to 30 in keeping withDOQI recommendations55 In KTRs receiv-
ng ACE inhibitors or ARBs it is important toducate patients to maintain adequate fluid
ntake during illness to prevent a prerenal
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ARTICLE IN PRESS
nsult to the allograft Similarly awareness isecessary when using diuretics in conjunctionith therapies that block the renin-angiotensin-
ldosterone-system59
Dyslipidemia
The KDIGO work group based their recom-endations for evaluation and treatment of
yperlipidemia on the KDOQI dyslipidemiauidelines for KTRs60 We agree with theseecommendations CNIs potentiate the toxicityf statins by slowing their metabolism throughhe cytochrome P-450 system This interactionccurs more commonly with cyclosporine61
han with tacrolimus Dyslipidemia especiallyypertriglyceridemia frequently complicatesTOR-inhibitor use and lipid-lowering therapy
s required in most patients using these agents
TobaccoUse
Not surprisingly tobacco use at the time ofransplant is associated with decreased patientnd graft survival as well as increased risk ofosttransplant cardiovascular disease (CVD)lthough the KDIGO work group recom-ends initial screening and intervention dur-
ng the hospitalization for transplant we be-ieve there may be benefit gained by startingounseling in the pretransplant period duringhe evaluation phase Unfortunately this doesot occur often because of time and personnelonstraints in transplant centers Ideally allransplant centers should have smoking-cessa-ion programs available to patients either in-ouse or through referral Ideally systemshould be created to continue to screen andonitor for smoking cessation at yearly inter-
als after transplant because there is a highate of relapse with this addiction As outlinedn KDIGO Table 253 although all pharmaco-ogic therapies for smoking cessation can besed in KTRs the starting dose of vareniclinehould be decreased in patients with GFR 30Lmin
Obesity
Obesity is an epidemic in the United Statesnd the proportion of obese kidney transplantandidates continues to grow In additioneight gain after transplant is very commonly
bserved Obesity in KTRs is associated with w
ncreased risks of wound complications de-ayed graft function acute rejection and NO-AT resulting in inferior patient and graftutcomes Attention to this potential complica-ion and counseling should be initiated duringhe pretransplant evaluation phase Informa-ion regarding pharmacologic therapies foreight loss in KTRs is not available and we
gree with the KDIGO work group that thera-eutic lifestyle measures should be encour-ged Data regarding steroid therapy with-rawal and weight gain are controversial Aecent double-blind randomized controlled trialxamining early steroid therapy withdrawalid not show a difference in weight gain at 5ears posttransplant compared with the cohortemaining on standard maintenance corticoste-oid therapy62
DIGORecommendations inChapter 17ardiovascularManagement
171 Consider managing CVD at least as intensively inKTRs as in the general population with appropri-ate diagnostic tests and treatments (Not Graded)
172 We suggest using aspirin (65-100 mgd) in allpatients with atherosclerotic CVD unless there arecontraindications (2B)
DOQIRationale andCommentary
Although outcomes are favorable comparedith remaining on the waiting list the risk of
ardiovascular mortality in KTRs is several-foldigher than observed in the general population63
specially in younger age groups and patientsith decreasing allograft function64 CVD is aajor cause of graft loss after the first post-
ransplant year In this context we strongly agreehat CVD should be managed in KTRs at least asntensively as in the general population Ideallyecreasing CVD risk in KTRs requires a multifac-ted and multidisciplinary approach Based onurrent practice models in the United States theransplant and nephrology community has notet been able to achieve these desirable goals65
his clearly deserves more attention becauseontrol of CVD has the potential to contributeore to long-term kidney graft survival than the
iscovery of newer drugs that decrease the ratef allograft rejection Our KDOQI working groupgreed with the use of low-dose aspirin in KTRs
ith evidence of atherosclerosis
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KDOQI Commentary 21
ARTICLE IN PRESS
SUMMARY OF COMMENTARY ONSECTION III CVD
COMMENTARY ON SECTION IV OF KDIGO
TRANSPLANT GUIDELINE MALIGNANCY
DIGORecommendations inChapter 18 Cancerf the Skin andLip
181 We recommend that KTRs especially thosewho have fair skin live in high sun-exposureclimates have occupations requiring sun expo-sure have had significant sun exposure as achild or have a history of skin cancer be toldthat their risk of skin and lip cancer is veryhigh (1C)
182 We recommend that KTRs minimize life-longsun exposure and use appropriate ultravioletlight blocking agents (1D)
183 We suggest that adult KTRs perform skin andlip self-examinations and report new lesions toa health-care provider (2D)
184 For adult KTRs we suggest that a qualified healthprofessional with experience in diagnosing skincancer perform annual skin and lip examinationon KTRs except possibly for KTRs with dark skinpigmentation (2D)
185 We suggest that patients with a history of skin orlip cancer or premalignant lesions be referred to andfollowed by a qualified health professional withexperience in diagnosing and treating skin cancer
With the decrease in acute rejection during the pastdecade in association with improved immunosuppres-sion regimens patient death now rivals chronic graftdysfunction as one of the leading causes of long-termgraft loss Because CVD is the most common cause ofpatient death in KTRs a concerted effort at minimizingrisk factors for heart disease likely will have as great oreven greater impact on optimizing patient and graftoutcomes than the discovery of new antirejection thera-pies CVD risk reduction strategies should include regularscreening for new-onset diabetes (using ADA-based defini-tions) in the posttransplant period in previously nondiabeticpatients good glycemic regulation for diabetic patients accord-ing to current ADA guidelines and lipid management andblood pressure control according to KDOQI recommenda-tions In addition promotion of a healthy lifestyle throughweight control exercise and smoking cessation should be acentral part of posttransplant counseling and care Whenimmunosuppression modification is being considered to miti-gate cardiovascular risk we recommend that this be inconjunction with the transplant center In summary we gener-ally concurred with the suggestions of the work group in thissection but based on current practice standards in the UnitedStateschallengesremainwith implementationof thisguideline
(2D) s
186 We suggest that patients with a history of skincancer be offered treatment with oral acitretin ifthere are no contraindications (2B)
DOQIRationale andCommentary
CounselingandSunscreen
We concur with recommendations 181 and82 because skin cancer is a major source oforbidity and sometimes mortality in KTRsarning patients at risk of the high danger of
kin cancer a 1C recommendation is reinforcedy a recent prospective case-control study ofrgan transplant recipients that showed that regu-ar use of broad-spectrum sunscreens that pro-ide UVA and UVB protection may prevent theevelopment of actinic keratosis invasive squa-ous cell carcinoma and to a lesser extent
asal cell carcinoma66 Most cancer-causing ra-iation is thought to come from the UVB spec-rum and newer broad-spectrum sunscreens pro-ide protection against UVA and UVB radiationounseling about sunscreen and the need for sunvoidance needs to be incorporated into routineffice visits although it may not always beuccessful In a recent study of KTRs in which1 of patients had been informed about theeed for sun protection only 46 used morehan a tube of sunscreen per year67
Dermatology Involvement
There is increased evidence to suggest thatpecialty dermatology clinics for organ trans-lant recipients improve outcome measures in-luding compliance with photoprotection andncreased awareness of skin cancer68 The re-ources required for these specialty clinics makemplementation difficult for community nephrol-gy groups that do not have direct access to aransplant center Transplant patients should bencouraged to have annual visits with their trans-lant center and if dermatology specialty clinicsre available attempt to coordinate a skin cancervaluation annually
UseofRetinoid-likeCompounds
There is a limited scientific basis for KDIGOuggestion recommendation 186 Although reti-oids now are used routinely in KTRs with aigh skin cancer burden our KDOQI work groupelieves that more data are needed before this
uggestion should be accepted as a guideline In
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ARTICLE IN PRESS
ow-immunologic-risk groups and particularlyifficult cases some data suggest that switchingrom CNI to sirolimus therapy may decrease thencidence of skin cancer69 however the riskersus benefit of this maneuver has not been welltudied
DIGORecommendations inChapter 19on-SkinMalignancies
191 Develop an individualized screening plan for eachKTR that takes into account the patientrsquos pastmedical and family history tobacco use compet-ing risks for death and the performance of thescreening methodology (Not Graded)
192 Screen for the following cancers as per localguidelines for the general population (Not Graded)Women cervical breast and colon cancer Menprostate and colon cancer
193 Obtain hepatic ultrasound and alpha feto-proteinevery 12 months in patients with compensatedcirrhosis (Not Graded) [See Recommendations1354 (HCV) and 1365 (HBV)]
DOQIRationale andCommentary
Screening
It is recognized that KTRs have a higher inci-ence of malignancy particularly those associatedith specific viral infections Although cancer
creening may have benefits in this higher riskopulation it should be reinforced that some meth-ds of screening have significant risks which shoulde considered on an individualized basis particu-arly in patients who have projected survival lesshan 5 years
Screening forCancer inPatientsWithHepatitis
Many patients who have underlying cirrhosisn the United States will be followed up by arofessional specializing in liver disease whoay provide additional insight into this cancer
creening recommendation Based on a recentuestionnaire of US gastroenterologists only 50creen patients for hepatocellular carcinoma70
herefore implementation of this guideline byS clinicians is unlikely to be widespread
DIGORecommendations inChapter 20anagingCancerwithReductionof
mmunosuppressiveMedication
201 We suggest consideration be given to reducingimmunosuppressive medications for KTRs with can-
cer (2C)
2011 Important factors for consideration in-clude (Not Graded)bull The stage of cancer at diagnosisbull Whether the cancer is likely to be
exacerbated by immunosuppressionbull The therapies available for the can-
cerbull Whether immunosuppressive medica-
tions interfere with ability to admin-ister the standard chemotherapy
202 For patients with Kaposi sarcoma we suggestusing mTORi along with a reduction in overallimmunosuppression (2C)
DOQIRationale andCommentary
Table 1 (Table 29 in the KDIGO report3 andxcerpted from Grulich et al71) lists cancershat are increased most in immunosuppressedTRs based on standardized incidence ratios
SIRs) which compare the incidence toatched populations Cancers with the highestIRs may be those most likely to respond to aecrease in immunosuppression Except foraposi sarcoma limited evidence is available
or a decrease in immunosuppression in theseettings A strategy to change immunosuppres-ion therapy must occur in consultation withhe transplant center Switching to sirolimusherapy and decreasing immunosuppression inatients who develop Kaposi sarcoma is basedn sound scientific rationale7273
SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
The incidence of cancer posttransplant is 2-20times higher than that in the general population andKDIGO guidelines have been written to outline stepsfor prevention and screening With few exceptions weagree with the recommendations as outlined Skincancer is common in US transplant patients andscreening and prevention are critical However imple-mentation of guidelines for doing so including theKDIGO guidelines is a challenge because of patientpreferences against the routine use of sunscreen aswell as time constraints during office visits Althoughmany posttransplant cancers are viral mediated andrelated to immunosuppression it is less clear how toalter immunosuppression after malignancy has oc-curred We agree that although age-specific screeningfor malignancy should be incorporated into care con-sideration must be given to the risk of screening inpatients with limited life spans (5 years) because of
comorbid conditions
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
ommonPopu
i sarco-Hodgmelanise sm
sophaemia
estima standa10 c
ut esti
0 case
alized t
to guide treatment specifically before the
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
REFERENCES1 McCullough KP Keith DS Meyer KH et al Kidney
nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
o2
Tf2
Tfh2
TfcM
CU1
dt
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wad6
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op
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ar
ti2
mi2
i2
uap
ba5
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cJ
sir
ml
gt1
p2
ps2
c2
p2
sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
ation Transpl Rev 200923191-19815 Abbud-Filho M Adams PL Alberuacute J et al A report
f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
A
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
cA
nrc
t2
dco9
trN
hUt
Iwa
rl5
mi8
oe1
DA
fsK
o
rN
sb2
iaT
Bt
It
ar3
tA2
hm2
EA
i2
dCA
s
aiCCSH
Bia et al30
ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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KDOQI Commentary 3
ARTICLE IN PRESS
xisting guidelines and ease of implementationorm the basis of these commentaries
Members of the KDOQI commentary workroup reached consensus on most commentariesnd have indicated when this was not the casee have relisted each KDIGO recommendation
y section with the grade for evidence support-ng it followed by our work grouprsquos rationalend commentary on the guideline If a guidelineecommendation statement was classified by theDIGO work group as important enough toecome a strong recommendation (category 1)he statement is highlighted by showing the guide-ine text in bold
COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
DIGORecommendations inChapter 1nduction Therapy
11 We recommend starting a combination of immu-nosuppressive medications before or at the timeof kidney transplantation (1A)
12 We recommend including induction therapy witha biologic agent as part of the initial immunosup-pressive regimen in KTRs (1A)121 We recommend that an IL2-RA [interleu-
kin-2 receptor antagonist] be the firstlineinduction therapy (1B)
122 We suggest using a lymphocyte-depletingagent rather than an IL2-RA for KTRs athigh immunologic risk (2B)
DOQIRationale andCommentary
It clearly is important to start immunosuppres-ion before or at the time of transplant Inductionherapy with a biologic agent such as interleukin
(IL-2) receptor antagonists or thymoglobulinecreases the frequency of acute rejection andow is used in up to 80 of US transplantenters However individual US transplant cen-ers determine immunosuppression protocolsased on their particular patient population or-an source experience ease of use and cost ofherapy Ethnic diversity of the population andhe number of high-risk patients vary in differentegions of the United States which explains inart variations in protocols used in differententers Applicability of the recommended
DIGO guidelines in this section must be inter- n
reted with these differences in mind The lastublished survey of immunosuppression use inS transplant centers was in the 2006 Organrocurement and Transplantation NetworkScien-
ific Registry of Transplant Recipients (OPTNRTR) Annual Report6 and reported on the usef calcineurin inhibitors (CNIs) mycophenolatecid compounds (MPA) mammalian target ofapamycin (mTOR) inhibitors and inductionherapy (Box 1)
Guidelines for induction therapy will be mostelevant not to community nephrologists but tohose working in transplant centers in whichnduction is used Not all patients need inductionherapy The cost of induction therapy is substan-ial and should be viewed in the context ofiskbenefit for a particular donorrecipient pro-le In the United States the use of lymphocyte-epleting antibodies (thymoglobulin and alemtuz-mab) for induction is increasing6 Many centersill use these agents in low-risk patients toinimize exposure to other maintenance drugs
ie steroids) It is unlikely that the current KDIGOuidelines recommending IL-2 receptor antago-
Box 1 2006 OPTNSRTR Annual Report
Induction Immunosuppressiona
78 used induction therapy composed ofŒ Thymoglobulin in 39Œ Interleukin 2 receptor antagonist in 28Œ Alemtuzumab in 9Œ Other in 2
22 did not receive induction therapy
Initial Immunosuppression (at discharge)
94 on CNI composed ofŒ 15 CsAŒ 79 Tac
87 on MPA 9 on mTOR inhibitor 26 steroid free
Maintenance Immunosuppression (1 year and beyond)
99 on CNI 87 on MPA 18 on mTOR inhibitors 20 steroid free
Abbreviations CNI calcineurin inhibitors CsA cyclo-porine MPA mycophenolic acid compounds mTORammalian target of rapamycin OPTNSRTR Organrocurement and Transplantation NetworkScientific Reg-
stry of Transplant Recipients Tac tacrolimusData source Andreoni et al6
ists as first-line induction therapy will alter US
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ARTICLE IN PRESS
ransplant practices in which these decisions tendo be transplant-center specific and based onactors described previously
DIGORecommendations inChapter 2 InitialndMaintenance Immunosuppressiveedications
21 We recommend using a combination of immuno-suppressive medications as maintenance therapyincluding a CNI and an antiproliferative agentwith or without corticosteroids (1B)
22 We suggest that tacrolimus be the first-line CNIused (2A)221 We suggest that tacrolimus or CsA be
started before or at the time of transplanta-tion rather than delayed until the onset ofgraft function (2D tacrolimus 2B CsA)
23 We suggest that mycophenolate be the first-lineantiproliferative agent (2B)
24 We suggest that in patients who are at low immuno-logical risk and who receive induction therapycorticosteroids could be discontinued during thefirst week after transplantation (2B)
25 We recommend that if mTOR inhibitors areused they should not be started until graftfunction is established and surgical wounds arehealed (1B)
DOQIRationale andCommentary
Initial Immunosuppression
We agree that optimum initial maintenanceherapy includes a CNI and an antiproliferativegent and that tacrolimus is the preferred CNI forost patients The Symphony Study a largeulticenter clinical trial showed that the combi-
ation of low-dose tacrolimus mycophenolateofetil (MMF) and steroids with daclizumab
nduction provided superior efficacy without theegative impact on renal function compared withither cyclosporine or a CNI-free regimen ofow-dose sirolimus78 However in a small num-er of patients other issues such as age ethnic-ty risk of new-onset diabetes mellitus and pre-ious toxicity with tacrolimus may result in thenitial use of cyclosporine Immediate CNI useas not been shown to cause a delay in renalecovery Although many centers briefly hold orodify the CNI dose in the setting of delayed
raft function especially when using antilympho-yte-depleting induction agents treatment withhese drugs should be initiated before or at theime of discharge from the hospital and not
ithheld because of delayed graft function As m
tated mycophenolate compounds (MMF andycophenolate sodium) are used as the initial
ntiproliferative agent of choice in most USransplant centers
SteroidTherapyDiscontinuation
Steroid sparing with discontinuation withinhe first few weeks after transplant has gainedidespread acceptance in the United States withore than 25 of patients being discharged after
ransplant off steroid therapy6 Although theDOQI work group agreed that steroid therapy
ould be discontinued in low-risk patients afternduction therapy we did not think that thisuggestion should be accepted as a universaluideline for several reasons Although short-nd medium-term results in corticosteroid therapyiscontinuation protocols show equivalent pa-ient and graft survival there may be a price toay in the long term Acute rejection rates areigher in well-designed randomized clinical tri-ls of steroid withdrawal In addition the pres-nce of chronic interstitial fibrosis and tubulartrophy may be greater in corticosteroid-freeatients portending decreased long-term graftunction The heterogeneity of the US donor andecipient population may have a role in thisssue Newer transplant regimens decrease pred-isone dosage to 5 mgd Apart from less boneisease the potential metabolic benefits of corti-osteroid-free protocols versus 5 mgd seem toe less significant What is clear is that discontinu-tion of steroid therapy early after transplanteems to be associated with less risk of rejectionhan discontinuation of steroids later (1 year)t should be noted that there are no studies ofifferent times in the first year to determine whenorticosteroid therapy can be discontinued safelyn some centers steroid therapy discontinuations accomplished up to 6 months posttransplantate discontinuation of steroid therapy (1 yearosttransplant) is no longer recommended andorms the basis of KDIGO guideline 25 withhich we agree It also must be emphasized that
teroid therapy withdrawal should be performednly when there is close frequent monitoring ofhe patient
EarlyUseofmTOR Inhibitors
Sirolimus and everolimus (agents known as
TOR inhibitors) delay wound healing prolong
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elayed graft function and are no longer used inhe early posttransplant period (KDIGO recom-endation 25) Furthermore studies show an
ncreased rejection rate with early use of theseompounds in place of CNIs The Symphonytudy showed that the highest rejection rateccurred in the arm using low-dose sirolimusith MMF and steroids78
DIGORecommendations inChapter 3ong-termMaintenance Immunosuppressiveedications
31 We suggest using the lowest planned doses ofmaintenance immunosuppressive medications by2-4 months after transplantation if there has beenno acute rejection (2C)
32 We suggest that CNIs be continued rather thanwithdrawn (2B)
32 If prednisone is being used beyond the first weekafter transplantation we suggest prednisone becontinued rather than withdrawn (2C)
DOQIRationale andCommentary
Decreasing ImmunosuppressiveDosage
Although our work group agreed with sugges-ion 31 we stress that dosing of immunosuppres-ion should at all times take into account thendividual patientrsquos risk profile balancing rejec-ion with the adverse effects of medications Inome patients this may mean higher drug dosingrug levels to account for a higher risk of rejec-ion Although most US transplant centers nowtrive for a lower dose of immunosuppressiveedication after the early posttransplant period
he transplant center should define each patientrsquosarget drug dosing based on immunologic riskhich depends on ethnicity age history of previ-us transplant and level of HLA antibodies
ContinueorWithdrawCNITherapy
Although we agreed that mTOR inhibitorshould not be used in the early posttransplanteriod78 newer clinical trials have exploredwitching from CNIs to mTOR inhibitors 3-6onths posttransplant910 Early results suggest
elative safety with improvement in renal func-ion Whether the trade-off of less nephrotoxic-ty with a different side-effect profile of mTORnhibitors will be beneficial in the long termemains to be determined The work groupelieved that suggestion 32 to continue CNI
herapy indefinitely in all patients required
ore study before it could be accepted as auideline
SteroidTherapyWithdrawal
We agree that late steroid therapy with-rawal (1 year) is inadvisable but stress thathe definition of ldquoearlyrdquo steroid discontinua-ion has not been well defined and may occurfter the first week (see commentary underhapter 2)
DIGORecommendations inChapter 4trategies toReduceDrugCosts
41 If drug costs block access to transplantation astrategy to minimize drug costs is appropriateeven if use of inferior drugs is necessary to obtainthe improved survival and quality of life benefitsof transplantation compared with dialysis (NotGraded)411 We suggest strategies that may reduce drug
costs includebull limiting use of a biologic agent for
induction to patients who are high-riskfor acute rejection (2C)
bull using ketoconazole to minimize CNIdose (2D)
bull using a nondihydropyridine CCB to mini-mize CNI dose (2C)
bull using azathioprine rather than mycophe-nolate (2B)
bull using adequately tested bioequivalent ge-neric drugs (2C)
bull using prednisone long-term (2C)
42 Do not use generic compounds that have not beencertified by an independent regulatory agency tomeet each of the following criteria when comparedto the reference compound (Not Graded)bull contains the same active ingredientbull is identical in strength dosage form and route of
administrationbull has the same use indicationsbull is bioequivalent in appropriate bioavailability
studiesbull meets the same batch requirements for identity
strength purity and qualitybull is manufactured under strict standards
43 It is important that the patient and the clinicianresponsible for the patientrsquos care be made aware ofany change in a prescribed immunosuppressivedrug including a change to a generic drug (NotGraded)
44 After switching to a generic medication that ismonitored using blood levels obtain levels andadjust the dose as often as necessary until a stable
therapeutic target is achieved (Not Graded)
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DOQIRationale andCommentary
Drug costs are becoming an increasing issue inransplantation that impacts on patient adherencend ultimately affects graft survival Currently im-unosuppressive drugs in the United States are
overed by the Centers for Medicare amp Medicaidervices (CMS) the primary insurer for manyTRs for 3 years after transplant although legisla-
ion is being considered to continue this coverageor the life of the kidney Most KTRs are usingany other medications in addition to immunosup-
ressive drugs In general the transplant commu-ity (patients health care providers and policyakers) need to embrace the concept of cost con-
ainment and the risk(s) to the patient and graft byhese measures However this needs to be balancedy who benefits and how much risk is at stake
Use of drugs that block the cytochrome P-450A system in an attempt to decrease CNIosing and costs are rarely used in the Unitedtates The concern is that inadvertent cessa-
ion of treatment with these drugs causing aignificant decrease in drug levels could resultn an acute rejection episode Therefore theork group did not think that many of the 411
uggestions should be accepted as a guidelinewitching from a mycophenolate compound ton azathioprine compound in the later posttrans-lant period may be considered in some pa-ients as another cost-saving maneuver espe-ially in view of recent US registry datahowing similar long-term survival with theserugs11 Although we agree with the sugges-ions outlined in 42 it should be recognizedhat many generic formulations have nevereen tested in transplant patients Patient con-usion with medications when a different ge-eric formulation or even different strengths ofhe same drug from different manufacturers isispensed at each refill can lead to inadvertentedication errors possibly affecting out-
omes Patient education is crucial to avoidrrors in medication administration We agreeith recommendation 44 that it is crucial toonitor patients after an immunosuppressive
osage change brand change or change to aeneric drug However it needs to be recog-ized that implementation of this guideline canecome burdensome as practices become inun-
ated with inquiries from patients payors and 5
harmacies regarding medications Transplantenters and practices that see many transplantatients bear an inordinate part of this burden
DIGORecommendations inChapter 5onitoring ImmunosuppressiveMedications
51 We recommend measuring CNI blood levels(1B) and suggest measuring at leastbull every other day during the immediate postopera-
tive period until target levels are reached (2C)bull whenever there is a change in medication or
patient status that may affect blood levels (2C)bull whenever there is a decline in kidney function that
may indicate nephrotoxicity or rejection (2C)511 We suggest monitoring CsA using 12-h
trough (C0) 2-h post-dose (C2) or abbrevi-ated AUC (2D)
512 We suggest monitoring tacrolimus using12-h trough (C0) (2C)
52 We suggest monitoring MMF levels (2D)53 We suggest monitoring mTOR inhibitor levels (2C)
DOQIRationale andCommentary
Because immunosuppressive drugs are classi-ed as narrow therapeutic agents drug-levelonitoring is a necessary tool to maximize effi-
iency and minimize toxicity The blood drugevel is not synonymous with level of immuno-uppression but may correlate imperfectly withhis effect In most US transplant centers levelsf CNI and mTOR inhibitors are monitoredPA monitoring is problematic because of the
oor correlation between trough levels and areander the curve (AUC) exposure Optimal moni-oring of MPA requires a 4- to 6-hour abbrevi-ted AUC measurement which is logisticallyifficult in the outpatient setting Although stud-es show that monitoring MPA levels in the earlyosttransplant period may be helpful in cyclospor-ne-treated patients recent evidence suggests thatuch monitoring may be less important in pa-ients on tacrolimus therapy12 With most USTRs now being started on tacrolimus as theNI of choice MPA monitoring is not routine inany US transplant centers Although one per-
on in our work group believed there may still beome value in monitoring MPA levels the otherembers questioned the value and applicability
f this practice (KDIGO suggestion 52) Cur-ently many US centers measure MPA only inhe setting of possible drug-related toxicities oride effects Although we agree with suggestion
3 to monitor mTOR inhibitor levels it should
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KDOQI Commentary 7
ARTICLE IN PRESS
e appreciated that therapeutic levels of thisgent have yet to be defined in controlled studies
DIGORecommendations inChapter 6reatment ofAcuteRejection
61 We recommend biopsy before treating acuterejection unless the biopsy will substantiallydelay treatment (1C)
62 We suggest treating subclinical and borderline acuterejection (2D)
63 We recommend corticosteroids for the initialtreatment of acute cellular rejection (1D)631 We suggest adding or restoring maintenance
prednisone in patients not on steroids whohave a rejection episode (2D)
632 We suggest using lymphocyte-depleting anti-bodies or OKT3 [muromonab-CD3] for acutecellular rejections that do not respond tocorticosteroids and for recurrent acute cellu-lar rejections (2C)
64 We suggest treating antibody-mediated acute rejec-tion with one or more of the following alternativeswith or without corticosteroids (2C)bull plasma exchangebull intravenous immunoglobulinbull anti-CD20 antibodybull lymphocyte-depleting antibody
65 For patients who have a rejection episode wesuggest adding mycophenolate if the patient is notreceiving mycophenolate or azathioprine or switch-ing azathioprine to mycophenolate (2D)
DOQIRationale andCommentary
We concur that biopsies should be performed onll KTRs suspected of having an acute rejectionrecommendation 61) Expert interpretation of theiopsy specimen by pathologists accustomed toeading kidney transplant biopsies is as importants expertise in performing the biopsy It is contro-ersial whether subclinical and borderline rejec-ions should be treated (recommendation 62 sup-orted by low evidence [2D]) Subclinical rejectionsre diagnosed in patients who have protocol biop-ies performed by design not for deterioration inidney function Recent data suggest that the riskf subclinical rejection in patients on tacrolimusnd mycophenolate compound therapy is so lowhat protocol biopsies may no longer be indi-ated13 Whether this is true in patients with highmmunologic risk or patients on minimization pro-ocols (ie steroid-free protocols or lower CNI doses)s uncertain Whether borderline rejection shoulde treated or some infiltrates may be protective also
s uncertain In most US centers steroids are used d
ost frequently as first-line treatment for acuteejection followed by lymphocyte-depleting anti-odies in steroid-resistant rejection but there maye exceptions to this approach Decision makingegarding appropriate initial treatment for acuteejection should be based on clinical and patho-ogic information Timing of the rejection episodeosttransplant type of induction agent used beforeejection degree of deterioration in kidney functiont the time of rejection and histologic grade of theejection may influence selection of the appropriatenitial antirejection therapy There is increasingecognition of the role of antibody-mediated mecha-isms in acute rejection This process requirespecial blood tests (to detect donor-specific antibod-es) and histochemical stains (immunofluorescenceor C4d) for diagnosis14 Coordination with theransplant center is critical to ensure that all appro-riate testing is performed and specific treatment isnitiated After treatment of an acute episode opti-
izing overall immunosuppression is requiredonsiderations should include changing the CNIdding a mycophenolate compound or increasinghe dose adding corticosteroids to previously ste-oid-free regimens or addingsubstituting an mTORnhibitor More than 85 of patients are alreadysing MPA agents so the number available forwitching will be relatively small
DIGORecommendations inChapter 7reatment of ChronicAllograft Injury (CAI)
71 We recommend kidney allograft biopsy for allpatients with declining kidney function of unclearcause to detect potentially reversible causes (1C)
72 For patients with CAI and histological evidence ofCNI toxicity we suggest reducing withdrawing orreplacing the CNI (2C)721 For patients with CAI eGFR 40 mLmin
173 m2 and urine total protein excretion500 mgg creatinine (or equivalent protein-uria by other measures) we suggest replac-ing the CNI with a mTOR inhibitor (2D)
DOQIRationale andCommentary
We agree with the need for kidney transplantiopsy in patients with decreasing kidney function71) and again stress the importance of expertise inathologic interpretation Important causes ofhronic allograft injury (CAI) which include rejec-ion BK nephropathy CNI toxicity or recurrentisease require special histochemical stains for
iagnosis that are not readily available in all labora-
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ARTICLE IN PRESS
ories Therefore coordination with the transplantenter where these techniques are available is essen-ial For patients with CAI caused by CNI toxicityithdrawing the CNI should occur only after at-
empts at decreasing the dosage have failed Onelso must ensure that all other causes of CAI arexcluded to avoid inappropriate drug adjustmentsr missed treatment options Although our workroup thought that KDIGO suggestion 721 maye reasonable in some patients we also want tomphasize that the role of mTOR inhibitors in thereatment of CAICNI toxicity is poorly defined Its clear that switching from a CNI to an mTORnhibitor should be avoided in patients with se-erely decreased glomerular filtration rate (GFR)ndor the presence of proteinuria however the exactuidelines for when to switch are still evolving
SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
DIGORecommendations inChapter 8onitoringKidneyAllograft Function
81 We suggest measuring urine volume (2C)bull Every 1-2 hours for at least 24 hours after
transplantation (2D)
In the United States immunosuppressive protocolsused may vary from center to center based on theirparticular patient population organ source experienceand opinion of the transplant team ease of use and costof therapy Although data about the efficacy and safety ofsteroid-free regimens are still evolving it is clear that ifsteroids are to be eliminated this should be done in theearly transplant period and not late (after 1 year)Community nephrologists need to coordinate any alter-ations in immunosuppressive medications with the trans-plant center and be vigilant for potential drug interactionswith the addition of any new medications Drug monitor-ing is an essential monitoring tool throughout the post-transplant course but not always applicable to everyimmunosuppressive medication Transplant biopsies fre-quently are necessary to determine the cause of renaldysfunction and the interpretation must be performed bypathologists with resources and experience in handlingand reading the transplant biopsy specimen
bull Daily until graft function is stable (2D) c
82 We suggest measuring urine protein excretion (2C)at leastbull Once in the first month to determine a baseline
(2D)bull Every 3 months during the first year (2D)bull Annually thereafter (2D)
83 We recommend measuring serum creatinine (1B) atleastbull Daily for 7 days or until hospital discharge
whichever occurs sooner (2C)bull 2-3 times per week for weeks 2-4 (2C)bull Weekly for months 2 and 3 (2C)bull Every 2 weeks for months 4-6 (2C)bull Monthly for months 7-12 (2C)bull Every 2-3 months thereafter (2C)
831 We suggest estimating GFR whenever se-rum creatinine is measured (2D) usingbull One of several formulas validated for
adults (2C) orbull The Schwartz formula for children and
adolescents (2C)
84 We suggest including a kidney allograft ultrasoundexamination as part of the assessment of kidneyallograft dysfunction (2C)
DOQIRationale andCommentary
RoutineScreeningTestsandTimeandFrequencyofMonitoring
Regular surveillance and vigilant monitoring ofidney allograft function are important in improv-ng short- and long-term outcomes Early detectionf kidney allograft dysfunction will allow timelyiagnosis and treatment that may improve patientnd graft survival Frequency and types of routinecreening tests after kidney transplant are shown inig 2Although there is no standard protocol for therequency and type of monitoring recommenda-ions are guided by the likelihood of problemspecific to the particular transplant population Inhe early posttransplant period when rejection andomplications are the most likely testing is per-ormed more frequently Thereafter the follow-upnterval will depend in part on the patientrsquos generalondition and the development of additional prob-ems The AST recommended routine posttrans-lant 2-3 visits per week during month 1 every 1-3eeks during month 2-3 every 4-8 weeks duringonths 4-12 and every 2-4 months after therst year These early visits often are providedy the transplant physician or surgeon of theransplant center After 3-6 months monitor-ng may be performed by the transplant physi-
ian or community nephrologist15 In a recent
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KDOQI Commentary 9
ARTICLE IN PRESS
urvey of posttransplant outpatient visits inedicare beneficiaries in the United States
requency of visits to transplant centers variedy center and region most visits were toephrologists16
At each clinic visit education regardingedication adherence diet and healthy life-
tyle should be given Screening for tobaccose should be implemented before dischargend annually Although the work group did notgree that screening all adults for Epstein-Barrirus (EBV) was of value (see commentarynder Chapter 13 for EBV) screening for allther elements listed in Fig 2 including screen-ng for proteinuria is reasonable In additiono these tests monitoring for HLA antibodiesgainst the donor (donor-specific antibodies)hich is not described in the KDIGO guide-
ine is becoming more common in some USenters The optimal timing and frequency ofuch screening has yet to be determined1718
SerumCreatinineandEstimatedGFR
Serum creatinine measurement remains theost commonly used index of renal allograft
unction It is reliable for detecting acute changesn kidney function Furthermore serum creati-ine level at year 1 after transplant is a riskactor for subsequent outcomes19 and mayelp in the management of the frequency ofisits However it is less reliable for detecting
Figure 2 Routine screen-ng after kidney transplantomplete blood cell count in-ludes white blood cells hemo-lobin and platelets Screenor diabetes is by fasting bloodlucose level glucose toler-nce test or hemoglobin A1c
evel Lipid profile includes fast-ng cholesterol low-density li-oprotein cholesterol high-ensity lipoprotein cholesterolnd triglyceride levels Screensor BK polyoma virus (BKV)nd Epstein-Barr virus (EBV)se plasma nucleic acid test-
ng (NAT) EBV screen is foratients with no antibody toBV at transplant Adapted
rom the KDIGO transplantuideline3 with permission ofDIGO
ong-term changes in kidney function in the
idney transplant recipient Formulas to esti-ate GFR using serum creatinine values have
een tested in KTRs but no formula consis-ently has been shown to be superior to an-ther As with CKD considerable renal patho-ogic states can be present without dramatichanges in serum creatinine levels
In 2005 the definition of CKD was amendedo include all KTRs regardless of markers ofidney damage or GFR2021 Although the workroup agreed that CKD staging in KTRs isseful it must be noted that there is consider-ble difference in the rate of progression inhese 2 groups Progression is much slower inTRs in whom kidney half-life is longer at
very level of CKD Renal ultrasound is thereferred imaging study in KTRs (KDIGOuggestion 84)22
DIGORecommendations inChapter 9 Kidneyllograft Biopsy
91 We recommend kidney allograft biopsy whenthere is a persistent unexplained increase inserum creatinine (1C)
92 We suggest kidney allograft biopsy when serumcreatinine has not returned to baseline after treat-ment of acute rejection (2D)
93 We suggest kidney allograft biopsy every 7-10 daysduring delayed function (2C)
94 We suggest kidney allograft biopsy if expectedkidney function is not achieved within the first 1-2months after transplantation (2D)
95 We suggest kidney allograft biopsy when there is
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ARTICLE IN PRESS
bull New onset of proteinuria (2C)bull Unexplained proteinuria 30 g per gram creati-
nine or 30 g per 24 hours (2C)
DOQIRationale andCommentary
Biopsy
Renal allograft biopsy is the gold standard foriagnosing the cause of a change in renal allo-raft function It is useful in all clinical situationsescribed in KDIGO suggestions 91-94 Poten-ial causes of allograft dysfunction include vol-me depletion compromised renal blood flowrinary outflow obstruction parenchymal causesuch as acute rejection (cellular andor humoral)hronic allograft nephropathy recurrent or deovo disease or BK nephropathy Patients show-ng a 20-25 increase in creatinine level aboveaseline values warrant consideration for biopsyther indications for pursuing renal allograftiopsy would be a less-than-expected responseo treatment of acute rejection The expectedesponse would be dependent on the severity ofissue injury noted on the diagnostic biopsy speci-
en Delayed graft function lasting longer than-7 days warrants biopsy with repeated biopsieserformed every 7-10 days until graft functionecovers New-onset proteinuria protein 20g creatinine or 20 g24 h also merits aidney biopsy De novo and recurrent glomerulariseases are common causes of new-onset pro-einuria Patients with de novo or recurrent glo-erular diseases should be followed up closely
y transplant nephrologists or community neph-ologists with close communication with theransplant center because treatment of some recur-ent kidney diseases may prevent or delay thenset of graft failure2324
SafetyandAccuracy
The safety of kidney transplant biopsies haseen documented and the overall risk of compli-ations is low Most biopsies are performed inhe transplant center by transplant nephrologistsommunity nephrologists also may perform bi-psies of the kidney in KTRs more than a yearosttransplant It is prudent to obtain a diagnosticltrasound before biopsy to rule out unexpectedlterations in blood flow or urinary tract obstruc-ion It is imperative that a pathologist familiar
ith the transplant process interprets the pathol-
gy in consultation with the referring nephrolo-ist using appropriate stains and other studies
MolecularMarkers
In addition to conventional histopathologicxamination several US transplant centers aresing molecular markers as well as genomic orroteomic methods to enhance our understand-ng of the mechanism of immunologic and non-mmunologic pathway of injury As an exampleolymerase chain reaction (PCR) has been usedo detect messenger RNA for IL-2 and otheriomarkers in biopsy samples Using this ap-roach IL-2 upregulated during rejection coulde detected 2 days before rejection was apparentsing histologic or clinical criteria Such PCRpproaches have been used to detect other generoducts upregulated during acute rejection suchs granzyme B perforin transforming growthactor IL-10 and IL-1525-27 These newerethods are performed almost exclusively in
ransplant centers and may become a standardethod of transplant biopsy analysis in the fu-
ure
DIGORecommendations inChapter 10ecurrentDisease
101 We suggest screening KTRs with primary kidneydisease caused by FSGS for proteinuria (2C) atleastbull Daily for 1 week (2D)bull Weekly for 4 weeks (2D)bull Every 3 months for the first year (2D) Every
year thereafter (2D)
102 We suggest screening KTRs with potentially treat-able recurrence of primary kidney disease fromIgA nephropathy MPGN anti-GBM disease orANCA-associated vasculitis for microhematuria(2C) at leastbull Once in the first month to determine a baseline
(2D)bull Every 3 months during the first year (2D)
Annually thereafter (2D)
103 During episodes of graft dysfunction in patientswith primary HUS we suggest screening forthrombotic microangiopathy (eg with plateletcount peripheral smear for blood cell morphologyplasma haptoglobin and serum lactate dehydroge-nase) (2D)
104 When screening suggests possible treatable recur-rent disease we suggest obtaining an allograftbiopsy (2C)
105 Treatment of recurrent kidney disease1051 We suggest plasma exchange if a biopsy
shows minimal change disease or FSGS
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KDOQI Commentary 11
ARTICLE IN PRESS
in those with primary FSGS as theirprimary kidney disease (2D)
1052 We suggest high-dose corticosteroids andcyclophosphamide in patients with recur-rent ANCA-associated vasculitis or anti-GBM disease (2D)
1053 We suggest using an ACE-I [ACE inhibi-tor] or an ARB for patients with recurrentglomerulonephritis and proteinuria (2C)
1054 For KTRs with primary hyperoxaluriawe suggest appropriate measures to pre-vent oxalate deposition until plasma andurine oxalate levels are normal (2C)includingbull Pyridoxine (2C)bull High calcium and low oxalate diet
(2C)bull Increased oral fluid intake to enhance
urinary dilution of oxalate (2C)bull Potassium or sodium citrate to alkalin-
ize the urine (2C)bull Orthophosphate (2C)bull Magnesium oxide (2C)bull Intensive hemodialysis to remove ox-
alate (2C)
DOQIRationale andCommentary
Recurrent disease accounts for a substantialmount of graft loss after renal transplant It isifficult to assess the percentage of grafts lost toecurrent disease because many patients presentith end-stage renal disease without benefit of aiagnostic native renal biopsy The likelihood ofecurrent disease after transplant is dependent onhe disease with certain diseases at particularlyigh risk of recurrence28
Recurrent Focal SegmentalGlomerulosclerosis
We agree with recommendation 101 regard-ng frequent and regular screening for protein-ria in patients with primary focal segmentallomerulosclerosis (FSGS) as the cause of end-tage renal disease If the patient is still produc-ng urine at the time of transplant a preoperativerine protein-creatinine ratio can be a very help-ul baseline measure of proteinuria Early detec-ion of FSGS recurrence which can present withormal light microscopy but foot-process efface-ent on electron microscopy29 provides the best
pportunity for intervention and amelioration ofisease
IgANephropathy
Recurrence rates of immunoglobulin A (IgA)
ephropathy are variable We agree with recom- b
endation 102 for screening routinely for micro-ematuria Recurrent disease is confirmed with aenal allograft biopsy Histologic recurrence ofisease is much more common than is clinicalisease recurrence There is no proven therapyor treatment of recurrent disease30
MembranoproliferativeGlomerulonephritis
Recurrence of membranoproliferative glomer-lonephritis (MPGN) is common as high as 80ith MPGN type II (dense-deposit disease) Theost common cause of MPGN type I is hepatitisndashassociated immune complex formation Wegree with the proposed regularly scheduledcreening for microhematuria and proteinuria inecommendation 102 Patients with known hepa-itis Cndashassociated MPGN pretransplant also maye screened for cryoglobulins which are associ-ted with MPGN31
HemolyticUremic Syndrome
Hemolytic uremic syndrome (HUS) typicallys divided into diarrheal associated (D) andonndashdiarrheal associated (D) D disease oc-urs mostly in children and rarely recurs post-ransplant However D HUS is more commonn adults and can recur In HUS associated with aomplement abnormality such as factor H defi-iency or factor I mutation recurrence rates cane as high as 80 Screening for evidence ofecurrence allows for an earlier diagnosis whichill require biopsy in most cases and provides
n opportunity for earlier intervention There iso comment in the guideline regarding recur-ence of thrombotic thrombocytopenic purpuraut early detection of recurrence provides anpportunity for treatment with plasmapheresisnd intravenous immune globulin (IVIG)
BiopsyandTreatment
As stated kidney biopsy and interpretation bypathologist with expertise in transplant speci-en readings is critical in the diagnosis of dis-
ase recurrence Treatment for most recurrentisease in renal transplantation is based on aombination of case reports case cohorts andetrospective reviews Recurrent diseases post-ransplant are not common enough that random-zed controlled trials can be implemented there-ore most recommendations for treatment are
ased on a consensus of opinion Despite this we
at
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Bia et al12
ARTICLE IN PRESS
gree in general with the recommendations de-ailed in 105
DIGORecommendations inChapter 11reventingDetecting andTreatingonadherence
111 Consider providing all KTRs and family memberswith education prevention and treatment mea-sures to minimize nonadherence to immunosup-pressive medications (Not Graded)
112 Consider providing KTRs at increased risk fornonadherence with increased levels of screeningfor nonadherence (Not Graded)
DOQIRationale andCommentary
Noncompliance or nonadherence to diet andedication is a common problem in KTRs Nonad-
erence to medication is associated with a high riskf acute rejection and allograft loss We agree thatarly efforts should be made to identify KTRs atncreased risk of nonadherence and that these pa-ients should be monitored closely Prevention iden-ification and treatment of nonadherence are inte-ral to the monitoring of kidney allograft functionnd long-term care of KTRs Certain subgroup ofTRs younger patients African Americans and
hose with financial hardships have an enhancedisk of nonadherence3233
In addition to identifying patients at risk it ismportant to have a system for addressing patientonadherence This requires coordinated efforts ofocial workers transplant coordinators financialounselors pharmacists primary nephrologists andhe patientrsquos family34 A combination of educa-ional behavioral and social support interventionsrovides the best results Because there is no per-ect measure of adherence consideration should beiven to multiple approaches for adherence moni-oring Similar team approaches also are importantn other areas requiring adherence such as dietxercise tobacco alcohol and drug use
DIGORecommendations inChapter 12accination
121 We recommend giving all KTRs approvedinactivated vaccines according to recommendedschedules for the general population except forHBV vaccination (1D)1211 We suggest HBV vaccination (ideally
prior to transplantation) and HBsAb titers6-12 weeks after completing the vaccina-
tion series (2D) h
12111 We suggest annual HBsAb[antibody to hepatitis B sur-face antigen] titers (2D)
12112 We suggest revaccination ifthe antibody titer falls below10 mIUmL (2D)
122 We suggest avoiding live vaccines in KTRs (2C)123 We suggest avoiding vaccinations except influ-
enza vaccination in the first 6 months followingkidney transplantation (2C)1231 We suggest resuming immunizations once
patients are receiving minimal mainte-nance doses of immunosuppressive medi-cations (2C)
1232 We recommend giving all KTRs whoare at least 1-month post-transplantinfluenza vaccination prior to the onsetof the annual influenza season regard-less of status of immunosuppression(1C)
124 We suggest giving the following vaccines to KTRswho due to age direct exposure residence ortravel to endemic areas or other epidemiologicalrisk factors are at increased risk for the specificdiseasesbull rabies (2D)bull tick-borne meningoencephalitis (2D)bull Japanese B encephalitismdashinactivated (2D)bull Meningococcus (2D)bull Pneumococcus (2D)bull Salmonella typhimdashinactivated (2D)1241 Consult an infectious disease specialist a
travel clinic or public health official forguidance on whether specific cases war-rant these vaccinations (Not Graded)
DOQIRationale andCommentary
KTRs are at particular risk of viral infectionsecause of the preferential suppression of T lympho-ytes by both induction and maintenance immuno-uppression The risk and consequence of develop-ng a viral infection warrant use of selected vaccineshe suggestions regarding which vaccines are safend which are contraindicated are based on whetherhe vaccine contains live or killed virus Live virusaccines are contraindicated in immunosuppressedTRs The KDIGO recommendations for vaccina-
ions agree with updated guidelines recently pub-ished by the AST35 Specific comments on theDIGO suggestions regarding vaccinations are
isted in the following sections
Hepatitis B
The work group did not concur with KDIGOuggestion 1211 Neither revaccination against
epatitis after transplant nor following up hepa-
tpapsipapc
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KDOQI Commentary 13
ARTICLE IN PRESS
itis B antibody titers annually is a commonractice in the United States Hepatitis B is nots prevalent in the United States as in otherarts of the world and evidence supportingcreening in all patients posttransplant is lack-ng However screening for seroconversion inatients at risk (receiving a hepatitis B corentibodyndashpositive kidney) is appropriate Theseatients may benefit from lamivudine or ente-avir therapy36
LiveVaccineandTimingofVaccine
There is no particular reason for a 6-monthag between transplant and vaccination Theheory is that vaccines are less likely to beffective in the period when immunosuppres-ion is high In the United States most individu-ls are on their baseline maintenance immuno-uppression therapy by 3 months posttransplantecisions regarding the timing of vaccines areade based on immunosuppression exposure
nd risk of infection Recipients also shouldvoid intimate contact with individuals whoave received live vaccines37 This includesvoiding close contact with children who haveeceived oral polio vaccine for 3 weeks anday include close contact with adults receiv-
ng the attenuated varicella vaccine to preventoster Immunosuppressed individuals are ad-ised to avoid contact for 7 days with individu-ls who have received live virus nasal spraysor influenza We concur with the recommenda-ion for flu vaccine but common practice inhe United States is to wait 3-6 months afterransplant before it is administered
DIGORecommendations inChapter 13 Viraliseases
131 BK POLYOMA VIRUS1311 We suggest screening all KTRs for BKV
with quantitative plasma NAT (2C) atleastbull monthly for the first 3-6 months after
transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull whenever there is an unexplained rise
in serum creatinine (2D)bull and after treatment for acute rejection
(2D)1312 We suggest reducing immunosuppressive
medications when BKV plasma NAT is
persistently greater than 10 000 cop-iesmL (107 copiesL) (2D)
132 CYTOMEGALOVIRUS1321 CMV prophylaxis We recommend that
KTRs (except when donor and recipi-ent both have negative CMV serolo-gies) receive chemoprophylaxis forCMV infection with oral ganciclovir orvalganciclovir for at least 3 monthsafter transplantation (1B) and for 6weeks after treatment with a T-cellndashdepleting antibody (1C)
1322 In patients with CMV disease we suggestweekly monitoring of CMV by NAT orpp65 antigenemia (2D)
1323 CMV treatment13231 We recommend that all pa-
tients with serious (includ-ing most patients with tissueinvasive) CMV disease betreated with intravenousganciclovir (1D)
13232 We recommend that CMVdisease in adult KTRs that isnot serious (eg episodes thatare associated with mildclinical symptoms) be treatedwith either intravenous gan-ciclovir or oral valganciclo-vir (1D)
13233 We recommend that allCMV disease in pediatricKTRs be treated with intra-venous ganciclovir (1D)
13234 We suggest continuing therapyuntil CMV is no longer detect-able by plasma NAT or pp65antigenemia (2D)
1324 We suggest reducing immunosuppressivemedication in life-threatening CMV dis-ease and CMV disease that persists in theface of treatment until CMV disease hasresolved (2D)13241 We suggest monitoring graft
function closely during CMVdisease (2D)
133 EPSTEIN-BARR VIRUS AND POST-TRANS-PLANT LYMPHOPROLIFERATIVE DISEASE1331 We suggest monitoring high-risk (donor
EBV seropositiverecipient seronegative)KTRs for EBV by NAT (2C)bull once in the first week after transplanta-
tion (2D)bull then at least monthly for the first 3-6
months after transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull and additionally after treatment for
acute rejection (2D)
Bia et al14
ARTICLE IN PRESS
1332 We suggest that EBV-seronegative pa-tients with an increasing EBV load haveimmunosuppressive medication reduced(2D)
1333 We recommend that patients with EBVdisease including PTLD have a reduc-tion or cessation of immunosuppres-sive medication (1C)
134 HERPES SIMPLEX VIRUS 1 2 AND VARI-CELLA ZOSTER VIRUS1341 We recommend that KTRs who de-
velop a superficial HSV 1 2 infectionbe treated (1B) with an appropriateoral antiviral agent (eg acyclovir vala-cyclovir or famciclovir) until all le-sions have resolved (1D)
1342 We recommend that KTRs with sys-temic HSV 1 2 infection be treated(1B) with intravenous acyclovir and areduction in immunosuppressive medi-cation (1D)13421 We recommend that intrave-
nous acyclovir continue un-til the patient has a clinicalresponse (1B) then switch toan appropriate oral antiviralagent (eg acyclovir valacy-clovir or famciclovir) to com-plete a total treatment durationof 14-21 days (2D)
1343 We suggest using a prophylactic antiviralagent for KTRs experiencing frequentrecurrences of HSV 12 infection (2D)
1344 We recommend that primary VZV infec-tion (chicken pox) in KTRs be treated(1C) with either intravenous or oral acy-clovir or valacyclovir and a temporaryreduction in amount of immunosuppres-sive medication (2D)
135 HEPATITIS C VIRUS1351 We suggest that HCV-infected KTRs be
treated only when the benefits of treat-ment clearly outweigh the risk of allo-graft rejection due to interferon-basedtherapy (eg fibrosing cholestatic hepati-tis life-threatening vasculitis) (2D)[Based on KDIGO Hepatitis C Recom-mendation 215]
1352 We suggest monotherapy with standardinterferon for HCV-infected KTRs inwhom the benefits of antiviral treatmentclearly outweigh the risks (2D) [Basedon KDIGO Hepatitis C Recommenda-tions 224 and 442]
1353 We suggest that all conventional currentinduction and maintenance immunosup-pressive regimens can be used in HCVinfected patients (2D) [Based on KDIGO
Hepatitis C Recommendation 43]
1354 Measure ALT in HCV-infected patientsmonthly for the first 6 months and every3-6 months thereafter Perform imagingannually to look for cirrhosis and hepato-cellular carcinoma (Not Graded) [Basedon KDIGO Hepatitis C Recommendation441] (See Recommendation 193)
1355 Test HCV-infected patients at least every3-6 months for proteinuria (Not Graded)[Based on KDIGO Hepatitis C Recom-mendation 444]13551 For patients who develop new
onset proteinuria (either urineproteincreatinine ratio 1 or24-hour urine protein 1 g ontwo or more occasions) per-form an allograft biopsy withimmunofluorescence and elec-tron microscopy (Not Graded)[Based on KDIGO Hepatitis CRecommendation 444]
1356 We suggest that patients with HCV asso-ciated glomerulopathy not receive inter-feron (2D) [Based on KDIGO HepatitisC Recommendation 445]
136 HEPATITIS B VIRUS1361 We suggest that any currently available
induction and maintenance immunosup-pressive medication can be used in HBV-infected KTRs (2D)
1362 We suggest that interferon treatmentshould generally be avoided in HBVinfected KTRs (2C)
1363 We suggest that all HBsAg-positive KTRsreceive prophylaxis with tenofovir ente-cavir or lamivudine (2B)13631 Tenofovir or entecavir are pref-
erable to lamivudine to mini-mize development of potentialdrug resistance unless medica-tion cost requires that lami-vudinebe used (Not Graded)
13632 During therapy with antivi-rals measure HBV DNA andALT levels every 3 months tomonitor efficacy and to detectdrug resistance (Not Graded)
1364 We suggest treatment with adefovir ortenofovir for KTRs with lamivudine resis-tance (5 log10 copiesmL rebound ofHBV-DNA) (2D)
1365 Screen HBsAg-positive patients with cir-rhosis for hepatocellular carcinoma every12 months with liver ultrasound andalpha feto-protein (Not Graded) (SeeRecommendation 193)
1366 We suggest that patients who are negativefor HBsAg and have HBsAb titer 10mIUmL receive booster vaccination to
raise the titer to 100 mIUmL (2D)
K
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KDOQI Commentary 15
ARTICLE IN PRESS
137 HUMAN IMMUNODEFICIENCY VIRUS1371 If not already done screen for HIV
infection (Not Graded)1372 To determine antiretroviral therapy refer
HIV-infected KTRs to an HIV specialistwho should pay special attention to drugndashdrug interactions and appropriate dosingof medications (Not Graded)
DOQIRationale andCommentary
Viral infections are particularly problematic inransplant recipients because of the preferentialnhibition of T-lymphocyte function by both induc-ion and maintenance immunosuppression Use ofnduction immunosuppression with lymphocyte-epleting agents (thymoglobulin or alemtuzumab)s associated with a greater risk of viral infectionosttransplant In general the greater the cumula-ive exposure to immunosuppression the greaterhe risk of infectious complications The presenta-ion of viral infections can be asymptomatic vaguend nonspecific or life-threatening acute illnessany viral infections seen in KTRs are rarely seen
n immunocompetent patients and therefore do notnter into the differential diagnosis for physiciansnfamiliar with transplant recipients Close commu-ication with the transplant center is crucial inaring for the transplant population Early detectionnd institution of therapy provide the best chanceor viral eradication
BKVirus
Although the work group agreed with KDIGOuggestions for BK virus screening posttransplante did not think it was practical to require screen-
ng exclusively with quantitative plasma nucleiccid testing (NAT) because many US centers usenitial urinary screening and then test plasma onlyf urine screening results are positive Howeverhere is no disagreement that some type of screen-ng for BK virus is critical to avoid BK nephropa-hy for which there is no specific treatment when its established Complicating screening for BK vi-us is the variability in results between laboratoriesnd uncertainty about the level of viremia thathould trigger a response to decrease in immunosup-ression In the presence of viremia and increase inerum creatinine level a renal allograft biopsy isndicated to confirm the presence of BK nephropa-
hy Because BK viremia and viruria certainly can b
e detected beyond the first year it is not clear howong screening should be continued posttransplantlthough most centers screen for the first year onlyngoing clinical trials are exploring effective treat-ent for BK nephropathy3839 Decisions about
ecreases in immunosuppression currently theainstay of BK viremia management always
hould be made in consultation with the transplantenter
Cytomegalovirus
KDIGO recommendation 1321 regarding cyto-egalovirus (CMV) prophylaxis is reasonable and
pplicable to the US population Universal prophy-axis for CMV now is recommended over initiatingre-emptive treatment after CMV develops40 Aajor concern for US patients is the cost of CMV
rophylaxis with oral valgancyclovir Leukopeniaan be observed in patients using mycophenolatereparations when prophylaxis with valgancyclo-ir is used Screening for CMV is best performedsing NAT methods (1322) CMV antigenemiassays are still in use in many facilities but are nots sensitive as PCR assays41 There is no utility inhecking for serologic response to CMV with IgGr IgM titers posttransplant because the immuneesponse is not predictable Patients with CMVisease should be cared for by clinicians familiarith treating this disease It is recommended that
reatment be continued until viral load is undetect-ble followed by prophylactic doses of valgancy-lovir for an additional 3 months35
Epstein-BarrVirus
Current practice regarding EBV screening variesmong centers in the United States and many doot routinely screen for EBV posttransplant evenn recipient-negative donor-positive cases In con-rast to KDIGO recommendation 1311 routineBV screening is not recommended in AST infec-
ious disease guidelines35 In many centers EBVcreening is reserved for children who are muchore commonly EBV negative pretransplant than
dults EBV-induced posttransplant lymphoprolif-rative disorder (PTLD) affects many more pediat-ic than adult KTRs If screening is someday to beoutinely implemented in US centers details regard-ng the best method of screening and levels ofiremia above which a clinical intervention should
e triggered need to be better defined
ttattt
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Bia et al16
ARTICLE IN PRESS
HerpesandVaricella
Systemic herpesvirus infections can be lifehreatening in transplant recipients and should bereated aggressively with intravenous antiviralgents as described in the KDIGO recommenda-ions Less aggressive cutaneous infection can bereated with oral antiviral agents as outlined inhe KDIGO guidelines
Varicella exposure is particularly concerning inransplant recipients The work group disputes theecommended dosing of acyclovir for varicellaxposure Acyclovir at a dose of 10 mgkg or about00 mg 4 times daily of oral acyclovir would betandard dosing We agree with the use of varicellammune globulin and emphasize the need to avoidhe varicella vaccine because it is a live virushould a transplant recipient develop a systemicaricella infection hospitalization and high-dosentravenous acyclovir therapy are warranted
Hepatitis C
Hepatitis C management posttransplant is ahallenge The KDIGO guidelines cited hereere based on the recently published KDIGOuideline for hepatitis C in CKD4 Hepatitis Cypically is not treated posttransplant because ofhe risk (50) of rejection precipitated bynterferon therapy particularly in US KTRs inhom hepatitis C commonly is genotype 1 which
s more resistant to treatment with interferon42
owever should hepatitis Cndashrelated glomerulo-ephritis develop the risk-benefit ratio may fa-or treatment in selected patients Such decisionslways should be made in consultation withepatology and infectious disease experts andhe transplant center Monitoring liver enzymeevels specifically alanine aminotransferaseALT) may reflect a change in hepatitis activityut monitoring hepatitis C viral load is not recom-ended because it does not seem to correlateith outcome Annual monitoring for hepatocel-
ular carcinoma using -fetoprotein and imagings encouraged but not often practiced
Hepatitis B
KDIGO recommendations for hepatitis B areeasonable and currently are followed in mostS centers except for recommendation 1366
see previous recommendation under vaccina-ions) KTRs with hepatitis C or hepatitis B also
hould be followed up by a hepatologist
Human ImmunodeficiencyVirus
Human immunodeficiency virus (HIV)-posi-ive individuals are now acceptable for transplantf CD4 count is 200 cellsL and viral loadVL) is undetectable3543 Transplant should beerformed at centers with expertise in managingIV-positive individuals and care should be co-rdinated carefully with HIV specialists Somentiretroviral agents in particular the proteasenhibitors have potentially serious drug interac-ions with immunosuppressive agents35
DIGORecommendations inChapter 14Othernfections
141 URINARY TRACT INFECTION1411 We suggest that all KTRs receive UTI
prophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 monthsafter transplantation (2B)
1412 For allograft pyelonephritis we suggestinitial hospitalization and treatment withintravenous antibiotics (2C)
142 PNEUMOCYSTIS JIROVECII PNEUMONIA1421 We recommend that all KTRs receive
PCP prophylaxis with daily tri-methoprimndashsulfamethoxazole for 3-6months after transplantation (1B)
1422 We suggest that all KTRs receive PCPprophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 weeksduring and after treatment for acute rejec-tion (2C)
1423 We recommend that KTRs with PCPdiagnosed by bronchial alveolar lavageandor lung biopsy be treated withhigh-dose intravenous trimethoprimndashsulfamethoxazole corticosteroids anda reduction in immunosuppressivemedication (1C)
1424 We recommend treatment with cortico-steroids for KTRs with moderate tosevere PCP (as defined by PaO2 lt70mm Hg in room air or an alveolargradient of gt35 mm Hg) (1C)
143 TUBERCULOSIS1431 We suggest that TB prophylaxis and
treatment regimens be the same in KTRsas would be used in the local generalpopulation who require therapy (2D)
1432 We recommend monitoring CNI andmTORi [mTOR inhibitor] blood levels inpatients receiving rifampin (1C)14321 Consider substituting rifabu-
tin for rifampin to minimize
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KDOQI Commentary 17
ARTICLE IN PRESS
interactions with CNIs andmTORi (Not Graded)
144 CANDIDA PROPHYLAXIS1441 We suggest oral and esophageal Candida
prophylaxis with oral clotrimazole loz-enges nystatin or fluconazole for 1-3months after transplantation and for 1month after treatment with an antilympho-cyte antibody (2C)
DOQIRationale andCommentary
UrinaryTract Infection
Urinary tract infections (UTIs) after kidneyransplant are very common and account for aarge percentage of readmissions posttransplantTIs are common because of multiple factors
ncluding the disrupted anatomy of the urinaryract with a ureteroneocystotomy incompleteladder emptying because of diabetes or pros-atic hypertrophy and impaired immune re-ponses Prophylaxis of UTIs usually is under-aken with trimethoprim-sulfamethoxazole for 6onths posttransplant although infections often
ccur despite therapy because of the develop-ent of drug resistance Although native kidney
yelonephritis does not always require hospital-zation it is recommended that all KTRs withhis diagnosis be hospitalized because the graftysfunction that usually accompanies transplantyelonephritis requires aggressive investigationnd treatment Individuals with recurrent UTIsarrant evaluation with urologic assessment Pa-
ients with recurrent UTIs may benefit fromong-term suppressive therapy
Pneumocystic Pneumonia
We agree that Pneumocystis jirovecii pneumoniaPCP) prophylaxis is important for the first 3-6onths posttransplant (1421)After the first month
very-other-day dosing of trimethoprim-sulfame-hoxazole or atovaquone is believed to be adequaterophylaxis In cases in which neither of thesegents can be used an individual may be treatedrophylactically with inhaled pentamidine OurDOQI work group emphasized that patients whoevelop PCP should be transferred to the transplantenter promptly for management and adjustmentsn immunosuppression
Tuberculosis
Monitoring for latent tuberculosis has posed a
hallenge in the immunosuppressed population be-
ause of the unreliable nature of skin testing Newerechniques involving interferon release assays aremerging as the new gold standard for detection ofatent tuberculosis4445
CandidaProphylaxis
Oral candidiasis must be screened for usingral mucosa examination on follow-up visitsn KTRs This is especially true in the earlyosttransplant period when immunosuppres-ive medication dosage is the highest Wegree with these recommendations and empha-ize that if fluconazole is used there is aotential for serious drug interactions becausef cytochrome P-450 3A4 inhibition
SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
Improvement in short-term outcomes has not trans-lated into significant improvements in long-term out-comes in KTRs The lack of significant improvement inlong-term survival may be related to post-transplantcomplications Frequent posttransplant monitoring mayimprove long-term outcomes by decreasing chronic graftfailure or death with a functioning graft Our work groupconcurred with the recommendation and schedules ofroutine screening in monitoring kidney allograft functionafter kidney transplant with a low threshold for perform-ing kidney biopsy in cases of graft dysfunction or protein-uria Expert tissue processing and interpretation of trans-plant biopsy specimens by pathologists with transplantexperience are critical Regular surveillance of the pa-tientrsquos kidney function at the transplant center or in thenephrologistrsquos office offers an opportunity to enhancepatient adherence to medication diet and healthy life-style Although CKD in KTRs progresses more slowlythan CKD in other patients the work group agreed thatthe KDIGO guidelines on CKD should be followed inKTRs
Opportunistic infections are common in KTRs al-though advances in diagnosis and treatment have led toimproved survival in KTRs with infection It is nowstandard of care to use vaccinations in KTRs as long asthe vaccine does not contain live or attenuated virus Italso is routine to screen for or use prophylaxis to preventseveral posttransplant viral infections With few excep-tions (related to EBV and BK virus screening andhepatitis B vaccination posttransplant) we concurredwith KDIGO guidelines for vaccination screening and
treatment of infection posttransplant
KD
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Bia et al18
ARTICLE IN PRESS
COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULAR
DISEASE
DIGORecommendations inChapter 15iabetesMellitus
151 Screening for New-Onset Diabetes after Transplan-tation1511 We recommend screening all nondia-
betic KTRs with fasting plasma glu-cose oral glucose tolerance testingandor HbA1c (1C) at leastbull weekly for 4 weeks (2D)bull every 3 months for 1 year (2D)bull and annually thereafter (2D)
1512 We suggest screening for NODAT withfasting glucose oral glucose tolerancetesting andor after starting or substan-tially increasing the dose of CNIsmTORi or corticosteroids (2D)
152 Managing NODAT or Diabetes Present at Trans-plantation1521 If NODAT develops consider modifying
the immunosuppressive drug regimen toreverse or ameliorate diabetes afterweighing the risk of rejection and otherpotential adverse effects (Not Graded)
1522 Consider targeting HbA1c 70-75and avoid targeting HbA1c 60 espe-cially if hypoglycemic reactions are com-mon (Not Graded)
1523 We suggest that in patients with diabetesaspirin (65-100 mgd) use for the primaryprevention of CVD be based on patientpreferences and values balancing the riskfor ischemic events to that of bleeding(2D)
DOQIRationale andCommentary
Diabetic Screening
We agree with screening for new-onset diabetesfter transplantation (NODAT) as outlined by theDIGO work group Definitions used are similar
o those of the American Diabetes AssociationADA) The greater frequency of testing initially isustified by the high risk of NODAT in the earlyosttransplant period however ongoing screenings required because the risk of the development ofODAT continues to increase over time4647 We
lso point out that prediabetic states (impairedasting glucose level and impaired glucose toler-nce) occur even more commonly than overt diabe-es48 and may be associated with metabolic syn-rome as well as with increased cardiovascular
ortality49-51 Potential implications of these predia-
etic states emphasize the importance of perform-ng blood tests under fasting conditions For pa-ients with fasting hyperglycemia an oral glucoseolerance test or hemoglobinA1c (HbA1c) test shoulde performed Although more cumbersome to per-orm data suggest that an oral glucose toleranceest is a more sensitive indicator of NODAT inyperglycemic KTRs52 This may allow earlieretection of overt diabetes and more prompt institu-ion of treatment
DiabetesManagement
Data supporting a substantial benefit in themelioration or reversal of NODAT using immu-osuppression modification in KTRs are veryimited There was consensus in our work grouphat considering the paucity of data for reversingODAT by changing immunosuppression and
he potential risk of an adverse outcome withuch a maneuver KDIGO suggestion 1521 couldot be supported Certainly if such a step waseing considered it should be done in conjunc-ion with the transplant center Targeting an HbA1c
evel of 7-75 and avoiding levels 6 isased on data showing increased cardiovascularvents with the lower HbA1c target5354
DIGORecommendations inChapter 16ypertensionDyslipidemias TobaccoUse andbesity
161 Hypertension1611 We recommend measuring blood pres-
sure at each clinic visit (1C)1612 We suggest maintaining blood pressure at
130 mm Hg systolic and 80 mm Hgdiastolic if 18 years of age and 90th
percentile for sex age and height if 18years old (2C)
1613 To treat hypertension (Not Graded)bull Use any class of antihypertensive
agentbull Monitor closely for adverse effects
and drug-drug interactions and whenurine protein excretion 1 gd for18 years old and 600 mgm224 hfor 18 years old consider an ACE-Ior an ARB as first-line therapy
162 Dyslipidemias (These recommendations are basedon KDOQI Dyslipidemia Guidelines and are thusnot graded)1621 Measure a complete lipid profile in all
adult (18 years old) and adolescent
(puberty to 18 years old) KTRs [Based on
K
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KDOQI Commentary 19
ARTICLE IN PRESS
KDOQI Dyslipidemia Recommendation1]bull 2-3 months after transplantationbull 2-3 months after a change in treatment
or other conditions known to causedyslipidemias
bull at least annually thereafter1622 Evaluate KTRs with dyslipidemias for
secondary causes [Based on KDOQI Dys-lipidemia Recommendation 3]16221 For KTRs with fasting triglyc-
erides 500 mgdL (565mmolL) that cannot be cor-rected by removing an under-lying cause treat withbull Adults therapeutic lifestyle
changes and a triglyceride-lowering agent [Based onKDOQI Recommendation41]
bull Adolescents therapeutic life-style changes [Based onKDOQI Recommendation51]
16222 For KTRs with elevatedLDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)treat to reduce LDL-C to100 mgdL (259mmolL) [Based on KDOQIGuideline 42]
bull Adolescents If LDL-C130 mgdL (336 mmolL) treat to reduce LDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 52]
16223 For KTRs with normalLDL-C elevated triglyceridesand elevated non-HDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)fasting triglycerides 200mgdL (226 mmolL)and non-HDL-C 130mgdL (336 mmolL)treat to reduce non-HDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 43]
bull Adolescents If LDL-C130 mgdL (336 mmolL) fasting triglycerides200 mgdL (226 mmolL) and non-HDL-C 160mgdL (414 mmolL)treat to reduce non-HDL-C
to 160 mgdL (414 i
mmolL) [Based on KDOQIGuideline 53]
163 Tobacco Use1631 Screen and counsel all KTRs including
adolescents and children for tobacco useand record the results in the medicalrecord (Not Graded)bull Screen during initial transplant hospi-
talizationbull Screen at least annually thereafter
1632 Offer treatment to all patients who usetobacco (Not Graded)
164 Obesity1641 Assess obesity at each visit (Not Graded)
bull Measure height and weight at eachvisit in adults and children
bull Calculate BMI at each visitbull Measure waist circumference when
weight and physical appearance sug-gest obesity but BMI is 35 kgm2
1642 Offer a weight-reduction program to allobese KTRs (Not Graded)
DOQIRationale andCommentary
Hypertension
The KDIGO work group adapted the KDOQI004 recommendations for target blood pres-ure in KTRs55 Self measurement is useful inssessing response to therapy and enhancesdherence56 In general we agree that the classf antihypertensive agent does not matter inhe treatment of blood pressure elevation inhis population and that attention should beiven to potential side effects of antihyperten-ive agents as well as possible interactionsith the immunosuppressive regimen (eg non-ihydropyridine calcium channel blockers andNIs) In the absence of adequate randomizedontrolled trials it is not known whether angio-ensin-converting enzyme (ACE) inhibitors andngiotensin receptor blockers (ARBs) prolongecipient or allograft survival Some but notll retrospective studies suggest a benefitowever all these studies are limited by selec-ion bias5758 Although ACE inhibitors andRBs commonly lead to some decrease inFR treatment with these drugs should be
ontinued unless serum creatinine level in-reases by 25 to 30 in keeping withDOQI recommendations55 In KTRs receiv-
ng ACE inhibitors or ARBs it is important toducate patients to maintain adequate fluid
ntake during illness to prevent a prerenal
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ARTICLE IN PRESS
nsult to the allograft Similarly awareness isecessary when using diuretics in conjunctionith therapies that block the renin-angiotensin-
ldosterone-system59
Dyslipidemia
The KDIGO work group based their recom-endations for evaluation and treatment of
yperlipidemia on the KDOQI dyslipidemiauidelines for KTRs60 We agree with theseecommendations CNIs potentiate the toxicityf statins by slowing their metabolism throughhe cytochrome P-450 system This interactionccurs more commonly with cyclosporine61
han with tacrolimus Dyslipidemia especiallyypertriglyceridemia frequently complicatesTOR-inhibitor use and lipid-lowering therapy
s required in most patients using these agents
TobaccoUse
Not surprisingly tobacco use at the time ofransplant is associated with decreased patientnd graft survival as well as increased risk ofosttransplant cardiovascular disease (CVD)lthough the KDIGO work group recom-ends initial screening and intervention dur-
ng the hospitalization for transplant we be-ieve there may be benefit gained by startingounseling in the pretransplant period duringhe evaluation phase Unfortunately this doesot occur often because of time and personnelonstraints in transplant centers Ideally allransplant centers should have smoking-cessa-ion programs available to patients either in-ouse or through referral Ideally systemshould be created to continue to screen andonitor for smoking cessation at yearly inter-
als after transplant because there is a highate of relapse with this addiction As outlinedn KDIGO Table 253 although all pharmaco-ogic therapies for smoking cessation can besed in KTRs the starting dose of vareniclinehould be decreased in patients with GFR 30Lmin
Obesity
Obesity is an epidemic in the United Statesnd the proportion of obese kidney transplantandidates continues to grow In additioneight gain after transplant is very commonly
bserved Obesity in KTRs is associated with w
ncreased risks of wound complications de-ayed graft function acute rejection and NO-AT resulting in inferior patient and graftutcomes Attention to this potential complica-ion and counseling should be initiated duringhe pretransplant evaluation phase Informa-ion regarding pharmacologic therapies foreight loss in KTRs is not available and we
gree with the KDIGO work group that thera-eutic lifestyle measures should be encour-ged Data regarding steroid therapy with-rawal and weight gain are controversial Aecent double-blind randomized controlled trialxamining early steroid therapy withdrawalid not show a difference in weight gain at 5ears posttransplant compared with the cohortemaining on standard maintenance corticoste-oid therapy62
DIGORecommendations inChapter 17ardiovascularManagement
171 Consider managing CVD at least as intensively inKTRs as in the general population with appropri-ate diagnostic tests and treatments (Not Graded)
172 We suggest using aspirin (65-100 mgd) in allpatients with atherosclerotic CVD unless there arecontraindications (2B)
DOQIRationale andCommentary
Although outcomes are favorable comparedith remaining on the waiting list the risk of
ardiovascular mortality in KTRs is several-foldigher than observed in the general population63
specially in younger age groups and patientsith decreasing allograft function64 CVD is aajor cause of graft loss after the first post-
ransplant year In this context we strongly agreehat CVD should be managed in KTRs at least asntensively as in the general population Ideallyecreasing CVD risk in KTRs requires a multifac-ted and multidisciplinary approach Based onurrent practice models in the United States theransplant and nephrology community has notet been able to achieve these desirable goals65
his clearly deserves more attention becauseontrol of CVD has the potential to contributeore to long-term kidney graft survival than the
iscovery of newer drugs that decrease the ratef allograft rejection Our KDOQI working groupgreed with the use of low-dose aspirin in KTRs
ith evidence of atherosclerosis
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KDOQI Commentary 21
ARTICLE IN PRESS
SUMMARY OF COMMENTARY ONSECTION III CVD
COMMENTARY ON SECTION IV OF KDIGO
TRANSPLANT GUIDELINE MALIGNANCY
DIGORecommendations inChapter 18 Cancerf the Skin andLip
181 We recommend that KTRs especially thosewho have fair skin live in high sun-exposureclimates have occupations requiring sun expo-sure have had significant sun exposure as achild or have a history of skin cancer be toldthat their risk of skin and lip cancer is veryhigh (1C)
182 We recommend that KTRs minimize life-longsun exposure and use appropriate ultravioletlight blocking agents (1D)
183 We suggest that adult KTRs perform skin andlip self-examinations and report new lesions toa health-care provider (2D)
184 For adult KTRs we suggest that a qualified healthprofessional with experience in diagnosing skincancer perform annual skin and lip examinationon KTRs except possibly for KTRs with dark skinpigmentation (2D)
185 We suggest that patients with a history of skin orlip cancer or premalignant lesions be referred to andfollowed by a qualified health professional withexperience in diagnosing and treating skin cancer
With the decrease in acute rejection during the pastdecade in association with improved immunosuppres-sion regimens patient death now rivals chronic graftdysfunction as one of the leading causes of long-termgraft loss Because CVD is the most common cause ofpatient death in KTRs a concerted effort at minimizingrisk factors for heart disease likely will have as great oreven greater impact on optimizing patient and graftoutcomes than the discovery of new antirejection thera-pies CVD risk reduction strategies should include regularscreening for new-onset diabetes (using ADA-based defini-tions) in the posttransplant period in previously nondiabeticpatients good glycemic regulation for diabetic patients accord-ing to current ADA guidelines and lipid management andblood pressure control according to KDOQI recommenda-tions In addition promotion of a healthy lifestyle throughweight control exercise and smoking cessation should be acentral part of posttransplant counseling and care Whenimmunosuppression modification is being considered to miti-gate cardiovascular risk we recommend that this be inconjunction with the transplant center In summary we gener-ally concurred with the suggestions of the work group in thissection but based on current practice standards in the UnitedStateschallengesremainwith implementationof thisguideline
(2D) s
186 We suggest that patients with a history of skincancer be offered treatment with oral acitretin ifthere are no contraindications (2B)
DOQIRationale andCommentary
CounselingandSunscreen
We concur with recommendations 181 and82 because skin cancer is a major source oforbidity and sometimes mortality in KTRsarning patients at risk of the high danger of
kin cancer a 1C recommendation is reinforcedy a recent prospective case-control study ofrgan transplant recipients that showed that regu-ar use of broad-spectrum sunscreens that pro-ide UVA and UVB protection may prevent theevelopment of actinic keratosis invasive squa-ous cell carcinoma and to a lesser extent
asal cell carcinoma66 Most cancer-causing ra-iation is thought to come from the UVB spec-rum and newer broad-spectrum sunscreens pro-ide protection against UVA and UVB radiationounseling about sunscreen and the need for sunvoidance needs to be incorporated into routineffice visits although it may not always beuccessful In a recent study of KTRs in which1 of patients had been informed about theeed for sun protection only 46 used morehan a tube of sunscreen per year67
Dermatology Involvement
There is increased evidence to suggest thatpecialty dermatology clinics for organ trans-lant recipients improve outcome measures in-luding compliance with photoprotection andncreased awareness of skin cancer68 The re-ources required for these specialty clinics makemplementation difficult for community nephrol-gy groups that do not have direct access to aransplant center Transplant patients should bencouraged to have annual visits with their trans-lant center and if dermatology specialty clinicsre available attempt to coordinate a skin cancervaluation annually
UseofRetinoid-likeCompounds
There is a limited scientific basis for KDIGOuggestion recommendation 186 Although reti-oids now are used routinely in KTRs with aigh skin cancer burden our KDOQI work groupelieves that more data are needed before this
uggestion should be accepted as a guideline In
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ARTICLE IN PRESS
ow-immunologic-risk groups and particularlyifficult cases some data suggest that switchingrom CNI to sirolimus therapy may decrease thencidence of skin cancer69 however the riskersus benefit of this maneuver has not been welltudied
DIGORecommendations inChapter 19on-SkinMalignancies
191 Develop an individualized screening plan for eachKTR that takes into account the patientrsquos pastmedical and family history tobacco use compet-ing risks for death and the performance of thescreening methodology (Not Graded)
192 Screen for the following cancers as per localguidelines for the general population (Not Graded)Women cervical breast and colon cancer Menprostate and colon cancer
193 Obtain hepatic ultrasound and alpha feto-proteinevery 12 months in patients with compensatedcirrhosis (Not Graded) [See Recommendations1354 (HCV) and 1365 (HBV)]
DOQIRationale andCommentary
Screening
It is recognized that KTRs have a higher inci-ence of malignancy particularly those associatedith specific viral infections Although cancer
creening may have benefits in this higher riskopulation it should be reinforced that some meth-ds of screening have significant risks which shoulde considered on an individualized basis particu-arly in patients who have projected survival lesshan 5 years
Screening forCancer inPatientsWithHepatitis
Many patients who have underlying cirrhosisn the United States will be followed up by arofessional specializing in liver disease whoay provide additional insight into this cancer
creening recommendation Based on a recentuestionnaire of US gastroenterologists only 50creen patients for hepatocellular carcinoma70
herefore implementation of this guideline byS clinicians is unlikely to be widespread
DIGORecommendations inChapter 20anagingCancerwithReductionof
mmunosuppressiveMedication
201 We suggest consideration be given to reducingimmunosuppressive medications for KTRs with can-
cer (2C)
2011 Important factors for consideration in-clude (Not Graded)bull The stage of cancer at diagnosisbull Whether the cancer is likely to be
exacerbated by immunosuppressionbull The therapies available for the can-
cerbull Whether immunosuppressive medica-
tions interfere with ability to admin-ister the standard chemotherapy
202 For patients with Kaposi sarcoma we suggestusing mTORi along with a reduction in overallimmunosuppression (2C)
DOQIRationale andCommentary
Table 1 (Table 29 in the KDIGO report3 andxcerpted from Grulich et al71) lists cancershat are increased most in immunosuppressedTRs based on standardized incidence ratios
SIRs) which compare the incidence toatched populations Cancers with the highestIRs may be those most likely to respond to aecrease in immunosuppression Except foraposi sarcoma limited evidence is available
or a decrease in immunosuppression in theseettings A strategy to change immunosuppres-ion therapy must occur in consultation withhe transplant center Switching to sirolimusherapy and decreasing immunosuppression inatients who develop Kaposi sarcoma is basedn sound scientific rationale7273
SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
The incidence of cancer posttransplant is 2-20times higher than that in the general population andKDIGO guidelines have been written to outline stepsfor prevention and screening With few exceptions weagree with the recommendations as outlined Skincancer is common in US transplant patients andscreening and prevention are critical However imple-mentation of guidelines for doing so including theKDIGO guidelines is a challenge because of patientpreferences against the routine use of sunscreen aswell as time constraints during office visits Althoughmany posttransplant cancers are viral mediated andrelated to immunosuppression it is less clear how toalter immunosuppression after malignancy has oc-curred We agree that although age-specific screeningfor malignancy should be incorporated into care con-sideration must be given to the risk of screening inpatients with limited life spans (5 years) because of
comorbid conditions
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
ommonPopu
i sarco-Hodgmelanise sm
sophaemia
estima standa10 c
ut esti
0 case
alized t
to guide treatment specifically before the
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
REFERENCES1 McCullough KP Keith DS Meyer KH et al Kidney
nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
o2
Tf2
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Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
ation Transpl Rev 200923191-19815 Abbud-Filho M Adams PL Alberuacute J et al A report
f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
A
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
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trN
hUt
Iwa
rl5
mi8
oe1
DA
fsK
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rN
sb2
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It
ar3
tA2
hm2
EA
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aiCCSH
Bia et al30
ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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Bia et al4
ARTICLE IN PRESS
ransplant practices in which these decisions tendo be transplant-center specific and based onactors described previously
DIGORecommendations inChapter 2 InitialndMaintenance Immunosuppressiveedications
21 We recommend using a combination of immuno-suppressive medications as maintenance therapyincluding a CNI and an antiproliferative agentwith or without corticosteroids (1B)
22 We suggest that tacrolimus be the first-line CNIused (2A)221 We suggest that tacrolimus or CsA be
started before or at the time of transplanta-tion rather than delayed until the onset ofgraft function (2D tacrolimus 2B CsA)
23 We suggest that mycophenolate be the first-lineantiproliferative agent (2B)
24 We suggest that in patients who are at low immuno-logical risk and who receive induction therapycorticosteroids could be discontinued during thefirst week after transplantation (2B)
25 We recommend that if mTOR inhibitors areused they should not be started until graftfunction is established and surgical wounds arehealed (1B)
DOQIRationale andCommentary
Initial Immunosuppression
We agree that optimum initial maintenanceherapy includes a CNI and an antiproliferativegent and that tacrolimus is the preferred CNI forost patients The Symphony Study a largeulticenter clinical trial showed that the combi-
ation of low-dose tacrolimus mycophenolateofetil (MMF) and steroids with daclizumab
nduction provided superior efficacy without theegative impact on renal function compared withither cyclosporine or a CNI-free regimen ofow-dose sirolimus78 However in a small num-er of patients other issues such as age ethnic-ty risk of new-onset diabetes mellitus and pre-ious toxicity with tacrolimus may result in thenitial use of cyclosporine Immediate CNI useas not been shown to cause a delay in renalecovery Although many centers briefly hold orodify the CNI dose in the setting of delayed
raft function especially when using antilympho-yte-depleting induction agents treatment withhese drugs should be initiated before or at theime of discharge from the hospital and not
ithheld because of delayed graft function As m
tated mycophenolate compounds (MMF andycophenolate sodium) are used as the initial
ntiproliferative agent of choice in most USransplant centers
SteroidTherapyDiscontinuation
Steroid sparing with discontinuation withinhe first few weeks after transplant has gainedidespread acceptance in the United States withore than 25 of patients being discharged after
ransplant off steroid therapy6 Although theDOQI work group agreed that steroid therapy
ould be discontinued in low-risk patients afternduction therapy we did not think that thisuggestion should be accepted as a universaluideline for several reasons Although short-nd medium-term results in corticosteroid therapyiscontinuation protocols show equivalent pa-ient and graft survival there may be a price toay in the long term Acute rejection rates areigher in well-designed randomized clinical tri-ls of steroid withdrawal In addition the pres-nce of chronic interstitial fibrosis and tubulartrophy may be greater in corticosteroid-freeatients portending decreased long-term graftunction The heterogeneity of the US donor andecipient population may have a role in thisssue Newer transplant regimens decrease pred-isone dosage to 5 mgd Apart from less boneisease the potential metabolic benefits of corti-osteroid-free protocols versus 5 mgd seem toe less significant What is clear is that discontinu-tion of steroid therapy early after transplanteems to be associated with less risk of rejectionhan discontinuation of steroids later (1 year)t should be noted that there are no studies ofifferent times in the first year to determine whenorticosteroid therapy can be discontinued safelyn some centers steroid therapy discontinuations accomplished up to 6 months posttransplantate discontinuation of steroid therapy (1 yearosttransplant) is no longer recommended andorms the basis of KDIGO guideline 25 withhich we agree It also must be emphasized that
teroid therapy withdrawal should be performednly when there is close frequent monitoring ofhe patient
EarlyUseofmTOR Inhibitors
Sirolimus and everolimus (agents known as
TOR inhibitors) delay wound healing prolong
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KDOQI Commentary 5
ARTICLE IN PRESS
elayed graft function and are no longer used inhe early posttransplant period (KDIGO recom-endation 25) Furthermore studies show an
ncreased rejection rate with early use of theseompounds in place of CNIs The Symphonytudy showed that the highest rejection rateccurred in the arm using low-dose sirolimusith MMF and steroids78
DIGORecommendations inChapter 3ong-termMaintenance Immunosuppressiveedications
31 We suggest using the lowest planned doses ofmaintenance immunosuppressive medications by2-4 months after transplantation if there has beenno acute rejection (2C)
32 We suggest that CNIs be continued rather thanwithdrawn (2B)
32 If prednisone is being used beyond the first weekafter transplantation we suggest prednisone becontinued rather than withdrawn (2C)
DOQIRationale andCommentary
Decreasing ImmunosuppressiveDosage
Although our work group agreed with sugges-ion 31 we stress that dosing of immunosuppres-ion should at all times take into account thendividual patientrsquos risk profile balancing rejec-ion with the adverse effects of medications Inome patients this may mean higher drug dosingrug levels to account for a higher risk of rejec-ion Although most US transplant centers nowtrive for a lower dose of immunosuppressiveedication after the early posttransplant period
he transplant center should define each patientrsquosarget drug dosing based on immunologic riskhich depends on ethnicity age history of previ-us transplant and level of HLA antibodies
ContinueorWithdrawCNITherapy
Although we agreed that mTOR inhibitorshould not be used in the early posttransplanteriod78 newer clinical trials have exploredwitching from CNIs to mTOR inhibitors 3-6onths posttransplant910 Early results suggest
elative safety with improvement in renal func-ion Whether the trade-off of less nephrotoxic-ty with a different side-effect profile of mTORnhibitors will be beneficial in the long termemains to be determined The work groupelieved that suggestion 32 to continue CNI
herapy indefinitely in all patients required
ore study before it could be accepted as auideline
SteroidTherapyWithdrawal
We agree that late steroid therapy with-rawal (1 year) is inadvisable but stress thathe definition of ldquoearlyrdquo steroid discontinua-ion has not been well defined and may occurfter the first week (see commentary underhapter 2)
DIGORecommendations inChapter 4trategies toReduceDrugCosts
41 If drug costs block access to transplantation astrategy to minimize drug costs is appropriateeven if use of inferior drugs is necessary to obtainthe improved survival and quality of life benefitsof transplantation compared with dialysis (NotGraded)411 We suggest strategies that may reduce drug
costs includebull limiting use of a biologic agent for
induction to patients who are high-riskfor acute rejection (2C)
bull using ketoconazole to minimize CNIdose (2D)
bull using a nondihydropyridine CCB to mini-mize CNI dose (2C)
bull using azathioprine rather than mycophe-nolate (2B)
bull using adequately tested bioequivalent ge-neric drugs (2C)
bull using prednisone long-term (2C)
42 Do not use generic compounds that have not beencertified by an independent regulatory agency tomeet each of the following criteria when comparedto the reference compound (Not Graded)bull contains the same active ingredientbull is identical in strength dosage form and route of
administrationbull has the same use indicationsbull is bioequivalent in appropriate bioavailability
studiesbull meets the same batch requirements for identity
strength purity and qualitybull is manufactured under strict standards
43 It is important that the patient and the clinicianresponsible for the patientrsquos care be made aware ofany change in a prescribed immunosuppressivedrug including a change to a generic drug (NotGraded)
44 After switching to a generic medication that ismonitored using blood levels obtain levels andadjust the dose as often as necessary until a stable
therapeutic target is achieved (Not Graded)
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DOQIRationale andCommentary
Drug costs are becoming an increasing issue inransplantation that impacts on patient adherencend ultimately affects graft survival Currently im-unosuppressive drugs in the United States are
overed by the Centers for Medicare amp Medicaidervices (CMS) the primary insurer for manyTRs for 3 years after transplant although legisla-
ion is being considered to continue this coverageor the life of the kidney Most KTRs are usingany other medications in addition to immunosup-
ressive drugs In general the transplant commu-ity (patients health care providers and policyakers) need to embrace the concept of cost con-
ainment and the risk(s) to the patient and graft byhese measures However this needs to be balancedy who benefits and how much risk is at stake
Use of drugs that block the cytochrome P-450A system in an attempt to decrease CNIosing and costs are rarely used in the Unitedtates The concern is that inadvertent cessa-
ion of treatment with these drugs causing aignificant decrease in drug levels could resultn an acute rejection episode Therefore theork group did not think that many of the 411
uggestions should be accepted as a guidelinewitching from a mycophenolate compound ton azathioprine compound in the later posttrans-lant period may be considered in some pa-ients as another cost-saving maneuver espe-ially in view of recent US registry datahowing similar long-term survival with theserugs11 Although we agree with the sugges-ions outlined in 42 it should be recognizedhat many generic formulations have nevereen tested in transplant patients Patient con-usion with medications when a different ge-eric formulation or even different strengths ofhe same drug from different manufacturers isispensed at each refill can lead to inadvertentedication errors possibly affecting out-
omes Patient education is crucial to avoidrrors in medication administration We agreeith recommendation 44 that it is crucial toonitor patients after an immunosuppressive
osage change brand change or change to aeneric drug However it needs to be recog-ized that implementation of this guideline canecome burdensome as practices become inun-
ated with inquiries from patients payors and 5
harmacies regarding medications Transplantenters and practices that see many transplantatients bear an inordinate part of this burden
DIGORecommendations inChapter 5onitoring ImmunosuppressiveMedications
51 We recommend measuring CNI blood levels(1B) and suggest measuring at leastbull every other day during the immediate postopera-
tive period until target levels are reached (2C)bull whenever there is a change in medication or
patient status that may affect blood levels (2C)bull whenever there is a decline in kidney function that
may indicate nephrotoxicity or rejection (2C)511 We suggest monitoring CsA using 12-h
trough (C0) 2-h post-dose (C2) or abbrevi-ated AUC (2D)
512 We suggest monitoring tacrolimus using12-h trough (C0) (2C)
52 We suggest monitoring MMF levels (2D)53 We suggest monitoring mTOR inhibitor levels (2C)
DOQIRationale andCommentary
Because immunosuppressive drugs are classi-ed as narrow therapeutic agents drug-levelonitoring is a necessary tool to maximize effi-
iency and minimize toxicity The blood drugevel is not synonymous with level of immuno-uppression but may correlate imperfectly withhis effect In most US transplant centers levelsf CNI and mTOR inhibitors are monitoredPA monitoring is problematic because of the
oor correlation between trough levels and areander the curve (AUC) exposure Optimal moni-oring of MPA requires a 4- to 6-hour abbrevi-ted AUC measurement which is logisticallyifficult in the outpatient setting Although stud-es show that monitoring MPA levels in the earlyosttransplant period may be helpful in cyclospor-ne-treated patients recent evidence suggests thatuch monitoring may be less important in pa-ients on tacrolimus therapy12 With most USTRs now being started on tacrolimus as theNI of choice MPA monitoring is not routine inany US transplant centers Although one per-
on in our work group believed there may still beome value in monitoring MPA levels the otherembers questioned the value and applicability
f this practice (KDIGO suggestion 52) Cur-ently many US centers measure MPA only inhe setting of possible drug-related toxicities oride effects Although we agree with suggestion
3 to monitor mTOR inhibitor levels it should
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KDOQI Commentary 7
ARTICLE IN PRESS
e appreciated that therapeutic levels of thisgent have yet to be defined in controlled studies
DIGORecommendations inChapter 6reatment ofAcuteRejection
61 We recommend biopsy before treating acuterejection unless the biopsy will substantiallydelay treatment (1C)
62 We suggest treating subclinical and borderline acuterejection (2D)
63 We recommend corticosteroids for the initialtreatment of acute cellular rejection (1D)631 We suggest adding or restoring maintenance
prednisone in patients not on steroids whohave a rejection episode (2D)
632 We suggest using lymphocyte-depleting anti-bodies or OKT3 [muromonab-CD3] for acutecellular rejections that do not respond tocorticosteroids and for recurrent acute cellu-lar rejections (2C)
64 We suggest treating antibody-mediated acute rejec-tion with one or more of the following alternativeswith or without corticosteroids (2C)bull plasma exchangebull intravenous immunoglobulinbull anti-CD20 antibodybull lymphocyte-depleting antibody
65 For patients who have a rejection episode wesuggest adding mycophenolate if the patient is notreceiving mycophenolate or azathioprine or switch-ing azathioprine to mycophenolate (2D)
DOQIRationale andCommentary
We concur that biopsies should be performed onll KTRs suspected of having an acute rejectionrecommendation 61) Expert interpretation of theiopsy specimen by pathologists accustomed toeading kidney transplant biopsies is as importants expertise in performing the biopsy It is contro-ersial whether subclinical and borderline rejec-ions should be treated (recommendation 62 sup-orted by low evidence [2D]) Subclinical rejectionsre diagnosed in patients who have protocol biop-ies performed by design not for deterioration inidney function Recent data suggest that the riskf subclinical rejection in patients on tacrolimusnd mycophenolate compound therapy is so lowhat protocol biopsies may no longer be indi-ated13 Whether this is true in patients with highmmunologic risk or patients on minimization pro-ocols (ie steroid-free protocols or lower CNI doses)s uncertain Whether borderline rejection shoulde treated or some infiltrates may be protective also
s uncertain In most US centers steroids are used d
ost frequently as first-line treatment for acuteejection followed by lymphocyte-depleting anti-odies in steroid-resistant rejection but there maye exceptions to this approach Decision makingegarding appropriate initial treatment for acuteejection should be based on clinical and patho-ogic information Timing of the rejection episodeosttransplant type of induction agent used beforeejection degree of deterioration in kidney functiont the time of rejection and histologic grade of theejection may influence selection of the appropriatenitial antirejection therapy There is increasingecognition of the role of antibody-mediated mecha-isms in acute rejection This process requirespecial blood tests (to detect donor-specific antibod-es) and histochemical stains (immunofluorescenceor C4d) for diagnosis14 Coordination with theransplant center is critical to ensure that all appro-riate testing is performed and specific treatment isnitiated After treatment of an acute episode opti-
izing overall immunosuppression is requiredonsiderations should include changing the CNIdding a mycophenolate compound or increasinghe dose adding corticosteroids to previously ste-oid-free regimens or addingsubstituting an mTORnhibitor More than 85 of patients are alreadysing MPA agents so the number available forwitching will be relatively small
DIGORecommendations inChapter 7reatment of ChronicAllograft Injury (CAI)
71 We recommend kidney allograft biopsy for allpatients with declining kidney function of unclearcause to detect potentially reversible causes (1C)
72 For patients with CAI and histological evidence ofCNI toxicity we suggest reducing withdrawing orreplacing the CNI (2C)721 For patients with CAI eGFR 40 mLmin
173 m2 and urine total protein excretion500 mgg creatinine (or equivalent protein-uria by other measures) we suggest replac-ing the CNI with a mTOR inhibitor (2D)
DOQIRationale andCommentary
We agree with the need for kidney transplantiopsy in patients with decreasing kidney function71) and again stress the importance of expertise inathologic interpretation Important causes ofhronic allograft injury (CAI) which include rejec-ion BK nephropathy CNI toxicity or recurrentisease require special histochemical stains for
iagnosis that are not readily available in all labora-
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Bia et al8
ARTICLE IN PRESS
ories Therefore coordination with the transplantenter where these techniques are available is essen-ial For patients with CAI caused by CNI toxicityithdrawing the CNI should occur only after at-
empts at decreasing the dosage have failed Onelso must ensure that all other causes of CAI arexcluded to avoid inappropriate drug adjustmentsr missed treatment options Although our workroup thought that KDIGO suggestion 721 maye reasonable in some patients we also want tomphasize that the role of mTOR inhibitors in thereatment of CAICNI toxicity is poorly defined Its clear that switching from a CNI to an mTORnhibitor should be avoided in patients with se-erely decreased glomerular filtration rate (GFR)ndor the presence of proteinuria however the exactuidelines for when to switch are still evolving
SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
DIGORecommendations inChapter 8onitoringKidneyAllograft Function
81 We suggest measuring urine volume (2C)bull Every 1-2 hours for at least 24 hours after
transplantation (2D)
In the United States immunosuppressive protocolsused may vary from center to center based on theirparticular patient population organ source experienceand opinion of the transplant team ease of use and costof therapy Although data about the efficacy and safety ofsteroid-free regimens are still evolving it is clear that ifsteroids are to be eliminated this should be done in theearly transplant period and not late (after 1 year)Community nephrologists need to coordinate any alter-ations in immunosuppressive medications with the trans-plant center and be vigilant for potential drug interactionswith the addition of any new medications Drug monitor-ing is an essential monitoring tool throughout the post-transplant course but not always applicable to everyimmunosuppressive medication Transplant biopsies fre-quently are necessary to determine the cause of renaldysfunction and the interpretation must be performed bypathologists with resources and experience in handlingand reading the transplant biopsy specimen
bull Daily until graft function is stable (2D) c
82 We suggest measuring urine protein excretion (2C)at leastbull Once in the first month to determine a baseline
(2D)bull Every 3 months during the first year (2D)bull Annually thereafter (2D)
83 We recommend measuring serum creatinine (1B) atleastbull Daily for 7 days or until hospital discharge
whichever occurs sooner (2C)bull 2-3 times per week for weeks 2-4 (2C)bull Weekly for months 2 and 3 (2C)bull Every 2 weeks for months 4-6 (2C)bull Monthly for months 7-12 (2C)bull Every 2-3 months thereafter (2C)
831 We suggest estimating GFR whenever se-rum creatinine is measured (2D) usingbull One of several formulas validated for
adults (2C) orbull The Schwartz formula for children and
adolescents (2C)
84 We suggest including a kidney allograft ultrasoundexamination as part of the assessment of kidneyallograft dysfunction (2C)
DOQIRationale andCommentary
RoutineScreeningTestsandTimeandFrequencyofMonitoring
Regular surveillance and vigilant monitoring ofidney allograft function are important in improv-ng short- and long-term outcomes Early detectionf kidney allograft dysfunction will allow timelyiagnosis and treatment that may improve patientnd graft survival Frequency and types of routinecreening tests after kidney transplant are shown inig 2Although there is no standard protocol for therequency and type of monitoring recommenda-ions are guided by the likelihood of problemspecific to the particular transplant population Inhe early posttransplant period when rejection andomplications are the most likely testing is per-ormed more frequently Thereafter the follow-upnterval will depend in part on the patientrsquos generalondition and the development of additional prob-ems The AST recommended routine posttrans-lant 2-3 visits per week during month 1 every 1-3eeks during month 2-3 every 4-8 weeks duringonths 4-12 and every 2-4 months after therst year These early visits often are providedy the transplant physician or surgeon of theransplant center After 3-6 months monitor-ng may be performed by the transplant physi-
ian or community nephrologist15 In a recent
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KDOQI Commentary 9
ARTICLE IN PRESS
urvey of posttransplant outpatient visits inedicare beneficiaries in the United States
requency of visits to transplant centers variedy center and region most visits were toephrologists16
At each clinic visit education regardingedication adherence diet and healthy life-
tyle should be given Screening for tobaccose should be implemented before dischargend annually Although the work group did notgree that screening all adults for Epstein-Barrirus (EBV) was of value (see commentarynder Chapter 13 for EBV) screening for allther elements listed in Fig 2 including screen-ng for proteinuria is reasonable In additiono these tests monitoring for HLA antibodiesgainst the donor (donor-specific antibodies)hich is not described in the KDIGO guide-
ine is becoming more common in some USenters The optimal timing and frequency ofuch screening has yet to be determined1718
SerumCreatinineandEstimatedGFR
Serum creatinine measurement remains theost commonly used index of renal allograft
unction It is reliable for detecting acute changesn kidney function Furthermore serum creati-ine level at year 1 after transplant is a riskactor for subsequent outcomes19 and mayelp in the management of the frequency ofisits However it is less reliable for detecting
Figure 2 Routine screen-ng after kidney transplantomplete blood cell count in-ludes white blood cells hemo-lobin and platelets Screenor diabetes is by fasting bloodlucose level glucose toler-nce test or hemoglobin A1c
evel Lipid profile includes fast-ng cholesterol low-density li-oprotein cholesterol high-ensity lipoprotein cholesterolnd triglyceride levels Screensor BK polyoma virus (BKV)nd Epstein-Barr virus (EBV)se plasma nucleic acid test-
ng (NAT) EBV screen is foratients with no antibody toBV at transplant Adapted
rom the KDIGO transplantuideline3 with permission ofDIGO
ong-term changes in kidney function in the
idney transplant recipient Formulas to esti-ate GFR using serum creatinine values have
een tested in KTRs but no formula consis-ently has been shown to be superior to an-ther As with CKD considerable renal patho-ogic states can be present without dramatichanges in serum creatinine levels
In 2005 the definition of CKD was amendedo include all KTRs regardless of markers ofidney damage or GFR2021 Although the workroup agreed that CKD staging in KTRs isseful it must be noted that there is consider-ble difference in the rate of progression inhese 2 groups Progression is much slower inTRs in whom kidney half-life is longer at
very level of CKD Renal ultrasound is thereferred imaging study in KTRs (KDIGOuggestion 84)22
DIGORecommendations inChapter 9 Kidneyllograft Biopsy
91 We recommend kidney allograft biopsy whenthere is a persistent unexplained increase inserum creatinine (1C)
92 We suggest kidney allograft biopsy when serumcreatinine has not returned to baseline after treat-ment of acute rejection (2D)
93 We suggest kidney allograft biopsy every 7-10 daysduring delayed function (2C)
94 We suggest kidney allograft biopsy if expectedkidney function is not achieved within the first 1-2months after transplantation (2D)
95 We suggest kidney allograft biopsy when there is
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ARTICLE IN PRESS
bull New onset of proteinuria (2C)bull Unexplained proteinuria 30 g per gram creati-
nine or 30 g per 24 hours (2C)
DOQIRationale andCommentary
Biopsy
Renal allograft biopsy is the gold standard foriagnosing the cause of a change in renal allo-raft function It is useful in all clinical situationsescribed in KDIGO suggestions 91-94 Poten-ial causes of allograft dysfunction include vol-me depletion compromised renal blood flowrinary outflow obstruction parenchymal causesuch as acute rejection (cellular andor humoral)hronic allograft nephropathy recurrent or deovo disease or BK nephropathy Patients show-ng a 20-25 increase in creatinine level aboveaseline values warrant consideration for biopsyther indications for pursuing renal allograftiopsy would be a less-than-expected responseo treatment of acute rejection The expectedesponse would be dependent on the severity ofissue injury noted on the diagnostic biopsy speci-
en Delayed graft function lasting longer than-7 days warrants biopsy with repeated biopsieserformed every 7-10 days until graft functionecovers New-onset proteinuria protein 20g creatinine or 20 g24 h also merits aidney biopsy De novo and recurrent glomerulariseases are common causes of new-onset pro-einuria Patients with de novo or recurrent glo-erular diseases should be followed up closely
y transplant nephrologists or community neph-ologists with close communication with theransplant center because treatment of some recur-ent kidney diseases may prevent or delay thenset of graft failure2324
SafetyandAccuracy
The safety of kidney transplant biopsies haseen documented and the overall risk of compli-ations is low Most biopsies are performed inhe transplant center by transplant nephrologistsommunity nephrologists also may perform bi-psies of the kidney in KTRs more than a yearosttransplant It is prudent to obtain a diagnosticltrasound before biopsy to rule out unexpectedlterations in blood flow or urinary tract obstruc-ion It is imperative that a pathologist familiar
ith the transplant process interprets the pathol-
gy in consultation with the referring nephrolo-ist using appropriate stains and other studies
MolecularMarkers
In addition to conventional histopathologicxamination several US transplant centers aresing molecular markers as well as genomic orroteomic methods to enhance our understand-ng of the mechanism of immunologic and non-mmunologic pathway of injury As an exampleolymerase chain reaction (PCR) has been usedo detect messenger RNA for IL-2 and otheriomarkers in biopsy samples Using this ap-roach IL-2 upregulated during rejection coulde detected 2 days before rejection was apparentsing histologic or clinical criteria Such PCRpproaches have been used to detect other generoducts upregulated during acute rejection suchs granzyme B perforin transforming growthactor IL-10 and IL-1525-27 These newerethods are performed almost exclusively in
ransplant centers and may become a standardethod of transplant biopsy analysis in the fu-
ure
DIGORecommendations inChapter 10ecurrentDisease
101 We suggest screening KTRs with primary kidneydisease caused by FSGS for proteinuria (2C) atleastbull Daily for 1 week (2D)bull Weekly for 4 weeks (2D)bull Every 3 months for the first year (2D) Every
year thereafter (2D)
102 We suggest screening KTRs with potentially treat-able recurrence of primary kidney disease fromIgA nephropathy MPGN anti-GBM disease orANCA-associated vasculitis for microhematuria(2C) at leastbull Once in the first month to determine a baseline
(2D)bull Every 3 months during the first year (2D)
Annually thereafter (2D)
103 During episodes of graft dysfunction in patientswith primary HUS we suggest screening forthrombotic microangiopathy (eg with plateletcount peripheral smear for blood cell morphologyplasma haptoglobin and serum lactate dehydroge-nase) (2D)
104 When screening suggests possible treatable recur-rent disease we suggest obtaining an allograftbiopsy (2C)
105 Treatment of recurrent kidney disease1051 We suggest plasma exchange if a biopsy
shows minimal change disease or FSGS
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KDOQI Commentary 11
ARTICLE IN PRESS
in those with primary FSGS as theirprimary kidney disease (2D)
1052 We suggest high-dose corticosteroids andcyclophosphamide in patients with recur-rent ANCA-associated vasculitis or anti-GBM disease (2D)
1053 We suggest using an ACE-I [ACE inhibi-tor] or an ARB for patients with recurrentglomerulonephritis and proteinuria (2C)
1054 For KTRs with primary hyperoxaluriawe suggest appropriate measures to pre-vent oxalate deposition until plasma andurine oxalate levels are normal (2C)includingbull Pyridoxine (2C)bull High calcium and low oxalate diet
(2C)bull Increased oral fluid intake to enhance
urinary dilution of oxalate (2C)bull Potassium or sodium citrate to alkalin-
ize the urine (2C)bull Orthophosphate (2C)bull Magnesium oxide (2C)bull Intensive hemodialysis to remove ox-
alate (2C)
DOQIRationale andCommentary
Recurrent disease accounts for a substantialmount of graft loss after renal transplant It isifficult to assess the percentage of grafts lost toecurrent disease because many patients presentith end-stage renal disease without benefit of aiagnostic native renal biopsy The likelihood ofecurrent disease after transplant is dependent onhe disease with certain diseases at particularlyigh risk of recurrence28
Recurrent Focal SegmentalGlomerulosclerosis
We agree with recommendation 101 regard-ng frequent and regular screening for protein-ria in patients with primary focal segmentallomerulosclerosis (FSGS) as the cause of end-tage renal disease If the patient is still produc-ng urine at the time of transplant a preoperativerine protein-creatinine ratio can be a very help-ul baseline measure of proteinuria Early detec-ion of FSGS recurrence which can present withormal light microscopy but foot-process efface-ent on electron microscopy29 provides the best
pportunity for intervention and amelioration ofisease
IgANephropathy
Recurrence rates of immunoglobulin A (IgA)
ephropathy are variable We agree with recom- b
endation 102 for screening routinely for micro-ematuria Recurrent disease is confirmed with aenal allograft biopsy Histologic recurrence ofisease is much more common than is clinicalisease recurrence There is no proven therapyor treatment of recurrent disease30
MembranoproliferativeGlomerulonephritis
Recurrence of membranoproliferative glomer-lonephritis (MPGN) is common as high as 80ith MPGN type II (dense-deposit disease) Theost common cause of MPGN type I is hepatitisndashassociated immune complex formation Wegree with the proposed regularly scheduledcreening for microhematuria and proteinuria inecommendation 102 Patients with known hepa-itis Cndashassociated MPGN pretransplant also maye screened for cryoglobulins which are associ-ted with MPGN31
HemolyticUremic Syndrome
Hemolytic uremic syndrome (HUS) typicallys divided into diarrheal associated (D) andonndashdiarrheal associated (D) D disease oc-urs mostly in children and rarely recurs post-ransplant However D HUS is more commonn adults and can recur In HUS associated with aomplement abnormality such as factor H defi-iency or factor I mutation recurrence rates cane as high as 80 Screening for evidence ofecurrence allows for an earlier diagnosis whichill require biopsy in most cases and provides
n opportunity for earlier intervention There iso comment in the guideline regarding recur-ence of thrombotic thrombocytopenic purpuraut early detection of recurrence provides anpportunity for treatment with plasmapheresisnd intravenous immune globulin (IVIG)
BiopsyandTreatment
As stated kidney biopsy and interpretation bypathologist with expertise in transplant speci-en readings is critical in the diagnosis of dis-
ase recurrence Treatment for most recurrentisease in renal transplantation is based on aombination of case reports case cohorts andetrospective reviews Recurrent diseases post-ransplant are not common enough that random-zed controlled trials can be implemented there-ore most recommendations for treatment are
ased on a consensus of opinion Despite this we
at
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ARTICLE IN PRESS
gree in general with the recommendations de-ailed in 105
DIGORecommendations inChapter 11reventingDetecting andTreatingonadherence
111 Consider providing all KTRs and family memberswith education prevention and treatment mea-sures to minimize nonadherence to immunosup-pressive medications (Not Graded)
112 Consider providing KTRs at increased risk fornonadherence with increased levels of screeningfor nonadherence (Not Graded)
DOQIRationale andCommentary
Noncompliance or nonadherence to diet andedication is a common problem in KTRs Nonad-
erence to medication is associated with a high riskf acute rejection and allograft loss We agree thatarly efforts should be made to identify KTRs atncreased risk of nonadherence and that these pa-ients should be monitored closely Prevention iden-ification and treatment of nonadherence are inte-ral to the monitoring of kidney allograft functionnd long-term care of KTRs Certain subgroup ofTRs younger patients African Americans and
hose with financial hardships have an enhancedisk of nonadherence3233
In addition to identifying patients at risk it ismportant to have a system for addressing patientonadherence This requires coordinated efforts ofocial workers transplant coordinators financialounselors pharmacists primary nephrologists andhe patientrsquos family34 A combination of educa-ional behavioral and social support interventionsrovides the best results Because there is no per-ect measure of adherence consideration should beiven to multiple approaches for adherence moni-oring Similar team approaches also are importantn other areas requiring adherence such as dietxercise tobacco alcohol and drug use
DIGORecommendations inChapter 12accination
121 We recommend giving all KTRs approvedinactivated vaccines according to recommendedschedules for the general population except forHBV vaccination (1D)1211 We suggest HBV vaccination (ideally
prior to transplantation) and HBsAb titers6-12 weeks after completing the vaccina-
tion series (2D) h
12111 We suggest annual HBsAb[antibody to hepatitis B sur-face antigen] titers (2D)
12112 We suggest revaccination ifthe antibody titer falls below10 mIUmL (2D)
122 We suggest avoiding live vaccines in KTRs (2C)123 We suggest avoiding vaccinations except influ-
enza vaccination in the first 6 months followingkidney transplantation (2C)1231 We suggest resuming immunizations once
patients are receiving minimal mainte-nance doses of immunosuppressive medi-cations (2C)
1232 We recommend giving all KTRs whoare at least 1-month post-transplantinfluenza vaccination prior to the onsetof the annual influenza season regard-less of status of immunosuppression(1C)
124 We suggest giving the following vaccines to KTRswho due to age direct exposure residence ortravel to endemic areas or other epidemiologicalrisk factors are at increased risk for the specificdiseasesbull rabies (2D)bull tick-borne meningoencephalitis (2D)bull Japanese B encephalitismdashinactivated (2D)bull Meningococcus (2D)bull Pneumococcus (2D)bull Salmonella typhimdashinactivated (2D)1241 Consult an infectious disease specialist a
travel clinic or public health official forguidance on whether specific cases war-rant these vaccinations (Not Graded)
DOQIRationale andCommentary
KTRs are at particular risk of viral infectionsecause of the preferential suppression of T lympho-ytes by both induction and maintenance immuno-uppression The risk and consequence of develop-ng a viral infection warrant use of selected vaccineshe suggestions regarding which vaccines are safend which are contraindicated are based on whetherhe vaccine contains live or killed virus Live virusaccines are contraindicated in immunosuppressedTRs The KDIGO recommendations for vaccina-
ions agree with updated guidelines recently pub-ished by the AST35 Specific comments on theDIGO suggestions regarding vaccinations are
isted in the following sections
Hepatitis B
The work group did not concur with KDIGOuggestion 1211 Neither revaccination against
epatitis after transplant nor following up hepa-
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KDOQI Commentary 13
ARTICLE IN PRESS
itis B antibody titers annually is a commonractice in the United States Hepatitis B is nots prevalent in the United States as in otherarts of the world and evidence supportingcreening in all patients posttransplant is lack-ng However screening for seroconversion inatients at risk (receiving a hepatitis B corentibodyndashpositive kidney) is appropriate Theseatients may benefit from lamivudine or ente-avir therapy36
LiveVaccineandTimingofVaccine
There is no particular reason for a 6-monthag between transplant and vaccination Theheory is that vaccines are less likely to beffective in the period when immunosuppres-ion is high In the United States most individu-ls are on their baseline maintenance immuno-uppression therapy by 3 months posttransplantecisions regarding the timing of vaccines areade based on immunosuppression exposure
nd risk of infection Recipients also shouldvoid intimate contact with individuals whoave received live vaccines37 This includesvoiding close contact with children who haveeceived oral polio vaccine for 3 weeks anday include close contact with adults receiv-
ng the attenuated varicella vaccine to preventoster Immunosuppressed individuals are ad-ised to avoid contact for 7 days with individu-ls who have received live virus nasal spraysor influenza We concur with the recommenda-ion for flu vaccine but common practice inhe United States is to wait 3-6 months afterransplant before it is administered
DIGORecommendations inChapter 13 Viraliseases
131 BK POLYOMA VIRUS1311 We suggest screening all KTRs for BKV
with quantitative plasma NAT (2C) atleastbull monthly for the first 3-6 months after
transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull whenever there is an unexplained rise
in serum creatinine (2D)bull and after treatment for acute rejection
(2D)1312 We suggest reducing immunosuppressive
medications when BKV plasma NAT is
persistently greater than 10 000 cop-iesmL (107 copiesL) (2D)
132 CYTOMEGALOVIRUS1321 CMV prophylaxis We recommend that
KTRs (except when donor and recipi-ent both have negative CMV serolo-gies) receive chemoprophylaxis forCMV infection with oral ganciclovir orvalganciclovir for at least 3 monthsafter transplantation (1B) and for 6weeks after treatment with a T-cellndashdepleting antibody (1C)
1322 In patients with CMV disease we suggestweekly monitoring of CMV by NAT orpp65 antigenemia (2D)
1323 CMV treatment13231 We recommend that all pa-
tients with serious (includ-ing most patients with tissueinvasive) CMV disease betreated with intravenousganciclovir (1D)
13232 We recommend that CMVdisease in adult KTRs that isnot serious (eg episodes thatare associated with mildclinical symptoms) be treatedwith either intravenous gan-ciclovir or oral valganciclo-vir (1D)
13233 We recommend that allCMV disease in pediatricKTRs be treated with intra-venous ganciclovir (1D)
13234 We suggest continuing therapyuntil CMV is no longer detect-able by plasma NAT or pp65antigenemia (2D)
1324 We suggest reducing immunosuppressivemedication in life-threatening CMV dis-ease and CMV disease that persists in theface of treatment until CMV disease hasresolved (2D)13241 We suggest monitoring graft
function closely during CMVdisease (2D)
133 EPSTEIN-BARR VIRUS AND POST-TRANS-PLANT LYMPHOPROLIFERATIVE DISEASE1331 We suggest monitoring high-risk (donor
EBV seropositiverecipient seronegative)KTRs for EBV by NAT (2C)bull once in the first week after transplanta-
tion (2D)bull then at least monthly for the first 3-6
months after transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull and additionally after treatment for
acute rejection (2D)
Bia et al14
ARTICLE IN PRESS
1332 We suggest that EBV-seronegative pa-tients with an increasing EBV load haveimmunosuppressive medication reduced(2D)
1333 We recommend that patients with EBVdisease including PTLD have a reduc-tion or cessation of immunosuppres-sive medication (1C)
134 HERPES SIMPLEX VIRUS 1 2 AND VARI-CELLA ZOSTER VIRUS1341 We recommend that KTRs who de-
velop a superficial HSV 1 2 infectionbe treated (1B) with an appropriateoral antiviral agent (eg acyclovir vala-cyclovir or famciclovir) until all le-sions have resolved (1D)
1342 We recommend that KTRs with sys-temic HSV 1 2 infection be treated(1B) with intravenous acyclovir and areduction in immunosuppressive medi-cation (1D)13421 We recommend that intrave-
nous acyclovir continue un-til the patient has a clinicalresponse (1B) then switch toan appropriate oral antiviralagent (eg acyclovir valacy-clovir or famciclovir) to com-plete a total treatment durationof 14-21 days (2D)
1343 We suggest using a prophylactic antiviralagent for KTRs experiencing frequentrecurrences of HSV 12 infection (2D)
1344 We recommend that primary VZV infec-tion (chicken pox) in KTRs be treated(1C) with either intravenous or oral acy-clovir or valacyclovir and a temporaryreduction in amount of immunosuppres-sive medication (2D)
135 HEPATITIS C VIRUS1351 We suggest that HCV-infected KTRs be
treated only when the benefits of treat-ment clearly outweigh the risk of allo-graft rejection due to interferon-basedtherapy (eg fibrosing cholestatic hepati-tis life-threatening vasculitis) (2D)[Based on KDIGO Hepatitis C Recom-mendation 215]
1352 We suggest monotherapy with standardinterferon for HCV-infected KTRs inwhom the benefits of antiviral treatmentclearly outweigh the risks (2D) [Basedon KDIGO Hepatitis C Recommenda-tions 224 and 442]
1353 We suggest that all conventional currentinduction and maintenance immunosup-pressive regimens can be used in HCVinfected patients (2D) [Based on KDIGO
Hepatitis C Recommendation 43]
1354 Measure ALT in HCV-infected patientsmonthly for the first 6 months and every3-6 months thereafter Perform imagingannually to look for cirrhosis and hepato-cellular carcinoma (Not Graded) [Basedon KDIGO Hepatitis C Recommendation441] (See Recommendation 193)
1355 Test HCV-infected patients at least every3-6 months for proteinuria (Not Graded)[Based on KDIGO Hepatitis C Recom-mendation 444]13551 For patients who develop new
onset proteinuria (either urineproteincreatinine ratio 1 or24-hour urine protein 1 g ontwo or more occasions) per-form an allograft biopsy withimmunofluorescence and elec-tron microscopy (Not Graded)[Based on KDIGO Hepatitis CRecommendation 444]
1356 We suggest that patients with HCV asso-ciated glomerulopathy not receive inter-feron (2D) [Based on KDIGO HepatitisC Recommendation 445]
136 HEPATITIS B VIRUS1361 We suggest that any currently available
induction and maintenance immunosup-pressive medication can be used in HBV-infected KTRs (2D)
1362 We suggest that interferon treatmentshould generally be avoided in HBVinfected KTRs (2C)
1363 We suggest that all HBsAg-positive KTRsreceive prophylaxis with tenofovir ente-cavir or lamivudine (2B)13631 Tenofovir or entecavir are pref-
erable to lamivudine to mini-mize development of potentialdrug resistance unless medica-tion cost requires that lami-vudinebe used (Not Graded)
13632 During therapy with antivi-rals measure HBV DNA andALT levels every 3 months tomonitor efficacy and to detectdrug resistance (Not Graded)
1364 We suggest treatment with adefovir ortenofovir for KTRs with lamivudine resis-tance (5 log10 copiesmL rebound ofHBV-DNA) (2D)
1365 Screen HBsAg-positive patients with cir-rhosis for hepatocellular carcinoma every12 months with liver ultrasound andalpha feto-protein (Not Graded) (SeeRecommendation 193)
1366 We suggest that patients who are negativefor HBsAg and have HBsAb titer 10mIUmL receive booster vaccination to
raise the titer to 100 mIUmL (2D)
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KDOQI Commentary 15
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137 HUMAN IMMUNODEFICIENCY VIRUS1371 If not already done screen for HIV
infection (Not Graded)1372 To determine antiretroviral therapy refer
HIV-infected KTRs to an HIV specialistwho should pay special attention to drugndashdrug interactions and appropriate dosingof medications (Not Graded)
DOQIRationale andCommentary
Viral infections are particularly problematic inransplant recipients because of the preferentialnhibition of T-lymphocyte function by both induc-ion and maintenance immunosuppression Use ofnduction immunosuppression with lymphocyte-epleting agents (thymoglobulin or alemtuzumab)s associated with a greater risk of viral infectionosttransplant In general the greater the cumula-ive exposure to immunosuppression the greaterhe risk of infectious complications The presenta-ion of viral infections can be asymptomatic vaguend nonspecific or life-threatening acute illnessany viral infections seen in KTRs are rarely seen
n immunocompetent patients and therefore do notnter into the differential diagnosis for physiciansnfamiliar with transplant recipients Close commu-ication with the transplant center is crucial inaring for the transplant population Early detectionnd institution of therapy provide the best chanceor viral eradication
BKVirus
Although the work group agreed with KDIGOuggestions for BK virus screening posttransplante did not think it was practical to require screen-
ng exclusively with quantitative plasma nucleiccid testing (NAT) because many US centers usenitial urinary screening and then test plasma onlyf urine screening results are positive Howeverhere is no disagreement that some type of screen-ng for BK virus is critical to avoid BK nephropa-hy for which there is no specific treatment when its established Complicating screening for BK vi-us is the variability in results between laboratoriesnd uncertainty about the level of viremia thathould trigger a response to decrease in immunosup-ression In the presence of viremia and increase inerum creatinine level a renal allograft biopsy isndicated to confirm the presence of BK nephropa-
hy Because BK viremia and viruria certainly can b
e detected beyond the first year it is not clear howong screening should be continued posttransplantlthough most centers screen for the first year onlyngoing clinical trials are exploring effective treat-ent for BK nephropathy3839 Decisions about
ecreases in immunosuppression currently theainstay of BK viremia management always
hould be made in consultation with the transplantenter
Cytomegalovirus
KDIGO recommendation 1321 regarding cyto-egalovirus (CMV) prophylaxis is reasonable and
pplicable to the US population Universal prophy-axis for CMV now is recommended over initiatingre-emptive treatment after CMV develops40 Aajor concern for US patients is the cost of CMV
rophylaxis with oral valgancyclovir Leukopeniaan be observed in patients using mycophenolatereparations when prophylaxis with valgancyclo-ir is used Screening for CMV is best performedsing NAT methods (1322) CMV antigenemiassays are still in use in many facilities but are nots sensitive as PCR assays41 There is no utility inhecking for serologic response to CMV with IgGr IgM titers posttransplant because the immuneesponse is not predictable Patients with CMVisease should be cared for by clinicians familiarith treating this disease It is recommended that
reatment be continued until viral load is undetect-ble followed by prophylactic doses of valgancy-lovir for an additional 3 months35
Epstein-BarrVirus
Current practice regarding EBV screening variesmong centers in the United States and many doot routinely screen for EBV posttransplant evenn recipient-negative donor-positive cases In con-rast to KDIGO recommendation 1311 routineBV screening is not recommended in AST infec-
ious disease guidelines35 In many centers EBVcreening is reserved for children who are muchore commonly EBV negative pretransplant than
dults EBV-induced posttransplant lymphoprolif-rative disorder (PTLD) affects many more pediat-ic than adult KTRs If screening is someday to beoutinely implemented in US centers details regard-ng the best method of screening and levels ofiremia above which a clinical intervention should
e triggered need to be better defined
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HerpesandVaricella
Systemic herpesvirus infections can be lifehreatening in transplant recipients and should bereated aggressively with intravenous antiviralgents as described in the KDIGO recommenda-ions Less aggressive cutaneous infection can bereated with oral antiviral agents as outlined inhe KDIGO guidelines
Varicella exposure is particularly concerning inransplant recipients The work group disputes theecommended dosing of acyclovir for varicellaxposure Acyclovir at a dose of 10 mgkg or about00 mg 4 times daily of oral acyclovir would betandard dosing We agree with the use of varicellammune globulin and emphasize the need to avoidhe varicella vaccine because it is a live virushould a transplant recipient develop a systemicaricella infection hospitalization and high-dosentravenous acyclovir therapy are warranted
Hepatitis C
Hepatitis C management posttransplant is ahallenge The KDIGO guidelines cited hereere based on the recently published KDIGOuideline for hepatitis C in CKD4 Hepatitis Cypically is not treated posttransplant because ofhe risk (50) of rejection precipitated bynterferon therapy particularly in US KTRs inhom hepatitis C commonly is genotype 1 which
s more resistant to treatment with interferon42
owever should hepatitis Cndashrelated glomerulo-ephritis develop the risk-benefit ratio may fa-or treatment in selected patients Such decisionslways should be made in consultation withepatology and infectious disease experts andhe transplant center Monitoring liver enzymeevels specifically alanine aminotransferaseALT) may reflect a change in hepatitis activityut monitoring hepatitis C viral load is not recom-ended because it does not seem to correlateith outcome Annual monitoring for hepatocel-
ular carcinoma using -fetoprotein and imagings encouraged but not often practiced
Hepatitis B
KDIGO recommendations for hepatitis B areeasonable and currently are followed in mostS centers except for recommendation 1366
see previous recommendation under vaccina-ions) KTRs with hepatitis C or hepatitis B also
hould be followed up by a hepatologist
Human ImmunodeficiencyVirus
Human immunodeficiency virus (HIV)-posi-ive individuals are now acceptable for transplantf CD4 count is 200 cellsL and viral loadVL) is undetectable3543 Transplant should beerformed at centers with expertise in managingIV-positive individuals and care should be co-rdinated carefully with HIV specialists Somentiretroviral agents in particular the proteasenhibitors have potentially serious drug interac-ions with immunosuppressive agents35
DIGORecommendations inChapter 14Othernfections
141 URINARY TRACT INFECTION1411 We suggest that all KTRs receive UTI
prophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 monthsafter transplantation (2B)
1412 For allograft pyelonephritis we suggestinitial hospitalization and treatment withintravenous antibiotics (2C)
142 PNEUMOCYSTIS JIROVECII PNEUMONIA1421 We recommend that all KTRs receive
PCP prophylaxis with daily tri-methoprimndashsulfamethoxazole for 3-6months after transplantation (1B)
1422 We suggest that all KTRs receive PCPprophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 weeksduring and after treatment for acute rejec-tion (2C)
1423 We recommend that KTRs with PCPdiagnosed by bronchial alveolar lavageandor lung biopsy be treated withhigh-dose intravenous trimethoprimndashsulfamethoxazole corticosteroids anda reduction in immunosuppressivemedication (1C)
1424 We recommend treatment with cortico-steroids for KTRs with moderate tosevere PCP (as defined by PaO2 lt70mm Hg in room air or an alveolargradient of gt35 mm Hg) (1C)
143 TUBERCULOSIS1431 We suggest that TB prophylaxis and
treatment regimens be the same in KTRsas would be used in the local generalpopulation who require therapy (2D)
1432 We recommend monitoring CNI andmTORi [mTOR inhibitor] blood levels inpatients receiving rifampin (1C)14321 Consider substituting rifabu-
tin for rifampin to minimize
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KDOQI Commentary 17
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interactions with CNIs andmTORi (Not Graded)
144 CANDIDA PROPHYLAXIS1441 We suggest oral and esophageal Candida
prophylaxis with oral clotrimazole loz-enges nystatin or fluconazole for 1-3months after transplantation and for 1month after treatment with an antilympho-cyte antibody (2C)
DOQIRationale andCommentary
UrinaryTract Infection
Urinary tract infections (UTIs) after kidneyransplant are very common and account for aarge percentage of readmissions posttransplantTIs are common because of multiple factors
ncluding the disrupted anatomy of the urinaryract with a ureteroneocystotomy incompleteladder emptying because of diabetes or pros-atic hypertrophy and impaired immune re-ponses Prophylaxis of UTIs usually is under-aken with trimethoprim-sulfamethoxazole for 6onths posttransplant although infections often
ccur despite therapy because of the develop-ent of drug resistance Although native kidney
yelonephritis does not always require hospital-zation it is recommended that all KTRs withhis diagnosis be hospitalized because the graftysfunction that usually accompanies transplantyelonephritis requires aggressive investigationnd treatment Individuals with recurrent UTIsarrant evaluation with urologic assessment Pa-
ients with recurrent UTIs may benefit fromong-term suppressive therapy
Pneumocystic Pneumonia
We agree that Pneumocystis jirovecii pneumoniaPCP) prophylaxis is important for the first 3-6onths posttransplant (1421)After the first month
very-other-day dosing of trimethoprim-sulfame-hoxazole or atovaquone is believed to be adequaterophylaxis In cases in which neither of thesegents can be used an individual may be treatedrophylactically with inhaled pentamidine OurDOQI work group emphasized that patients whoevelop PCP should be transferred to the transplantenter promptly for management and adjustmentsn immunosuppression
Tuberculosis
Monitoring for latent tuberculosis has posed a
hallenge in the immunosuppressed population be-
ause of the unreliable nature of skin testing Newerechniques involving interferon release assays aremerging as the new gold standard for detection ofatent tuberculosis4445
CandidaProphylaxis
Oral candidiasis must be screened for usingral mucosa examination on follow-up visitsn KTRs This is especially true in the earlyosttransplant period when immunosuppres-ive medication dosage is the highest Wegree with these recommendations and empha-ize that if fluconazole is used there is aotential for serious drug interactions becausef cytochrome P-450 3A4 inhibition
SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
Improvement in short-term outcomes has not trans-lated into significant improvements in long-term out-comes in KTRs The lack of significant improvement inlong-term survival may be related to post-transplantcomplications Frequent posttransplant monitoring mayimprove long-term outcomes by decreasing chronic graftfailure or death with a functioning graft Our work groupconcurred with the recommendation and schedules ofroutine screening in monitoring kidney allograft functionafter kidney transplant with a low threshold for perform-ing kidney biopsy in cases of graft dysfunction or protein-uria Expert tissue processing and interpretation of trans-plant biopsy specimens by pathologists with transplantexperience are critical Regular surveillance of the pa-tientrsquos kidney function at the transplant center or in thenephrologistrsquos office offers an opportunity to enhancepatient adherence to medication diet and healthy life-style Although CKD in KTRs progresses more slowlythan CKD in other patients the work group agreed thatthe KDIGO guidelines on CKD should be followed inKTRs
Opportunistic infections are common in KTRs al-though advances in diagnosis and treatment have led toimproved survival in KTRs with infection It is nowstandard of care to use vaccinations in KTRs as long asthe vaccine does not contain live or attenuated virus Italso is routine to screen for or use prophylaxis to preventseveral posttransplant viral infections With few excep-tions (related to EBV and BK virus screening andhepatitis B vaccination posttransplant) we concurredwith KDIGO guidelines for vaccination screening and
treatment of infection posttransplant
KD
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COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULAR
DISEASE
DIGORecommendations inChapter 15iabetesMellitus
151 Screening for New-Onset Diabetes after Transplan-tation1511 We recommend screening all nondia-
betic KTRs with fasting plasma glu-cose oral glucose tolerance testingandor HbA1c (1C) at leastbull weekly for 4 weeks (2D)bull every 3 months for 1 year (2D)bull and annually thereafter (2D)
1512 We suggest screening for NODAT withfasting glucose oral glucose tolerancetesting andor after starting or substan-tially increasing the dose of CNIsmTORi or corticosteroids (2D)
152 Managing NODAT or Diabetes Present at Trans-plantation1521 If NODAT develops consider modifying
the immunosuppressive drug regimen toreverse or ameliorate diabetes afterweighing the risk of rejection and otherpotential adverse effects (Not Graded)
1522 Consider targeting HbA1c 70-75and avoid targeting HbA1c 60 espe-cially if hypoglycemic reactions are com-mon (Not Graded)
1523 We suggest that in patients with diabetesaspirin (65-100 mgd) use for the primaryprevention of CVD be based on patientpreferences and values balancing the riskfor ischemic events to that of bleeding(2D)
DOQIRationale andCommentary
Diabetic Screening
We agree with screening for new-onset diabetesfter transplantation (NODAT) as outlined by theDIGO work group Definitions used are similar
o those of the American Diabetes AssociationADA) The greater frequency of testing initially isustified by the high risk of NODAT in the earlyosttransplant period however ongoing screenings required because the risk of the development ofODAT continues to increase over time4647 We
lso point out that prediabetic states (impairedasting glucose level and impaired glucose toler-nce) occur even more commonly than overt diabe-es48 and may be associated with metabolic syn-rome as well as with increased cardiovascular
ortality49-51 Potential implications of these predia-
etic states emphasize the importance of perform-ng blood tests under fasting conditions For pa-ients with fasting hyperglycemia an oral glucoseolerance test or hemoglobinA1c (HbA1c) test shoulde performed Although more cumbersome to per-orm data suggest that an oral glucose toleranceest is a more sensitive indicator of NODAT inyperglycemic KTRs52 This may allow earlieretection of overt diabetes and more prompt institu-ion of treatment
DiabetesManagement
Data supporting a substantial benefit in themelioration or reversal of NODAT using immu-osuppression modification in KTRs are veryimited There was consensus in our work grouphat considering the paucity of data for reversingODAT by changing immunosuppression and
he potential risk of an adverse outcome withuch a maneuver KDIGO suggestion 1521 couldot be supported Certainly if such a step waseing considered it should be done in conjunc-ion with the transplant center Targeting an HbA1c
evel of 7-75 and avoiding levels 6 isased on data showing increased cardiovascularvents with the lower HbA1c target5354
DIGORecommendations inChapter 16ypertensionDyslipidemias TobaccoUse andbesity
161 Hypertension1611 We recommend measuring blood pres-
sure at each clinic visit (1C)1612 We suggest maintaining blood pressure at
130 mm Hg systolic and 80 mm Hgdiastolic if 18 years of age and 90th
percentile for sex age and height if 18years old (2C)
1613 To treat hypertension (Not Graded)bull Use any class of antihypertensive
agentbull Monitor closely for adverse effects
and drug-drug interactions and whenurine protein excretion 1 gd for18 years old and 600 mgm224 hfor 18 years old consider an ACE-Ior an ARB as first-line therapy
162 Dyslipidemias (These recommendations are basedon KDOQI Dyslipidemia Guidelines and are thusnot graded)1621 Measure a complete lipid profile in all
adult (18 years old) and adolescent
(puberty to 18 years old) KTRs [Based on
K
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KDOQI Commentary 19
ARTICLE IN PRESS
KDOQI Dyslipidemia Recommendation1]bull 2-3 months after transplantationbull 2-3 months after a change in treatment
or other conditions known to causedyslipidemias
bull at least annually thereafter1622 Evaluate KTRs with dyslipidemias for
secondary causes [Based on KDOQI Dys-lipidemia Recommendation 3]16221 For KTRs with fasting triglyc-
erides 500 mgdL (565mmolL) that cannot be cor-rected by removing an under-lying cause treat withbull Adults therapeutic lifestyle
changes and a triglyceride-lowering agent [Based onKDOQI Recommendation41]
bull Adolescents therapeutic life-style changes [Based onKDOQI Recommendation51]
16222 For KTRs with elevatedLDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)treat to reduce LDL-C to100 mgdL (259mmolL) [Based on KDOQIGuideline 42]
bull Adolescents If LDL-C130 mgdL (336 mmolL) treat to reduce LDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 52]
16223 For KTRs with normalLDL-C elevated triglyceridesand elevated non-HDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)fasting triglycerides 200mgdL (226 mmolL)and non-HDL-C 130mgdL (336 mmolL)treat to reduce non-HDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 43]
bull Adolescents If LDL-C130 mgdL (336 mmolL) fasting triglycerides200 mgdL (226 mmolL) and non-HDL-C 160mgdL (414 mmolL)treat to reduce non-HDL-C
to 160 mgdL (414 i
mmolL) [Based on KDOQIGuideline 53]
163 Tobacco Use1631 Screen and counsel all KTRs including
adolescents and children for tobacco useand record the results in the medicalrecord (Not Graded)bull Screen during initial transplant hospi-
talizationbull Screen at least annually thereafter
1632 Offer treatment to all patients who usetobacco (Not Graded)
164 Obesity1641 Assess obesity at each visit (Not Graded)
bull Measure height and weight at eachvisit in adults and children
bull Calculate BMI at each visitbull Measure waist circumference when
weight and physical appearance sug-gest obesity but BMI is 35 kgm2
1642 Offer a weight-reduction program to allobese KTRs (Not Graded)
DOQIRationale andCommentary
Hypertension
The KDIGO work group adapted the KDOQI004 recommendations for target blood pres-ure in KTRs55 Self measurement is useful inssessing response to therapy and enhancesdherence56 In general we agree that the classf antihypertensive agent does not matter inhe treatment of blood pressure elevation inhis population and that attention should beiven to potential side effects of antihyperten-ive agents as well as possible interactionsith the immunosuppressive regimen (eg non-ihydropyridine calcium channel blockers andNIs) In the absence of adequate randomizedontrolled trials it is not known whether angio-ensin-converting enzyme (ACE) inhibitors andngiotensin receptor blockers (ARBs) prolongecipient or allograft survival Some but notll retrospective studies suggest a benefitowever all these studies are limited by selec-ion bias5758 Although ACE inhibitors andRBs commonly lead to some decrease inFR treatment with these drugs should be
ontinued unless serum creatinine level in-reases by 25 to 30 in keeping withDOQI recommendations55 In KTRs receiv-
ng ACE inhibitors or ARBs it is important toducate patients to maintain adequate fluid
ntake during illness to prevent a prerenal
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ARTICLE IN PRESS
nsult to the allograft Similarly awareness isecessary when using diuretics in conjunctionith therapies that block the renin-angiotensin-
ldosterone-system59
Dyslipidemia
The KDIGO work group based their recom-endations for evaluation and treatment of
yperlipidemia on the KDOQI dyslipidemiauidelines for KTRs60 We agree with theseecommendations CNIs potentiate the toxicityf statins by slowing their metabolism throughhe cytochrome P-450 system This interactionccurs more commonly with cyclosporine61
han with tacrolimus Dyslipidemia especiallyypertriglyceridemia frequently complicatesTOR-inhibitor use and lipid-lowering therapy
s required in most patients using these agents
TobaccoUse
Not surprisingly tobacco use at the time ofransplant is associated with decreased patientnd graft survival as well as increased risk ofosttransplant cardiovascular disease (CVD)lthough the KDIGO work group recom-ends initial screening and intervention dur-
ng the hospitalization for transplant we be-ieve there may be benefit gained by startingounseling in the pretransplant period duringhe evaluation phase Unfortunately this doesot occur often because of time and personnelonstraints in transplant centers Ideally allransplant centers should have smoking-cessa-ion programs available to patients either in-ouse or through referral Ideally systemshould be created to continue to screen andonitor for smoking cessation at yearly inter-
als after transplant because there is a highate of relapse with this addiction As outlinedn KDIGO Table 253 although all pharmaco-ogic therapies for smoking cessation can besed in KTRs the starting dose of vareniclinehould be decreased in patients with GFR 30Lmin
Obesity
Obesity is an epidemic in the United Statesnd the proportion of obese kidney transplantandidates continues to grow In additioneight gain after transplant is very commonly
bserved Obesity in KTRs is associated with w
ncreased risks of wound complications de-ayed graft function acute rejection and NO-AT resulting in inferior patient and graftutcomes Attention to this potential complica-ion and counseling should be initiated duringhe pretransplant evaluation phase Informa-ion regarding pharmacologic therapies foreight loss in KTRs is not available and we
gree with the KDIGO work group that thera-eutic lifestyle measures should be encour-ged Data regarding steroid therapy with-rawal and weight gain are controversial Aecent double-blind randomized controlled trialxamining early steroid therapy withdrawalid not show a difference in weight gain at 5ears posttransplant compared with the cohortemaining on standard maintenance corticoste-oid therapy62
DIGORecommendations inChapter 17ardiovascularManagement
171 Consider managing CVD at least as intensively inKTRs as in the general population with appropri-ate diagnostic tests and treatments (Not Graded)
172 We suggest using aspirin (65-100 mgd) in allpatients with atherosclerotic CVD unless there arecontraindications (2B)
DOQIRationale andCommentary
Although outcomes are favorable comparedith remaining on the waiting list the risk of
ardiovascular mortality in KTRs is several-foldigher than observed in the general population63
specially in younger age groups and patientsith decreasing allograft function64 CVD is aajor cause of graft loss after the first post-
ransplant year In this context we strongly agreehat CVD should be managed in KTRs at least asntensively as in the general population Ideallyecreasing CVD risk in KTRs requires a multifac-ted and multidisciplinary approach Based onurrent practice models in the United States theransplant and nephrology community has notet been able to achieve these desirable goals65
his clearly deserves more attention becauseontrol of CVD has the potential to contributeore to long-term kidney graft survival than the
iscovery of newer drugs that decrease the ratef allograft rejection Our KDOQI working groupgreed with the use of low-dose aspirin in KTRs
ith evidence of atherosclerosis
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KDOQI Commentary 21
ARTICLE IN PRESS
SUMMARY OF COMMENTARY ONSECTION III CVD
COMMENTARY ON SECTION IV OF KDIGO
TRANSPLANT GUIDELINE MALIGNANCY
DIGORecommendations inChapter 18 Cancerf the Skin andLip
181 We recommend that KTRs especially thosewho have fair skin live in high sun-exposureclimates have occupations requiring sun expo-sure have had significant sun exposure as achild or have a history of skin cancer be toldthat their risk of skin and lip cancer is veryhigh (1C)
182 We recommend that KTRs minimize life-longsun exposure and use appropriate ultravioletlight blocking agents (1D)
183 We suggest that adult KTRs perform skin andlip self-examinations and report new lesions toa health-care provider (2D)
184 For adult KTRs we suggest that a qualified healthprofessional with experience in diagnosing skincancer perform annual skin and lip examinationon KTRs except possibly for KTRs with dark skinpigmentation (2D)
185 We suggest that patients with a history of skin orlip cancer or premalignant lesions be referred to andfollowed by a qualified health professional withexperience in diagnosing and treating skin cancer
With the decrease in acute rejection during the pastdecade in association with improved immunosuppres-sion regimens patient death now rivals chronic graftdysfunction as one of the leading causes of long-termgraft loss Because CVD is the most common cause ofpatient death in KTRs a concerted effort at minimizingrisk factors for heart disease likely will have as great oreven greater impact on optimizing patient and graftoutcomes than the discovery of new antirejection thera-pies CVD risk reduction strategies should include regularscreening for new-onset diabetes (using ADA-based defini-tions) in the posttransplant period in previously nondiabeticpatients good glycemic regulation for diabetic patients accord-ing to current ADA guidelines and lipid management andblood pressure control according to KDOQI recommenda-tions In addition promotion of a healthy lifestyle throughweight control exercise and smoking cessation should be acentral part of posttransplant counseling and care Whenimmunosuppression modification is being considered to miti-gate cardiovascular risk we recommend that this be inconjunction with the transplant center In summary we gener-ally concurred with the suggestions of the work group in thissection but based on current practice standards in the UnitedStateschallengesremainwith implementationof thisguideline
(2D) s
186 We suggest that patients with a history of skincancer be offered treatment with oral acitretin ifthere are no contraindications (2B)
DOQIRationale andCommentary
CounselingandSunscreen
We concur with recommendations 181 and82 because skin cancer is a major source oforbidity and sometimes mortality in KTRsarning patients at risk of the high danger of
kin cancer a 1C recommendation is reinforcedy a recent prospective case-control study ofrgan transplant recipients that showed that regu-ar use of broad-spectrum sunscreens that pro-ide UVA and UVB protection may prevent theevelopment of actinic keratosis invasive squa-ous cell carcinoma and to a lesser extent
asal cell carcinoma66 Most cancer-causing ra-iation is thought to come from the UVB spec-rum and newer broad-spectrum sunscreens pro-ide protection against UVA and UVB radiationounseling about sunscreen and the need for sunvoidance needs to be incorporated into routineffice visits although it may not always beuccessful In a recent study of KTRs in which1 of patients had been informed about theeed for sun protection only 46 used morehan a tube of sunscreen per year67
Dermatology Involvement
There is increased evidence to suggest thatpecialty dermatology clinics for organ trans-lant recipients improve outcome measures in-luding compliance with photoprotection andncreased awareness of skin cancer68 The re-ources required for these specialty clinics makemplementation difficult for community nephrol-gy groups that do not have direct access to aransplant center Transplant patients should bencouraged to have annual visits with their trans-lant center and if dermatology specialty clinicsre available attempt to coordinate a skin cancervaluation annually
UseofRetinoid-likeCompounds
There is a limited scientific basis for KDIGOuggestion recommendation 186 Although reti-oids now are used routinely in KTRs with aigh skin cancer burden our KDOQI work groupelieves that more data are needed before this
uggestion should be accepted as a guideline In
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ARTICLE IN PRESS
ow-immunologic-risk groups and particularlyifficult cases some data suggest that switchingrom CNI to sirolimus therapy may decrease thencidence of skin cancer69 however the riskersus benefit of this maneuver has not been welltudied
DIGORecommendations inChapter 19on-SkinMalignancies
191 Develop an individualized screening plan for eachKTR that takes into account the patientrsquos pastmedical and family history tobacco use compet-ing risks for death and the performance of thescreening methodology (Not Graded)
192 Screen for the following cancers as per localguidelines for the general population (Not Graded)Women cervical breast and colon cancer Menprostate and colon cancer
193 Obtain hepatic ultrasound and alpha feto-proteinevery 12 months in patients with compensatedcirrhosis (Not Graded) [See Recommendations1354 (HCV) and 1365 (HBV)]
DOQIRationale andCommentary
Screening
It is recognized that KTRs have a higher inci-ence of malignancy particularly those associatedith specific viral infections Although cancer
creening may have benefits in this higher riskopulation it should be reinforced that some meth-ds of screening have significant risks which shoulde considered on an individualized basis particu-arly in patients who have projected survival lesshan 5 years
Screening forCancer inPatientsWithHepatitis
Many patients who have underlying cirrhosisn the United States will be followed up by arofessional specializing in liver disease whoay provide additional insight into this cancer
creening recommendation Based on a recentuestionnaire of US gastroenterologists only 50creen patients for hepatocellular carcinoma70
herefore implementation of this guideline byS clinicians is unlikely to be widespread
DIGORecommendations inChapter 20anagingCancerwithReductionof
mmunosuppressiveMedication
201 We suggest consideration be given to reducingimmunosuppressive medications for KTRs with can-
cer (2C)
2011 Important factors for consideration in-clude (Not Graded)bull The stage of cancer at diagnosisbull Whether the cancer is likely to be
exacerbated by immunosuppressionbull The therapies available for the can-
cerbull Whether immunosuppressive medica-
tions interfere with ability to admin-ister the standard chemotherapy
202 For patients with Kaposi sarcoma we suggestusing mTORi along with a reduction in overallimmunosuppression (2C)
DOQIRationale andCommentary
Table 1 (Table 29 in the KDIGO report3 andxcerpted from Grulich et al71) lists cancershat are increased most in immunosuppressedTRs based on standardized incidence ratios
SIRs) which compare the incidence toatched populations Cancers with the highestIRs may be those most likely to respond to aecrease in immunosuppression Except foraposi sarcoma limited evidence is available
or a decrease in immunosuppression in theseettings A strategy to change immunosuppres-ion therapy must occur in consultation withhe transplant center Switching to sirolimusherapy and decreasing immunosuppression inatients who develop Kaposi sarcoma is basedn sound scientific rationale7273
SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
The incidence of cancer posttransplant is 2-20times higher than that in the general population andKDIGO guidelines have been written to outline stepsfor prevention and screening With few exceptions weagree with the recommendations as outlined Skincancer is common in US transplant patients andscreening and prevention are critical However imple-mentation of guidelines for doing so including theKDIGO guidelines is a challenge because of patientpreferences against the routine use of sunscreen aswell as time constraints during office visits Althoughmany posttransplant cancers are viral mediated andrelated to immunosuppression it is less clear how toalter immunosuppression after malignancy has oc-curred We agree that although age-specific screeningfor malignancy should be incorporated into care con-sideration must be given to the risk of screening inpatients with limited life spans (5 years) because of
comorbid conditions
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
ommonPopu
i sarco-Hodgmelanise sm
sophaemia
estima standa10 c
ut esti
0 case
alized t
to guide treatment specifically before the
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
K
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ttlhA(o
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
KF
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
REFERENCES1 McCullough KP Keith DS Meyer KH et al Kidney
nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
o2
Tf2
Tfh2
TfcM
CU1
dt
coT
wad6
osA
wt
tdp
eT2
t
op
Mpp
apt
pI
ar
ti2
mi2
i2
uap
ba5
ra2
cJ
sir
ml
gt1
p2
ps2
c2
p2
sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
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f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
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t2
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Iwa
rl5
mi8
oe1
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Bia et al30
ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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KDOQI Commentary 5
ARTICLE IN PRESS
elayed graft function and are no longer used inhe early posttransplant period (KDIGO recom-endation 25) Furthermore studies show an
ncreased rejection rate with early use of theseompounds in place of CNIs The Symphonytudy showed that the highest rejection rateccurred in the arm using low-dose sirolimusith MMF and steroids78
DIGORecommendations inChapter 3ong-termMaintenance Immunosuppressiveedications
31 We suggest using the lowest planned doses ofmaintenance immunosuppressive medications by2-4 months after transplantation if there has beenno acute rejection (2C)
32 We suggest that CNIs be continued rather thanwithdrawn (2B)
32 If prednisone is being used beyond the first weekafter transplantation we suggest prednisone becontinued rather than withdrawn (2C)
DOQIRationale andCommentary
Decreasing ImmunosuppressiveDosage
Although our work group agreed with sugges-ion 31 we stress that dosing of immunosuppres-ion should at all times take into account thendividual patientrsquos risk profile balancing rejec-ion with the adverse effects of medications Inome patients this may mean higher drug dosingrug levels to account for a higher risk of rejec-ion Although most US transplant centers nowtrive for a lower dose of immunosuppressiveedication after the early posttransplant period
he transplant center should define each patientrsquosarget drug dosing based on immunologic riskhich depends on ethnicity age history of previ-us transplant and level of HLA antibodies
ContinueorWithdrawCNITherapy
Although we agreed that mTOR inhibitorshould not be used in the early posttransplanteriod78 newer clinical trials have exploredwitching from CNIs to mTOR inhibitors 3-6onths posttransplant910 Early results suggest
elative safety with improvement in renal func-ion Whether the trade-off of less nephrotoxic-ty with a different side-effect profile of mTORnhibitors will be beneficial in the long termemains to be determined The work groupelieved that suggestion 32 to continue CNI
herapy indefinitely in all patients required
ore study before it could be accepted as auideline
SteroidTherapyWithdrawal
We agree that late steroid therapy with-rawal (1 year) is inadvisable but stress thathe definition of ldquoearlyrdquo steroid discontinua-ion has not been well defined and may occurfter the first week (see commentary underhapter 2)
DIGORecommendations inChapter 4trategies toReduceDrugCosts
41 If drug costs block access to transplantation astrategy to minimize drug costs is appropriateeven if use of inferior drugs is necessary to obtainthe improved survival and quality of life benefitsof transplantation compared with dialysis (NotGraded)411 We suggest strategies that may reduce drug
costs includebull limiting use of a biologic agent for
induction to patients who are high-riskfor acute rejection (2C)
bull using ketoconazole to minimize CNIdose (2D)
bull using a nondihydropyridine CCB to mini-mize CNI dose (2C)
bull using azathioprine rather than mycophe-nolate (2B)
bull using adequately tested bioequivalent ge-neric drugs (2C)
bull using prednisone long-term (2C)
42 Do not use generic compounds that have not beencertified by an independent regulatory agency tomeet each of the following criteria when comparedto the reference compound (Not Graded)bull contains the same active ingredientbull is identical in strength dosage form and route of
administrationbull has the same use indicationsbull is bioequivalent in appropriate bioavailability
studiesbull meets the same batch requirements for identity
strength purity and qualitybull is manufactured under strict standards
43 It is important that the patient and the clinicianresponsible for the patientrsquos care be made aware ofany change in a prescribed immunosuppressivedrug including a change to a generic drug (NotGraded)
44 After switching to a generic medication that ismonitored using blood levels obtain levels andadjust the dose as often as necessary until a stable
therapeutic target is achieved (Not Graded)
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ARTICLE IN PRESS
DOQIRationale andCommentary
Drug costs are becoming an increasing issue inransplantation that impacts on patient adherencend ultimately affects graft survival Currently im-unosuppressive drugs in the United States are
overed by the Centers for Medicare amp Medicaidervices (CMS) the primary insurer for manyTRs for 3 years after transplant although legisla-
ion is being considered to continue this coverageor the life of the kidney Most KTRs are usingany other medications in addition to immunosup-
ressive drugs In general the transplant commu-ity (patients health care providers and policyakers) need to embrace the concept of cost con-
ainment and the risk(s) to the patient and graft byhese measures However this needs to be balancedy who benefits and how much risk is at stake
Use of drugs that block the cytochrome P-450A system in an attempt to decrease CNIosing and costs are rarely used in the Unitedtates The concern is that inadvertent cessa-
ion of treatment with these drugs causing aignificant decrease in drug levels could resultn an acute rejection episode Therefore theork group did not think that many of the 411
uggestions should be accepted as a guidelinewitching from a mycophenolate compound ton azathioprine compound in the later posttrans-lant period may be considered in some pa-ients as another cost-saving maneuver espe-ially in view of recent US registry datahowing similar long-term survival with theserugs11 Although we agree with the sugges-ions outlined in 42 it should be recognizedhat many generic formulations have nevereen tested in transplant patients Patient con-usion with medications when a different ge-eric formulation or even different strengths ofhe same drug from different manufacturers isispensed at each refill can lead to inadvertentedication errors possibly affecting out-
omes Patient education is crucial to avoidrrors in medication administration We agreeith recommendation 44 that it is crucial toonitor patients after an immunosuppressive
osage change brand change or change to aeneric drug However it needs to be recog-ized that implementation of this guideline canecome burdensome as practices become inun-
ated with inquiries from patients payors and 5
harmacies regarding medications Transplantenters and practices that see many transplantatients bear an inordinate part of this burden
DIGORecommendations inChapter 5onitoring ImmunosuppressiveMedications
51 We recommend measuring CNI blood levels(1B) and suggest measuring at leastbull every other day during the immediate postopera-
tive period until target levels are reached (2C)bull whenever there is a change in medication or
patient status that may affect blood levels (2C)bull whenever there is a decline in kidney function that
may indicate nephrotoxicity or rejection (2C)511 We suggest monitoring CsA using 12-h
trough (C0) 2-h post-dose (C2) or abbrevi-ated AUC (2D)
512 We suggest monitoring tacrolimus using12-h trough (C0) (2C)
52 We suggest monitoring MMF levels (2D)53 We suggest monitoring mTOR inhibitor levels (2C)
DOQIRationale andCommentary
Because immunosuppressive drugs are classi-ed as narrow therapeutic agents drug-levelonitoring is a necessary tool to maximize effi-
iency and minimize toxicity The blood drugevel is not synonymous with level of immuno-uppression but may correlate imperfectly withhis effect In most US transplant centers levelsf CNI and mTOR inhibitors are monitoredPA monitoring is problematic because of the
oor correlation between trough levels and areander the curve (AUC) exposure Optimal moni-oring of MPA requires a 4- to 6-hour abbrevi-ted AUC measurement which is logisticallyifficult in the outpatient setting Although stud-es show that monitoring MPA levels in the earlyosttransplant period may be helpful in cyclospor-ne-treated patients recent evidence suggests thatuch monitoring may be less important in pa-ients on tacrolimus therapy12 With most USTRs now being started on tacrolimus as theNI of choice MPA monitoring is not routine inany US transplant centers Although one per-
on in our work group believed there may still beome value in monitoring MPA levels the otherembers questioned the value and applicability
f this practice (KDIGO suggestion 52) Cur-ently many US centers measure MPA only inhe setting of possible drug-related toxicities oride effects Although we agree with suggestion
3 to monitor mTOR inhibitor levels it should
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KDOQI Commentary 7
ARTICLE IN PRESS
e appreciated that therapeutic levels of thisgent have yet to be defined in controlled studies
DIGORecommendations inChapter 6reatment ofAcuteRejection
61 We recommend biopsy before treating acuterejection unless the biopsy will substantiallydelay treatment (1C)
62 We suggest treating subclinical and borderline acuterejection (2D)
63 We recommend corticosteroids for the initialtreatment of acute cellular rejection (1D)631 We suggest adding or restoring maintenance
prednisone in patients not on steroids whohave a rejection episode (2D)
632 We suggest using lymphocyte-depleting anti-bodies or OKT3 [muromonab-CD3] for acutecellular rejections that do not respond tocorticosteroids and for recurrent acute cellu-lar rejections (2C)
64 We suggest treating antibody-mediated acute rejec-tion with one or more of the following alternativeswith or without corticosteroids (2C)bull plasma exchangebull intravenous immunoglobulinbull anti-CD20 antibodybull lymphocyte-depleting antibody
65 For patients who have a rejection episode wesuggest adding mycophenolate if the patient is notreceiving mycophenolate or azathioprine or switch-ing azathioprine to mycophenolate (2D)
DOQIRationale andCommentary
We concur that biopsies should be performed onll KTRs suspected of having an acute rejectionrecommendation 61) Expert interpretation of theiopsy specimen by pathologists accustomed toeading kidney transplant biopsies is as importants expertise in performing the biopsy It is contro-ersial whether subclinical and borderline rejec-ions should be treated (recommendation 62 sup-orted by low evidence [2D]) Subclinical rejectionsre diagnosed in patients who have protocol biop-ies performed by design not for deterioration inidney function Recent data suggest that the riskf subclinical rejection in patients on tacrolimusnd mycophenolate compound therapy is so lowhat protocol biopsies may no longer be indi-ated13 Whether this is true in patients with highmmunologic risk or patients on minimization pro-ocols (ie steroid-free protocols or lower CNI doses)s uncertain Whether borderline rejection shoulde treated or some infiltrates may be protective also
s uncertain In most US centers steroids are used d
ost frequently as first-line treatment for acuteejection followed by lymphocyte-depleting anti-odies in steroid-resistant rejection but there maye exceptions to this approach Decision makingegarding appropriate initial treatment for acuteejection should be based on clinical and patho-ogic information Timing of the rejection episodeosttransplant type of induction agent used beforeejection degree of deterioration in kidney functiont the time of rejection and histologic grade of theejection may influence selection of the appropriatenitial antirejection therapy There is increasingecognition of the role of antibody-mediated mecha-isms in acute rejection This process requirespecial blood tests (to detect donor-specific antibod-es) and histochemical stains (immunofluorescenceor C4d) for diagnosis14 Coordination with theransplant center is critical to ensure that all appro-riate testing is performed and specific treatment isnitiated After treatment of an acute episode opti-
izing overall immunosuppression is requiredonsiderations should include changing the CNIdding a mycophenolate compound or increasinghe dose adding corticosteroids to previously ste-oid-free regimens or addingsubstituting an mTORnhibitor More than 85 of patients are alreadysing MPA agents so the number available forwitching will be relatively small
DIGORecommendations inChapter 7reatment of ChronicAllograft Injury (CAI)
71 We recommend kidney allograft biopsy for allpatients with declining kidney function of unclearcause to detect potentially reversible causes (1C)
72 For patients with CAI and histological evidence ofCNI toxicity we suggest reducing withdrawing orreplacing the CNI (2C)721 For patients with CAI eGFR 40 mLmin
173 m2 and urine total protein excretion500 mgg creatinine (or equivalent protein-uria by other measures) we suggest replac-ing the CNI with a mTOR inhibitor (2D)
DOQIRationale andCommentary
We agree with the need for kidney transplantiopsy in patients with decreasing kidney function71) and again stress the importance of expertise inathologic interpretation Important causes ofhronic allograft injury (CAI) which include rejec-ion BK nephropathy CNI toxicity or recurrentisease require special histochemical stains for
iagnosis that are not readily available in all labora-
tctwtaeogbetiivag
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Bia et al8
ARTICLE IN PRESS
ories Therefore coordination with the transplantenter where these techniques are available is essen-ial For patients with CAI caused by CNI toxicityithdrawing the CNI should occur only after at-
empts at decreasing the dosage have failed Onelso must ensure that all other causes of CAI arexcluded to avoid inappropriate drug adjustmentsr missed treatment options Although our workroup thought that KDIGO suggestion 721 maye reasonable in some patients we also want tomphasize that the role of mTOR inhibitors in thereatment of CAICNI toxicity is poorly defined Its clear that switching from a CNI to an mTORnhibitor should be avoided in patients with se-erely decreased glomerular filtration rate (GFR)ndor the presence of proteinuria however the exactuidelines for when to switch are still evolving
SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
DIGORecommendations inChapter 8onitoringKidneyAllograft Function
81 We suggest measuring urine volume (2C)bull Every 1-2 hours for at least 24 hours after
transplantation (2D)
In the United States immunosuppressive protocolsused may vary from center to center based on theirparticular patient population organ source experienceand opinion of the transplant team ease of use and costof therapy Although data about the efficacy and safety ofsteroid-free regimens are still evolving it is clear that ifsteroids are to be eliminated this should be done in theearly transplant period and not late (after 1 year)Community nephrologists need to coordinate any alter-ations in immunosuppressive medications with the trans-plant center and be vigilant for potential drug interactionswith the addition of any new medications Drug monitor-ing is an essential monitoring tool throughout the post-transplant course but not always applicable to everyimmunosuppressive medication Transplant biopsies fre-quently are necessary to determine the cause of renaldysfunction and the interpretation must be performed bypathologists with resources and experience in handlingand reading the transplant biopsy specimen
bull Daily until graft function is stable (2D) c
82 We suggest measuring urine protein excretion (2C)at leastbull Once in the first month to determine a baseline
(2D)bull Every 3 months during the first year (2D)bull Annually thereafter (2D)
83 We recommend measuring serum creatinine (1B) atleastbull Daily for 7 days or until hospital discharge
whichever occurs sooner (2C)bull 2-3 times per week for weeks 2-4 (2C)bull Weekly for months 2 and 3 (2C)bull Every 2 weeks for months 4-6 (2C)bull Monthly for months 7-12 (2C)bull Every 2-3 months thereafter (2C)
831 We suggest estimating GFR whenever se-rum creatinine is measured (2D) usingbull One of several formulas validated for
adults (2C) orbull The Schwartz formula for children and
adolescents (2C)
84 We suggest including a kidney allograft ultrasoundexamination as part of the assessment of kidneyallograft dysfunction (2C)
DOQIRationale andCommentary
RoutineScreeningTestsandTimeandFrequencyofMonitoring
Regular surveillance and vigilant monitoring ofidney allograft function are important in improv-ng short- and long-term outcomes Early detectionf kidney allograft dysfunction will allow timelyiagnosis and treatment that may improve patientnd graft survival Frequency and types of routinecreening tests after kidney transplant are shown inig 2Although there is no standard protocol for therequency and type of monitoring recommenda-ions are guided by the likelihood of problemspecific to the particular transplant population Inhe early posttransplant period when rejection andomplications are the most likely testing is per-ormed more frequently Thereafter the follow-upnterval will depend in part on the patientrsquos generalondition and the development of additional prob-ems The AST recommended routine posttrans-lant 2-3 visits per week during month 1 every 1-3eeks during month 2-3 every 4-8 weeks duringonths 4-12 and every 2-4 months after therst year These early visits often are providedy the transplant physician or surgeon of theransplant center After 3-6 months monitor-ng may be performed by the transplant physi-
ian or community nephrologist15 In a recent
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KDOQI Commentary 9
ARTICLE IN PRESS
urvey of posttransplant outpatient visits inedicare beneficiaries in the United States
requency of visits to transplant centers variedy center and region most visits were toephrologists16
At each clinic visit education regardingedication adherence diet and healthy life-
tyle should be given Screening for tobaccose should be implemented before dischargend annually Although the work group did notgree that screening all adults for Epstein-Barrirus (EBV) was of value (see commentarynder Chapter 13 for EBV) screening for allther elements listed in Fig 2 including screen-ng for proteinuria is reasonable In additiono these tests monitoring for HLA antibodiesgainst the donor (donor-specific antibodies)hich is not described in the KDIGO guide-
ine is becoming more common in some USenters The optimal timing and frequency ofuch screening has yet to be determined1718
SerumCreatinineandEstimatedGFR
Serum creatinine measurement remains theost commonly used index of renal allograft
unction It is reliable for detecting acute changesn kidney function Furthermore serum creati-ine level at year 1 after transplant is a riskactor for subsequent outcomes19 and mayelp in the management of the frequency ofisits However it is less reliable for detecting
Figure 2 Routine screen-ng after kidney transplantomplete blood cell count in-ludes white blood cells hemo-lobin and platelets Screenor diabetes is by fasting bloodlucose level glucose toler-nce test or hemoglobin A1c
evel Lipid profile includes fast-ng cholesterol low-density li-oprotein cholesterol high-ensity lipoprotein cholesterolnd triglyceride levels Screensor BK polyoma virus (BKV)nd Epstein-Barr virus (EBV)se plasma nucleic acid test-
ng (NAT) EBV screen is foratients with no antibody toBV at transplant Adapted
rom the KDIGO transplantuideline3 with permission ofDIGO
ong-term changes in kidney function in the
idney transplant recipient Formulas to esti-ate GFR using serum creatinine values have
een tested in KTRs but no formula consis-ently has been shown to be superior to an-ther As with CKD considerable renal patho-ogic states can be present without dramatichanges in serum creatinine levels
In 2005 the definition of CKD was amendedo include all KTRs regardless of markers ofidney damage or GFR2021 Although the workroup agreed that CKD staging in KTRs isseful it must be noted that there is consider-ble difference in the rate of progression inhese 2 groups Progression is much slower inTRs in whom kidney half-life is longer at
very level of CKD Renal ultrasound is thereferred imaging study in KTRs (KDIGOuggestion 84)22
DIGORecommendations inChapter 9 Kidneyllograft Biopsy
91 We recommend kidney allograft biopsy whenthere is a persistent unexplained increase inserum creatinine (1C)
92 We suggest kidney allograft biopsy when serumcreatinine has not returned to baseline after treat-ment of acute rejection (2D)
93 We suggest kidney allograft biopsy every 7-10 daysduring delayed function (2C)
94 We suggest kidney allograft biopsy if expectedkidney function is not achieved within the first 1-2months after transplantation (2D)
95 We suggest kidney allograft biopsy when there is
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bull New onset of proteinuria (2C)bull Unexplained proteinuria 30 g per gram creati-
nine or 30 g per 24 hours (2C)
DOQIRationale andCommentary
Biopsy
Renal allograft biopsy is the gold standard foriagnosing the cause of a change in renal allo-raft function It is useful in all clinical situationsescribed in KDIGO suggestions 91-94 Poten-ial causes of allograft dysfunction include vol-me depletion compromised renal blood flowrinary outflow obstruction parenchymal causesuch as acute rejection (cellular andor humoral)hronic allograft nephropathy recurrent or deovo disease or BK nephropathy Patients show-ng a 20-25 increase in creatinine level aboveaseline values warrant consideration for biopsyther indications for pursuing renal allograftiopsy would be a less-than-expected responseo treatment of acute rejection The expectedesponse would be dependent on the severity ofissue injury noted on the diagnostic biopsy speci-
en Delayed graft function lasting longer than-7 days warrants biopsy with repeated biopsieserformed every 7-10 days until graft functionecovers New-onset proteinuria protein 20g creatinine or 20 g24 h also merits aidney biopsy De novo and recurrent glomerulariseases are common causes of new-onset pro-einuria Patients with de novo or recurrent glo-erular diseases should be followed up closely
y transplant nephrologists or community neph-ologists with close communication with theransplant center because treatment of some recur-ent kidney diseases may prevent or delay thenset of graft failure2324
SafetyandAccuracy
The safety of kidney transplant biopsies haseen documented and the overall risk of compli-ations is low Most biopsies are performed inhe transplant center by transplant nephrologistsommunity nephrologists also may perform bi-psies of the kidney in KTRs more than a yearosttransplant It is prudent to obtain a diagnosticltrasound before biopsy to rule out unexpectedlterations in blood flow or urinary tract obstruc-ion It is imperative that a pathologist familiar
ith the transplant process interprets the pathol-
gy in consultation with the referring nephrolo-ist using appropriate stains and other studies
MolecularMarkers
In addition to conventional histopathologicxamination several US transplant centers aresing molecular markers as well as genomic orroteomic methods to enhance our understand-ng of the mechanism of immunologic and non-mmunologic pathway of injury As an exampleolymerase chain reaction (PCR) has been usedo detect messenger RNA for IL-2 and otheriomarkers in biopsy samples Using this ap-roach IL-2 upregulated during rejection coulde detected 2 days before rejection was apparentsing histologic or clinical criteria Such PCRpproaches have been used to detect other generoducts upregulated during acute rejection suchs granzyme B perforin transforming growthactor IL-10 and IL-1525-27 These newerethods are performed almost exclusively in
ransplant centers and may become a standardethod of transplant biopsy analysis in the fu-
ure
DIGORecommendations inChapter 10ecurrentDisease
101 We suggest screening KTRs with primary kidneydisease caused by FSGS for proteinuria (2C) atleastbull Daily for 1 week (2D)bull Weekly for 4 weeks (2D)bull Every 3 months for the first year (2D) Every
year thereafter (2D)
102 We suggest screening KTRs with potentially treat-able recurrence of primary kidney disease fromIgA nephropathy MPGN anti-GBM disease orANCA-associated vasculitis for microhematuria(2C) at leastbull Once in the first month to determine a baseline
(2D)bull Every 3 months during the first year (2D)
Annually thereafter (2D)
103 During episodes of graft dysfunction in patientswith primary HUS we suggest screening forthrombotic microangiopathy (eg with plateletcount peripheral smear for blood cell morphologyplasma haptoglobin and serum lactate dehydroge-nase) (2D)
104 When screening suggests possible treatable recur-rent disease we suggest obtaining an allograftbiopsy (2C)
105 Treatment of recurrent kidney disease1051 We suggest plasma exchange if a biopsy
shows minimal change disease or FSGS
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KDOQI Commentary 11
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in those with primary FSGS as theirprimary kidney disease (2D)
1052 We suggest high-dose corticosteroids andcyclophosphamide in patients with recur-rent ANCA-associated vasculitis or anti-GBM disease (2D)
1053 We suggest using an ACE-I [ACE inhibi-tor] or an ARB for patients with recurrentglomerulonephritis and proteinuria (2C)
1054 For KTRs with primary hyperoxaluriawe suggest appropriate measures to pre-vent oxalate deposition until plasma andurine oxalate levels are normal (2C)includingbull Pyridoxine (2C)bull High calcium and low oxalate diet
(2C)bull Increased oral fluid intake to enhance
urinary dilution of oxalate (2C)bull Potassium or sodium citrate to alkalin-
ize the urine (2C)bull Orthophosphate (2C)bull Magnesium oxide (2C)bull Intensive hemodialysis to remove ox-
alate (2C)
DOQIRationale andCommentary
Recurrent disease accounts for a substantialmount of graft loss after renal transplant It isifficult to assess the percentage of grafts lost toecurrent disease because many patients presentith end-stage renal disease without benefit of aiagnostic native renal biopsy The likelihood ofecurrent disease after transplant is dependent onhe disease with certain diseases at particularlyigh risk of recurrence28
Recurrent Focal SegmentalGlomerulosclerosis
We agree with recommendation 101 regard-ng frequent and regular screening for protein-ria in patients with primary focal segmentallomerulosclerosis (FSGS) as the cause of end-tage renal disease If the patient is still produc-ng urine at the time of transplant a preoperativerine protein-creatinine ratio can be a very help-ul baseline measure of proteinuria Early detec-ion of FSGS recurrence which can present withormal light microscopy but foot-process efface-ent on electron microscopy29 provides the best
pportunity for intervention and amelioration ofisease
IgANephropathy
Recurrence rates of immunoglobulin A (IgA)
ephropathy are variable We agree with recom- b
endation 102 for screening routinely for micro-ematuria Recurrent disease is confirmed with aenal allograft biopsy Histologic recurrence ofisease is much more common than is clinicalisease recurrence There is no proven therapyor treatment of recurrent disease30
MembranoproliferativeGlomerulonephritis
Recurrence of membranoproliferative glomer-lonephritis (MPGN) is common as high as 80ith MPGN type II (dense-deposit disease) Theost common cause of MPGN type I is hepatitisndashassociated immune complex formation Wegree with the proposed regularly scheduledcreening for microhematuria and proteinuria inecommendation 102 Patients with known hepa-itis Cndashassociated MPGN pretransplant also maye screened for cryoglobulins which are associ-ted with MPGN31
HemolyticUremic Syndrome
Hemolytic uremic syndrome (HUS) typicallys divided into diarrheal associated (D) andonndashdiarrheal associated (D) D disease oc-urs mostly in children and rarely recurs post-ransplant However D HUS is more commonn adults and can recur In HUS associated with aomplement abnormality such as factor H defi-iency or factor I mutation recurrence rates cane as high as 80 Screening for evidence ofecurrence allows for an earlier diagnosis whichill require biopsy in most cases and provides
n opportunity for earlier intervention There iso comment in the guideline regarding recur-ence of thrombotic thrombocytopenic purpuraut early detection of recurrence provides anpportunity for treatment with plasmapheresisnd intravenous immune globulin (IVIG)
BiopsyandTreatment
As stated kidney biopsy and interpretation bypathologist with expertise in transplant speci-en readings is critical in the diagnosis of dis-
ase recurrence Treatment for most recurrentisease in renal transplantation is based on aombination of case reports case cohorts andetrospective reviews Recurrent diseases post-ransplant are not common enough that random-zed controlled trials can be implemented there-ore most recommendations for treatment are
ased on a consensus of opinion Despite this we
at
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gree in general with the recommendations de-ailed in 105
DIGORecommendations inChapter 11reventingDetecting andTreatingonadherence
111 Consider providing all KTRs and family memberswith education prevention and treatment mea-sures to minimize nonadherence to immunosup-pressive medications (Not Graded)
112 Consider providing KTRs at increased risk fornonadherence with increased levels of screeningfor nonadherence (Not Graded)
DOQIRationale andCommentary
Noncompliance or nonadherence to diet andedication is a common problem in KTRs Nonad-
erence to medication is associated with a high riskf acute rejection and allograft loss We agree thatarly efforts should be made to identify KTRs atncreased risk of nonadherence and that these pa-ients should be monitored closely Prevention iden-ification and treatment of nonadherence are inte-ral to the monitoring of kidney allograft functionnd long-term care of KTRs Certain subgroup ofTRs younger patients African Americans and
hose with financial hardships have an enhancedisk of nonadherence3233
In addition to identifying patients at risk it ismportant to have a system for addressing patientonadherence This requires coordinated efforts ofocial workers transplant coordinators financialounselors pharmacists primary nephrologists andhe patientrsquos family34 A combination of educa-ional behavioral and social support interventionsrovides the best results Because there is no per-ect measure of adherence consideration should beiven to multiple approaches for adherence moni-oring Similar team approaches also are importantn other areas requiring adherence such as dietxercise tobacco alcohol and drug use
DIGORecommendations inChapter 12accination
121 We recommend giving all KTRs approvedinactivated vaccines according to recommendedschedules for the general population except forHBV vaccination (1D)1211 We suggest HBV vaccination (ideally
prior to transplantation) and HBsAb titers6-12 weeks after completing the vaccina-
tion series (2D) h
12111 We suggest annual HBsAb[antibody to hepatitis B sur-face antigen] titers (2D)
12112 We suggest revaccination ifthe antibody titer falls below10 mIUmL (2D)
122 We suggest avoiding live vaccines in KTRs (2C)123 We suggest avoiding vaccinations except influ-
enza vaccination in the first 6 months followingkidney transplantation (2C)1231 We suggest resuming immunizations once
patients are receiving minimal mainte-nance doses of immunosuppressive medi-cations (2C)
1232 We recommend giving all KTRs whoare at least 1-month post-transplantinfluenza vaccination prior to the onsetof the annual influenza season regard-less of status of immunosuppression(1C)
124 We suggest giving the following vaccines to KTRswho due to age direct exposure residence ortravel to endemic areas or other epidemiologicalrisk factors are at increased risk for the specificdiseasesbull rabies (2D)bull tick-borne meningoencephalitis (2D)bull Japanese B encephalitismdashinactivated (2D)bull Meningococcus (2D)bull Pneumococcus (2D)bull Salmonella typhimdashinactivated (2D)1241 Consult an infectious disease specialist a
travel clinic or public health official forguidance on whether specific cases war-rant these vaccinations (Not Graded)
DOQIRationale andCommentary
KTRs are at particular risk of viral infectionsecause of the preferential suppression of T lympho-ytes by both induction and maintenance immuno-uppression The risk and consequence of develop-ng a viral infection warrant use of selected vaccineshe suggestions regarding which vaccines are safend which are contraindicated are based on whetherhe vaccine contains live or killed virus Live virusaccines are contraindicated in immunosuppressedTRs The KDIGO recommendations for vaccina-
ions agree with updated guidelines recently pub-ished by the AST35 Specific comments on theDIGO suggestions regarding vaccinations are
isted in the following sections
Hepatitis B
The work group did not concur with KDIGOuggestion 1211 Neither revaccination against
epatitis after transplant nor following up hepa-
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KDOQI Commentary 13
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itis B antibody titers annually is a commonractice in the United States Hepatitis B is nots prevalent in the United States as in otherarts of the world and evidence supportingcreening in all patients posttransplant is lack-ng However screening for seroconversion inatients at risk (receiving a hepatitis B corentibodyndashpositive kidney) is appropriate Theseatients may benefit from lamivudine or ente-avir therapy36
LiveVaccineandTimingofVaccine
There is no particular reason for a 6-monthag between transplant and vaccination Theheory is that vaccines are less likely to beffective in the period when immunosuppres-ion is high In the United States most individu-ls are on their baseline maintenance immuno-uppression therapy by 3 months posttransplantecisions regarding the timing of vaccines areade based on immunosuppression exposure
nd risk of infection Recipients also shouldvoid intimate contact with individuals whoave received live vaccines37 This includesvoiding close contact with children who haveeceived oral polio vaccine for 3 weeks anday include close contact with adults receiv-
ng the attenuated varicella vaccine to preventoster Immunosuppressed individuals are ad-ised to avoid contact for 7 days with individu-ls who have received live virus nasal spraysor influenza We concur with the recommenda-ion for flu vaccine but common practice inhe United States is to wait 3-6 months afterransplant before it is administered
DIGORecommendations inChapter 13 Viraliseases
131 BK POLYOMA VIRUS1311 We suggest screening all KTRs for BKV
with quantitative plasma NAT (2C) atleastbull monthly for the first 3-6 months after
transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull whenever there is an unexplained rise
in serum creatinine (2D)bull and after treatment for acute rejection
(2D)1312 We suggest reducing immunosuppressive
medications when BKV plasma NAT is
persistently greater than 10 000 cop-iesmL (107 copiesL) (2D)
132 CYTOMEGALOVIRUS1321 CMV prophylaxis We recommend that
KTRs (except when donor and recipi-ent both have negative CMV serolo-gies) receive chemoprophylaxis forCMV infection with oral ganciclovir orvalganciclovir for at least 3 monthsafter transplantation (1B) and for 6weeks after treatment with a T-cellndashdepleting antibody (1C)
1322 In patients with CMV disease we suggestweekly monitoring of CMV by NAT orpp65 antigenemia (2D)
1323 CMV treatment13231 We recommend that all pa-
tients with serious (includ-ing most patients with tissueinvasive) CMV disease betreated with intravenousganciclovir (1D)
13232 We recommend that CMVdisease in adult KTRs that isnot serious (eg episodes thatare associated with mildclinical symptoms) be treatedwith either intravenous gan-ciclovir or oral valganciclo-vir (1D)
13233 We recommend that allCMV disease in pediatricKTRs be treated with intra-venous ganciclovir (1D)
13234 We suggest continuing therapyuntil CMV is no longer detect-able by plasma NAT or pp65antigenemia (2D)
1324 We suggest reducing immunosuppressivemedication in life-threatening CMV dis-ease and CMV disease that persists in theface of treatment until CMV disease hasresolved (2D)13241 We suggest monitoring graft
function closely during CMVdisease (2D)
133 EPSTEIN-BARR VIRUS AND POST-TRANS-PLANT LYMPHOPROLIFERATIVE DISEASE1331 We suggest monitoring high-risk (donor
EBV seropositiverecipient seronegative)KTRs for EBV by NAT (2C)bull once in the first week after transplanta-
tion (2D)bull then at least monthly for the first 3-6
months after transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull and additionally after treatment for
acute rejection (2D)
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1332 We suggest that EBV-seronegative pa-tients with an increasing EBV load haveimmunosuppressive medication reduced(2D)
1333 We recommend that patients with EBVdisease including PTLD have a reduc-tion or cessation of immunosuppres-sive medication (1C)
134 HERPES SIMPLEX VIRUS 1 2 AND VARI-CELLA ZOSTER VIRUS1341 We recommend that KTRs who de-
velop a superficial HSV 1 2 infectionbe treated (1B) with an appropriateoral antiviral agent (eg acyclovir vala-cyclovir or famciclovir) until all le-sions have resolved (1D)
1342 We recommend that KTRs with sys-temic HSV 1 2 infection be treated(1B) with intravenous acyclovir and areduction in immunosuppressive medi-cation (1D)13421 We recommend that intrave-
nous acyclovir continue un-til the patient has a clinicalresponse (1B) then switch toan appropriate oral antiviralagent (eg acyclovir valacy-clovir or famciclovir) to com-plete a total treatment durationof 14-21 days (2D)
1343 We suggest using a prophylactic antiviralagent for KTRs experiencing frequentrecurrences of HSV 12 infection (2D)
1344 We recommend that primary VZV infec-tion (chicken pox) in KTRs be treated(1C) with either intravenous or oral acy-clovir or valacyclovir and a temporaryreduction in amount of immunosuppres-sive medication (2D)
135 HEPATITIS C VIRUS1351 We suggest that HCV-infected KTRs be
treated only when the benefits of treat-ment clearly outweigh the risk of allo-graft rejection due to interferon-basedtherapy (eg fibrosing cholestatic hepati-tis life-threatening vasculitis) (2D)[Based on KDIGO Hepatitis C Recom-mendation 215]
1352 We suggest monotherapy with standardinterferon for HCV-infected KTRs inwhom the benefits of antiviral treatmentclearly outweigh the risks (2D) [Basedon KDIGO Hepatitis C Recommenda-tions 224 and 442]
1353 We suggest that all conventional currentinduction and maintenance immunosup-pressive regimens can be used in HCVinfected patients (2D) [Based on KDIGO
Hepatitis C Recommendation 43]
1354 Measure ALT in HCV-infected patientsmonthly for the first 6 months and every3-6 months thereafter Perform imagingannually to look for cirrhosis and hepato-cellular carcinoma (Not Graded) [Basedon KDIGO Hepatitis C Recommendation441] (See Recommendation 193)
1355 Test HCV-infected patients at least every3-6 months for proteinuria (Not Graded)[Based on KDIGO Hepatitis C Recom-mendation 444]13551 For patients who develop new
onset proteinuria (either urineproteincreatinine ratio 1 or24-hour urine protein 1 g ontwo or more occasions) per-form an allograft biopsy withimmunofluorescence and elec-tron microscopy (Not Graded)[Based on KDIGO Hepatitis CRecommendation 444]
1356 We suggest that patients with HCV asso-ciated glomerulopathy not receive inter-feron (2D) [Based on KDIGO HepatitisC Recommendation 445]
136 HEPATITIS B VIRUS1361 We suggest that any currently available
induction and maintenance immunosup-pressive medication can be used in HBV-infected KTRs (2D)
1362 We suggest that interferon treatmentshould generally be avoided in HBVinfected KTRs (2C)
1363 We suggest that all HBsAg-positive KTRsreceive prophylaxis with tenofovir ente-cavir or lamivudine (2B)13631 Tenofovir or entecavir are pref-
erable to lamivudine to mini-mize development of potentialdrug resistance unless medica-tion cost requires that lami-vudinebe used (Not Graded)
13632 During therapy with antivi-rals measure HBV DNA andALT levels every 3 months tomonitor efficacy and to detectdrug resistance (Not Graded)
1364 We suggest treatment with adefovir ortenofovir for KTRs with lamivudine resis-tance (5 log10 copiesmL rebound ofHBV-DNA) (2D)
1365 Screen HBsAg-positive patients with cir-rhosis for hepatocellular carcinoma every12 months with liver ultrasound andalpha feto-protein (Not Graded) (SeeRecommendation 193)
1366 We suggest that patients who are negativefor HBsAg and have HBsAb titer 10mIUmL receive booster vaccination to
raise the titer to 100 mIUmL (2D)
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KDOQI Commentary 15
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137 HUMAN IMMUNODEFICIENCY VIRUS1371 If not already done screen for HIV
infection (Not Graded)1372 To determine antiretroviral therapy refer
HIV-infected KTRs to an HIV specialistwho should pay special attention to drugndashdrug interactions and appropriate dosingof medications (Not Graded)
DOQIRationale andCommentary
Viral infections are particularly problematic inransplant recipients because of the preferentialnhibition of T-lymphocyte function by both induc-ion and maintenance immunosuppression Use ofnduction immunosuppression with lymphocyte-epleting agents (thymoglobulin or alemtuzumab)s associated with a greater risk of viral infectionosttransplant In general the greater the cumula-ive exposure to immunosuppression the greaterhe risk of infectious complications The presenta-ion of viral infections can be asymptomatic vaguend nonspecific or life-threatening acute illnessany viral infections seen in KTRs are rarely seen
n immunocompetent patients and therefore do notnter into the differential diagnosis for physiciansnfamiliar with transplant recipients Close commu-ication with the transplant center is crucial inaring for the transplant population Early detectionnd institution of therapy provide the best chanceor viral eradication
BKVirus
Although the work group agreed with KDIGOuggestions for BK virus screening posttransplante did not think it was practical to require screen-
ng exclusively with quantitative plasma nucleiccid testing (NAT) because many US centers usenitial urinary screening and then test plasma onlyf urine screening results are positive Howeverhere is no disagreement that some type of screen-ng for BK virus is critical to avoid BK nephropa-hy for which there is no specific treatment when its established Complicating screening for BK vi-us is the variability in results between laboratoriesnd uncertainty about the level of viremia thathould trigger a response to decrease in immunosup-ression In the presence of viremia and increase inerum creatinine level a renal allograft biopsy isndicated to confirm the presence of BK nephropa-
hy Because BK viremia and viruria certainly can b
e detected beyond the first year it is not clear howong screening should be continued posttransplantlthough most centers screen for the first year onlyngoing clinical trials are exploring effective treat-ent for BK nephropathy3839 Decisions about
ecreases in immunosuppression currently theainstay of BK viremia management always
hould be made in consultation with the transplantenter
Cytomegalovirus
KDIGO recommendation 1321 regarding cyto-egalovirus (CMV) prophylaxis is reasonable and
pplicable to the US population Universal prophy-axis for CMV now is recommended over initiatingre-emptive treatment after CMV develops40 Aajor concern for US patients is the cost of CMV
rophylaxis with oral valgancyclovir Leukopeniaan be observed in patients using mycophenolatereparations when prophylaxis with valgancyclo-ir is used Screening for CMV is best performedsing NAT methods (1322) CMV antigenemiassays are still in use in many facilities but are nots sensitive as PCR assays41 There is no utility inhecking for serologic response to CMV with IgGr IgM titers posttransplant because the immuneesponse is not predictable Patients with CMVisease should be cared for by clinicians familiarith treating this disease It is recommended that
reatment be continued until viral load is undetect-ble followed by prophylactic doses of valgancy-lovir for an additional 3 months35
Epstein-BarrVirus
Current practice regarding EBV screening variesmong centers in the United States and many doot routinely screen for EBV posttransplant evenn recipient-negative donor-positive cases In con-rast to KDIGO recommendation 1311 routineBV screening is not recommended in AST infec-
ious disease guidelines35 In many centers EBVcreening is reserved for children who are muchore commonly EBV negative pretransplant than
dults EBV-induced posttransplant lymphoprolif-rative disorder (PTLD) affects many more pediat-ic than adult KTRs If screening is someday to beoutinely implemented in US centers details regard-ng the best method of screening and levels ofiremia above which a clinical intervention should
e triggered need to be better defined
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HerpesandVaricella
Systemic herpesvirus infections can be lifehreatening in transplant recipients and should bereated aggressively with intravenous antiviralgents as described in the KDIGO recommenda-ions Less aggressive cutaneous infection can bereated with oral antiviral agents as outlined inhe KDIGO guidelines
Varicella exposure is particularly concerning inransplant recipients The work group disputes theecommended dosing of acyclovir for varicellaxposure Acyclovir at a dose of 10 mgkg or about00 mg 4 times daily of oral acyclovir would betandard dosing We agree with the use of varicellammune globulin and emphasize the need to avoidhe varicella vaccine because it is a live virushould a transplant recipient develop a systemicaricella infection hospitalization and high-dosentravenous acyclovir therapy are warranted
Hepatitis C
Hepatitis C management posttransplant is ahallenge The KDIGO guidelines cited hereere based on the recently published KDIGOuideline for hepatitis C in CKD4 Hepatitis Cypically is not treated posttransplant because ofhe risk (50) of rejection precipitated bynterferon therapy particularly in US KTRs inhom hepatitis C commonly is genotype 1 which
s more resistant to treatment with interferon42
owever should hepatitis Cndashrelated glomerulo-ephritis develop the risk-benefit ratio may fa-or treatment in selected patients Such decisionslways should be made in consultation withepatology and infectious disease experts andhe transplant center Monitoring liver enzymeevels specifically alanine aminotransferaseALT) may reflect a change in hepatitis activityut monitoring hepatitis C viral load is not recom-ended because it does not seem to correlateith outcome Annual monitoring for hepatocel-
ular carcinoma using -fetoprotein and imagings encouraged but not often practiced
Hepatitis B
KDIGO recommendations for hepatitis B areeasonable and currently are followed in mostS centers except for recommendation 1366
see previous recommendation under vaccina-ions) KTRs with hepatitis C or hepatitis B also
hould be followed up by a hepatologist
Human ImmunodeficiencyVirus
Human immunodeficiency virus (HIV)-posi-ive individuals are now acceptable for transplantf CD4 count is 200 cellsL and viral loadVL) is undetectable3543 Transplant should beerformed at centers with expertise in managingIV-positive individuals and care should be co-rdinated carefully with HIV specialists Somentiretroviral agents in particular the proteasenhibitors have potentially serious drug interac-ions with immunosuppressive agents35
DIGORecommendations inChapter 14Othernfections
141 URINARY TRACT INFECTION1411 We suggest that all KTRs receive UTI
prophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 monthsafter transplantation (2B)
1412 For allograft pyelonephritis we suggestinitial hospitalization and treatment withintravenous antibiotics (2C)
142 PNEUMOCYSTIS JIROVECII PNEUMONIA1421 We recommend that all KTRs receive
PCP prophylaxis with daily tri-methoprimndashsulfamethoxazole for 3-6months after transplantation (1B)
1422 We suggest that all KTRs receive PCPprophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 weeksduring and after treatment for acute rejec-tion (2C)
1423 We recommend that KTRs with PCPdiagnosed by bronchial alveolar lavageandor lung biopsy be treated withhigh-dose intravenous trimethoprimndashsulfamethoxazole corticosteroids anda reduction in immunosuppressivemedication (1C)
1424 We recommend treatment with cortico-steroids for KTRs with moderate tosevere PCP (as defined by PaO2 lt70mm Hg in room air or an alveolargradient of gt35 mm Hg) (1C)
143 TUBERCULOSIS1431 We suggest that TB prophylaxis and
treatment regimens be the same in KTRsas would be used in the local generalpopulation who require therapy (2D)
1432 We recommend monitoring CNI andmTORi [mTOR inhibitor] blood levels inpatients receiving rifampin (1C)14321 Consider substituting rifabu-
tin for rifampin to minimize
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KDOQI Commentary 17
ARTICLE IN PRESS
interactions with CNIs andmTORi (Not Graded)
144 CANDIDA PROPHYLAXIS1441 We suggest oral and esophageal Candida
prophylaxis with oral clotrimazole loz-enges nystatin or fluconazole for 1-3months after transplantation and for 1month after treatment with an antilympho-cyte antibody (2C)
DOQIRationale andCommentary
UrinaryTract Infection
Urinary tract infections (UTIs) after kidneyransplant are very common and account for aarge percentage of readmissions posttransplantTIs are common because of multiple factors
ncluding the disrupted anatomy of the urinaryract with a ureteroneocystotomy incompleteladder emptying because of diabetes or pros-atic hypertrophy and impaired immune re-ponses Prophylaxis of UTIs usually is under-aken with trimethoprim-sulfamethoxazole for 6onths posttransplant although infections often
ccur despite therapy because of the develop-ent of drug resistance Although native kidney
yelonephritis does not always require hospital-zation it is recommended that all KTRs withhis diagnosis be hospitalized because the graftysfunction that usually accompanies transplantyelonephritis requires aggressive investigationnd treatment Individuals with recurrent UTIsarrant evaluation with urologic assessment Pa-
ients with recurrent UTIs may benefit fromong-term suppressive therapy
Pneumocystic Pneumonia
We agree that Pneumocystis jirovecii pneumoniaPCP) prophylaxis is important for the first 3-6onths posttransplant (1421)After the first month
very-other-day dosing of trimethoprim-sulfame-hoxazole or atovaquone is believed to be adequaterophylaxis In cases in which neither of thesegents can be used an individual may be treatedrophylactically with inhaled pentamidine OurDOQI work group emphasized that patients whoevelop PCP should be transferred to the transplantenter promptly for management and adjustmentsn immunosuppression
Tuberculosis
Monitoring for latent tuberculosis has posed a
hallenge in the immunosuppressed population be-
ause of the unreliable nature of skin testing Newerechniques involving interferon release assays aremerging as the new gold standard for detection ofatent tuberculosis4445
CandidaProphylaxis
Oral candidiasis must be screened for usingral mucosa examination on follow-up visitsn KTRs This is especially true in the earlyosttransplant period when immunosuppres-ive medication dosage is the highest Wegree with these recommendations and empha-ize that if fluconazole is used there is aotential for serious drug interactions becausef cytochrome P-450 3A4 inhibition
SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
Improvement in short-term outcomes has not trans-lated into significant improvements in long-term out-comes in KTRs The lack of significant improvement inlong-term survival may be related to post-transplantcomplications Frequent posttransplant monitoring mayimprove long-term outcomes by decreasing chronic graftfailure or death with a functioning graft Our work groupconcurred with the recommendation and schedules ofroutine screening in monitoring kidney allograft functionafter kidney transplant with a low threshold for perform-ing kidney biopsy in cases of graft dysfunction or protein-uria Expert tissue processing and interpretation of trans-plant biopsy specimens by pathologists with transplantexperience are critical Regular surveillance of the pa-tientrsquos kidney function at the transplant center or in thenephrologistrsquos office offers an opportunity to enhancepatient adherence to medication diet and healthy life-style Although CKD in KTRs progresses more slowlythan CKD in other patients the work group agreed thatthe KDIGO guidelines on CKD should be followed inKTRs
Opportunistic infections are common in KTRs al-though advances in diagnosis and treatment have led toimproved survival in KTRs with infection It is nowstandard of care to use vaccinations in KTRs as long asthe vaccine does not contain live or attenuated virus Italso is routine to screen for or use prophylaxis to preventseveral posttransplant viral infections With few excep-tions (related to EBV and BK virus screening andhepatitis B vaccination posttransplant) we concurredwith KDIGO guidelines for vaccination screening and
treatment of infection posttransplant
KD
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ARTICLE IN PRESS
COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULAR
DISEASE
DIGORecommendations inChapter 15iabetesMellitus
151 Screening for New-Onset Diabetes after Transplan-tation1511 We recommend screening all nondia-
betic KTRs with fasting plasma glu-cose oral glucose tolerance testingandor HbA1c (1C) at leastbull weekly for 4 weeks (2D)bull every 3 months for 1 year (2D)bull and annually thereafter (2D)
1512 We suggest screening for NODAT withfasting glucose oral glucose tolerancetesting andor after starting or substan-tially increasing the dose of CNIsmTORi or corticosteroids (2D)
152 Managing NODAT or Diabetes Present at Trans-plantation1521 If NODAT develops consider modifying
the immunosuppressive drug regimen toreverse or ameliorate diabetes afterweighing the risk of rejection and otherpotential adverse effects (Not Graded)
1522 Consider targeting HbA1c 70-75and avoid targeting HbA1c 60 espe-cially if hypoglycemic reactions are com-mon (Not Graded)
1523 We suggest that in patients with diabetesaspirin (65-100 mgd) use for the primaryprevention of CVD be based on patientpreferences and values balancing the riskfor ischemic events to that of bleeding(2D)
DOQIRationale andCommentary
Diabetic Screening
We agree with screening for new-onset diabetesfter transplantation (NODAT) as outlined by theDIGO work group Definitions used are similar
o those of the American Diabetes AssociationADA) The greater frequency of testing initially isustified by the high risk of NODAT in the earlyosttransplant period however ongoing screenings required because the risk of the development ofODAT continues to increase over time4647 We
lso point out that prediabetic states (impairedasting glucose level and impaired glucose toler-nce) occur even more commonly than overt diabe-es48 and may be associated with metabolic syn-rome as well as with increased cardiovascular
ortality49-51 Potential implications of these predia-
etic states emphasize the importance of perform-ng blood tests under fasting conditions For pa-ients with fasting hyperglycemia an oral glucoseolerance test or hemoglobinA1c (HbA1c) test shoulde performed Although more cumbersome to per-orm data suggest that an oral glucose toleranceest is a more sensitive indicator of NODAT inyperglycemic KTRs52 This may allow earlieretection of overt diabetes and more prompt institu-ion of treatment
DiabetesManagement
Data supporting a substantial benefit in themelioration or reversal of NODAT using immu-osuppression modification in KTRs are veryimited There was consensus in our work grouphat considering the paucity of data for reversingODAT by changing immunosuppression and
he potential risk of an adverse outcome withuch a maneuver KDIGO suggestion 1521 couldot be supported Certainly if such a step waseing considered it should be done in conjunc-ion with the transplant center Targeting an HbA1c
evel of 7-75 and avoiding levels 6 isased on data showing increased cardiovascularvents with the lower HbA1c target5354
DIGORecommendations inChapter 16ypertensionDyslipidemias TobaccoUse andbesity
161 Hypertension1611 We recommend measuring blood pres-
sure at each clinic visit (1C)1612 We suggest maintaining blood pressure at
130 mm Hg systolic and 80 mm Hgdiastolic if 18 years of age and 90th
percentile for sex age and height if 18years old (2C)
1613 To treat hypertension (Not Graded)bull Use any class of antihypertensive
agentbull Monitor closely for adverse effects
and drug-drug interactions and whenurine protein excretion 1 gd for18 years old and 600 mgm224 hfor 18 years old consider an ACE-Ior an ARB as first-line therapy
162 Dyslipidemias (These recommendations are basedon KDOQI Dyslipidemia Guidelines and are thusnot graded)1621 Measure a complete lipid profile in all
adult (18 years old) and adolescent
(puberty to 18 years old) KTRs [Based on
K
2saaottgswdCctarahtAGccKie
KDOQI Commentary 19
ARTICLE IN PRESS
KDOQI Dyslipidemia Recommendation1]bull 2-3 months after transplantationbull 2-3 months after a change in treatment
or other conditions known to causedyslipidemias
bull at least annually thereafter1622 Evaluate KTRs with dyslipidemias for
secondary causes [Based on KDOQI Dys-lipidemia Recommendation 3]16221 For KTRs with fasting triglyc-
erides 500 mgdL (565mmolL) that cannot be cor-rected by removing an under-lying cause treat withbull Adults therapeutic lifestyle
changes and a triglyceride-lowering agent [Based onKDOQI Recommendation41]
bull Adolescents therapeutic life-style changes [Based onKDOQI Recommendation51]
16222 For KTRs with elevatedLDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)treat to reduce LDL-C to100 mgdL (259mmolL) [Based on KDOQIGuideline 42]
bull Adolescents If LDL-C130 mgdL (336 mmolL) treat to reduce LDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 52]
16223 For KTRs with normalLDL-C elevated triglyceridesand elevated non-HDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)fasting triglycerides 200mgdL (226 mmolL)and non-HDL-C 130mgdL (336 mmolL)treat to reduce non-HDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 43]
bull Adolescents If LDL-C130 mgdL (336 mmolL) fasting triglycerides200 mgdL (226 mmolL) and non-HDL-C 160mgdL (414 mmolL)treat to reduce non-HDL-C
to 160 mgdL (414 i
mmolL) [Based on KDOQIGuideline 53]
163 Tobacco Use1631 Screen and counsel all KTRs including
adolescents and children for tobacco useand record the results in the medicalrecord (Not Graded)bull Screen during initial transplant hospi-
talizationbull Screen at least annually thereafter
1632 Offer treatment to all patients who usetobacco (Not Graded)
164 Obesity1641 Assess obesity at each visit (Not Graded)
bull Measure height and weight at eachvisit in adults and children
bull Calculate BMI at each visitbull Measure waist circumference when
weight and physical appearance sug-gest obesity but BMI is 35 kgm2
1642 Offer a weight-reduction program to allobese KTRs (Not Graded)
DOQIRationale andCommentary
Hypertension
The KDIGO work group adapted the KDOQI004 recommendations for target blood pres-ure in KTRs55 Self measurement is useful inssessing response to therapy and enhancesdherence56 In general we agree that the classf antihypertensive agent does not matter inhe treatment of blood pressure elevation inhis population and that attention should beiven to potential side effects of antihyperten-ive agents as well as possible interactionsith the immunosuppressive regimen (eg non-ihydropyridine calcium channel blockers andNIs) In the absence of adequate randomizedontrolled trials it is not known whether angio-ensin-converting enzyme (ACE) inhibitors andngiotensin receptor blockers (ARBs) prolongecipient or allograft survival Some but notll retrospective studies suggest a benefitowever all these studies are limited by selec-ion bias5758 Although ACE inhibitors andRBs commonly lead to some decrease inFR treatment with these drugs should be
ontinued unless serum creatinine level in-reases by 25 to 30 in keeping withDOQI recommendations55 In KTRs receiv-
ng ACE inhibitors or ARBs it is important toducate patients to maintain adequate fluid
ntake during illness to prevent a prerenal
inwa
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ARTICLE IN PRESS
nsult to the allograft Similarly awareness isecessary when using diuretics in conjunctionith therapies that block the renin-angiotensin-
ldosterone-system59
Dyslipidemia
The KDIGO work group based their recom-endations for evaluation and treatment of
yperlipidemia on the KDOQI dyslipidemiauidelines for KTRs60 We agree with theseecommendations CNIs potentiate the toxicityf statins by slowing their metabolism throughhe cytochrome P-450 system This interactionccurs more commonly with cyclosporine61
han with tacrolimus Dyslipidemia especiallyypertriglyceridemia frequently complicatesTOR-inhibitor use and lipid-lowering therapy
s required in most patients using these agents
TobaccoUse
Not surprisingly tobacco use at the time ofransplant is associated with decreased patientnd graft survival as well as increased risk ofosttransplant cardiovascular disease (CVD)lthough the KDIGO work group recom-ends initial screening and intervention dur-
ng the hospitalization for transplant we be-ieve there may be benefit gained by startingounseling in the pretransplant period duringhe evaluation phase Unfortunately this doesot occur often because of time and personnelonstraints in transplant centers Ideally allransplant centers should have smoking-cessa-ion programs available to patients either in-ouse or through referral Ideally systemshould be created to continue to screen andonitor for smoking cessation at yearly inter-
als after transplant because there is a highate of relapse with this addiction As outlinedn KDIGO Table 253 although all pharmaco-ogic therapies for smoking cessation can besed in KTRs the starting dose of vareniclinehould be decreased in patients with GFR 30Lmin
Obesity
Obesity is an epidemic in the United Statesnd the proportion of obese kidney transplantandidates continues to grow In additioneight gain after transplant is very commonly
bserved Obesity in KTRs is associated with w
ncreased risks of wound complications de-ayed graft function acute rejection and NO-AT resulting in inferior patient and graftutcomes Attention to this potential complica-ion and counseling should be initiated duringhe pretransplant evaluation phase Informa-ion regarding pharmacologic therapies foreight loss in KTRs is not available and we
gree with the KDIGO work group that thera-eutic lifestyle measures should be encour-ged Data regarding steroid therapy with-rawal and weight gain are controversial Aecent double-blind randomized controlled trialxamining early steroid therapy withdrawalid not show a difference in weight gain at 5ears posttransplant compared with the cohortemaining on standard maintenance corticoste-oid therapy62
DIGORecommendations inChapter 17ardiovascularManagement
171 Consider managing CVD at least as intensively inKTRs as in the general population with appropri-ate diagnostic tests and treatments (Not Graded)
172 We suggest using aspirin (65-100 mgd) in allpatients with atherosclerotic CVD unless there arecontraindications (2B)
DOQIRationale andCommentary
Although outcomes are favorable comparedith remaining on the waiting list the risk of
ardiovascular mortality in KTRs is several-foldigher than observed in the general population63
specially in younger age groups and patientsith decreasing allograft function64 CVD is aajor cause of graft loss after the first post-
ransplant year In this context we strongly agreehat CVD should be managed in KTRs at least asntensively as in the general population Ideallyecreasing CVD risk in KTRs requires a multifac-ted and multidisciplinary approach Based onurrent practice models in the United States theransplant and nephrology community has notet been able to achieve these desirable goals65
his clearly deserves more attention becauseontrol of CVD has the potential to contributeore to long-term kidney graft survival than the
iscovery of newer drugs that decrease the ratef allograft rejection Our KDOQI working groupgreed with the use of low-dose aspirin in KTRs
ith evidence of atherosclerosis
Ko
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KDOQI Commentary 21
ARTICLE IN PRESS
SUMMARY OF COMMENTARY ONSECTION III CVD
COMMENTARY ON SECTION IV OF KDIGO
TRANSPLANT GUIDELINE MALIGNANCY
DIGORecommendations inChapter 18 Cancerf the Skin andLip
181 We recommend that KTRs especially thosewho have fair skin live in high sun-exposureclimates have occupations requiring sun expo-sure have had significant sun exposure as achild or have a history of skin cancer be toldthat their risk of skin and lip cancer is veryhigh (1C)
182 We recommend that KTRs minimize life-longsun exposure and use appropriate ultravioletlight blocking agents (1D)
183 We suggest that adult KTRs perform skin andlip self-examinations and report new lesions toa health-care provider (2D)
184 For adult KTRs we suggest that a qualified healthprofessional with experience in diagnosing skincancer perform annual skin and lip examinationon KTRs except possibly for KTRs with dark skinpigmentation (2D)
185 We suggest that patients with a history of skin orlip cancer or premalignant lesions be referred to andfollowed by a qualified health professional withexperience in diagnosing and treating skin cancer
With the decrease in acute rejection during the pastdecade in association with improved immunosuppres-sion regimens patient death now rivals chronic graftdysfunction as one of the leading causes of long-termgraft loss Because CVD is the most common cause ofpatient death in KTRs a concerted effort at minimizingrisk factors for heart disease likely will have as great oreven greater impact on optimizing patient and graftoutcomes than the discovery of new antirejection thera-pies CVD risk reduction strategies should include regularscreening for new-onset diabetes (using ADA-based defini-tions) in the posttransplant period in previously nondiabeticpatients good glycemic regulation for diabetic patients accord-ing to current ADA guidelines and lipid management andblood pressure control according to KDOQI recommenda-tions In addition promotion of a healthy lifestyle throughweight control exercise and smoking cessation should be acentral part of posttransplant counseling and care Whenimmunosuppression modification is being considered to miti-gate cardiovascular risk we recommend that this be inconjunction with the transplant center In summary we gener-ally concurred with the suggestions of the work group in thissection but based on current practice standards in the UnitedStateschallengesremainwith implementationof thisguideline
(2D) s
186 We suggest that patients with a history of skincancer be offered treatment with oral acitretin ifthere are no contraindications (2B)
DOQIRationale andCommentary
CounselingandSunscreen
We concur with recommendations 181 and82 because skin cancer is a major source oforbidity and sometimes mortality in KTRsarning patients at risk of the high danger of
kin cancer a 1C recommendation is reinforcedy a recent prospective case-control study ofrgan transplant recipients that showed that regu-ar use of broad-spectrum sunscreens that pro-ide UVA and UVB protection may prevent theevelopment of actinic keratosis invasive squa-ous cell carcinoma and to a lesser extent
asal cell carcinoma66 Most cancer-causing ra-iation is thought to come from the UVB spec-rum and newer broad-spectrum sunscreens pro-ide protection against UVA and UVB radiationounseling about sunscreen and the need for sunvoidance needs to be incorporated into routineffice visits although it may not always beuccessful In a recent study of KTRs in which1 of patients had been informed about theeed for sun protection only 46 used morehan a tube of sunscreen per year67
Dermatology Involvement
There is increased evidence to suggest thatpecialty dermatology clinics for organ trans-lant recipients improve outcome measures in-luding compliance with photoprotection andncreased awareness of skin cancer68 The re-ources required for these specialty clinics makemplementation difficult for community nephrol-gy groups that do not have direct access to aransplant center Transplant patients should bencouraged to have annual visits with their trans-lant center and if dermatology specialty clinicsre available attempt to coordinate a skin cancervaluation annually
UseofRetinoid-likeCompounds
There is a limited scientific basis for KDIGOuggestion recommendation 186 Although reti-oids now are used routinely in KTRs with aigh skin cancer burden our KDOQI work groupelieves that more data are needed before this
uggestion should be accepted as a guideline In
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ARTICLE IN PRESS
ow-immunologic-risk groups and particularlyifficult cases some data suggest that switchingrom CNI to sirolimus therapy may decrease thencidence of skin cancer69 however the riskersus benefit of this maneuver has not been welltudied
DIGORecommendations inChapter 19on-SkinMalignancies
191 Develop an individualized screening plan for eachKTR that takes into account the patientrsquos pastmedical and family history tobacco use compet-ing risks for death and the performance of thescreening methodology (Not Graded)
192 Screen for the following cancers as per localguidelines for the general population (Not Graded)Women cervical breast and colon cancer Menprostate and colon cancer
193 Obtain hepatic ultrasound and alpha feto-proteinevery 12 months in patients with compensatedcirrhosis (Not Graded) [See Recommendations1354 (HCV) and 1365 (HBV)]
DOQIRationale andCommentary
Screening
It is recognized that KTRs have a higher inci-ence of malignancy particularly those associatedith specific viral infections Although cancer
creening may have benefits in this higher riskopulation it should be reinforced that some meth-ds of screening have significant risks which shoulde considered on an individualized basis particu-arly in patients who have projected survival lesshan 5 years
Screening forCancer inPatientsWithHepatitis
Many patients who have underlying cirrhosisn the United States will be followed up by arofessional specializing in liver disease whoay provide additional insight into this cancer
creening recommendation Based on a recentuestionnaire of US gastroenterologists only 50creen patients for hepatocellular carcinoma70
herefore implementation of this guideline byS clinicians is unlikely to be widespread
DIGORecommendations inChapter 20anagingCancerwithReductionof
mmunosuppressiveMedication
201 We suggest consideration be given to reducingimmunosuppressive medications for KTRs with can-
cer (2C)
2011 Important factors for consideration in-clude (Not Graded)bull The stage of cancer at diagnosisbull Whether the cancer is likely to be
exacerbated by immunosuppressionbull The therapies available for the can-
cerbull Whether immunosuppressive medica-
tions interfere with ability to admin-ister the standard chemotherapy
202 For patients with Kaposi sarcoma we suggestusing mTORi along with a reduction in overallimmunosuppression (2C)
DOQIRationale andCommentary
Table 1 (Table 29 in the KDIGO report3 andxcerpted from Grulich et al71) lists cancershat are increased most in immunosuppressedTRs based on standardized incidence ratios
SIRs) which compare the incidence toatched populations Cancers with the highestIRs may be those most likely to respond to aecrease in immunosuppression Except foraposi sarcoma limited evidence is available
or a decrease in immunosuppression in theseettings A strategy to change immunosuppres-ion therapy must occur in consultation withhe transplant center Switching to sirolimusherapy and decreasing immunosuppression inatients who develop Kaposi sarcoma is basedn sound scientific rationale7273
SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
The incidence of cancer posttransplant is 2-20times higher than that in the general population andKDIGO guidelines have been written to outline stepsfor prevention and screening With few exceptions weagree with the recommendations as outlined Skincancer is common in US transplant patients andscreening and prevention are critical However imple-mentation of guidelines for doing so including theKDIGO guidelines is a challenge because of patientpreferences against the routine use of sunscreen aswell as time constraints during office visits Althoughmany posttransplant cancers are viral mediated andrelated to immunosuppression it is less clear how toalter immunosuppression after malignancy has oc-curred We agree that although age-specific screeningfor malignancy should be incorporated into care con-sideration must be given to the risk of screening inpatients with limited life spans (5 years) because of
comorbid conditions
KT
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
ommonPopu
i sarco-Hodgmelanise sm
sophaemia
estima standa10 c
ut esti
0 case
alized t
to guide treatment specifically before the
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
K
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CUcneucetcitdt
ttlhA(o
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
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nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
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ml
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c2
p2
sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
ation Transpl Rev 200923191-19815 Abbud-Filho M Adams PL Alberuacute J et al A report
f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
cA
nrc
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trN
hUt
Iwa
rl5
mi8
oe1
DA
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hm2
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Bia et al30
ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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ARTICLE IN PRESS
DOQIRationale andCommentary
Drug costs are becoming an increasing issue inransplantation that impacts on patient adherencend ultimately affects graft survival Currently im-unosuppressive drugs in the United States are
overed by the Centers for Medicare amp Medicaidervices (CMS) the primary insurer for manyTRs for 3 years after transplant although legisla-
ion is being considered to continue this coverageor the life of the kidney Most KTRs are usingany other medications in addition to immunosup-
ressive drugs In general the transplant commu-ity (patients health care providers and policyakers) need to embrace the concept of cost con-
ainment and the risk(s) to the patient and graft byhese measures However this needs to be balancedy who benefits and how much risk is at stake
Use of drugs that block the cytochrome P-450A system in an attempt to decrease CNIosing and costs are rarely used in the Unitedtates The concern is that inadvertent cessa-
ion of treatment with these drugs causing aignificant decrease in drug levels could resultn an acute rejection episode Therefore theork group did not think that many of the 411
uggestions should be accepted as a guidelinewitching from a mycophenolate compound ton azathioprine compound in the later posttrans-lant period may be considered in some pa-ients as another cost-saving maneuver espe-ially in view of recent US registry datahowing similar long-term survival with theserugs11 Although we agree with the sugges-ions outlined in 42 it should be recognizedhat many generic formulations have nevereen tested in transplant patients Patient con-usion with medications when a different ge-eric formulation or even different strengths ofhe same drug from different manufacturers isispensed at each refill can lead to inadvertentedication errors possibly affecting out-
omes Patient education is crucial to avoidrrors in medication administration We agreeith recommendation 44 that it is crucial toonitor patients after an immunosuppressive
osage change brand change or change to aeneric drug However it needs to be recog-ized that implementation of this guideline canecome burdensome as practices become inun-
ated with inquiries from patients payors and 5
harmacies regarding medications Transplantenters and practices that see many transplantatients bear an inordinate part of this burden
DIGORecommendations inChapter 5onitoring ImmunosuppressiveMedications
51 We recommend measuring CNI blood levels(1B) and suggest measuring at leastbull every other day during the immediate postopera-
tive period until target levels are reached (2C)bull whenever there is a change in medication or
patient status that may affect blood levels (2C)bull whenever there is a decline in kidney function that
may indicate nephrotoxicity or rejection (2C)511 We suggest monitoring CsA using 12-h
trough (C0) 2-h post-dose (C2) or abbrevi-ated AUC (2D)
512 We suggest monitoring tacrolimus using12-h trough (C0) (2C)
52 We suggest monitoring MMF levels (2D)53 We suggest monitoring mTOR inhibitor levels (2C)
DOQIRationale andCommentary
Because immunosuppressive drugs are classi-ed as narrow therapeutic agents drug-levelonitoring is a necessary tool to maximize effi-
iency and minimize toxicity The blood drugevel is not synonymous with level of immuno-uppression but may correlate imperfectly withhis effect In most US transplant centers levelsf CNI and mTOR inhibitors are monitoredPA monitoring is problematic because of the
oor correlation between trough levels and areander the curve (AUC) exposure Optimal moni-oring of MPA requires a 4- to 6-hour abbrevi-ted AUC measurement which is logisticallyifficult in the outpatient setting Although stud-es show that monitoring MPA levels in the earlyosttransplant period may be helpful in cyclospor-ne-treated patients recent evidence suggests thatuch monitoring may be less important in pa-ients on tacrolimus therapy12 With most USTRs now being started on tacrolimus as theNI of choice MPA monitoring is not routine inany US transplant centers Although one per-
on in our work group believed there may still beome value in monitoring MPA levels the otherembers questioned the value and applicability
f this practice (KDIGO suggestion 52) Cur-ently many US centers measure MPA only inhe setting of possible drug-related toxicities oride effects Although we agree with suggestion
3 to monitor mTOR inhibitor levels it should
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KDOQI Commentary 7
ARTICLE IN PRESS
e appreciated that therapeutic levels of thisgent have yet to be defined in controlled studies
DIGORecommendations inChapter 6reatment ofAcuteRejection
61 We recommend biopsy before treating acuterejection unless the biopsy will substantiallydelay treatment (1C)
62 We suggest treating subclinical and borderline acuterejection (2D)
63 We recommend corticosteroids for the initialtreatment of acute cellular rejection (1D)631 We suggest adding or restoring maintenance
prednisone in patients not on steroids whohave a rejection episode (2D)
632 We suggest using lymphocyte-depleting anti-bodies or OKT3 [muromonab-CD3] for acutecellular rejections that do not respond tocorticosteroids and for recurrent acute cellu-lar rejections (2C)
64 We suggest treating antibody-mediated acute rejec-tion with one or more of the following alternativeswith or without corticosteroids (2C)bull plasma exchangebull intravenous immunoglobulinbull anti-CD20 antibodybull lymphocyte-depleting antibody
65 For patients who have a rejection episode wesuggest adding mycophenolate if the patient is notreceiving mycophenolate or azathioprine or switch-ing azathioprine to mycophenolate (2D)
DOQIRationale andCommentary
We concur that biopsies should be performed onll KTRs suspected of having an acute rejectionrecommendation 61) Expert interpretation of theiopsy specimen by pathologists accustomed toeading kidney transplant biopsies is as importants expertise in performing the biopsy It is contro-ersial whether subclinical and borderline rejec-ions should be treated (recommendation 62 sup-orted by low evidence [2D]) Subclinical rejectionsre diagnosed in patients who have protocol biop-ies performed by design not for deterioration inidney function Recent data suggest that the riskf subclinical rejection in patients on tacrolimusnd mycophenolate compound therapy is so lowhat protocol biopsies may no longer be indi-ated13 Whether this is true in patients with highmmunologic risk or patients on minimization pro-ocols (ie steroid-free protocols or lower CNI doses)s uncertain Whether borderline rejection shoulde treated or some infiltrates may be protective also
s uncertain In most US centers steroids are used d
ost frequently as first-line treatment for acuteejection followed by lymphocyte-depleting anti-odies in steroid-resistant rejection but there maye exceptions to this approach Decision makingegarding appropriate initial treatment for acuteejection should be based on clinical and patho-ogic information Timing of the rejection episodeosttransplant type of induction agent used beforeejection degree of deterioration in kidney functiont the time of rejection and histologic grade of theejection may influence selection of the appropriatenitial antirejection therapy There is increasingecognition of the role of antibody-mediated mecha-isms in acute rejection This process requirespecial blood tests (to detect donor-specific antibod-es) and histochemical stains (immunofluorescenceor C4d) for diagnosis14 Coordination with theransplant center is critical to ensure that all appro-riate testing is performed and specific treatment isnitiated After treatment of an acute episode opti-
izing overall immunosuppression is requiredonsiderations should include changing the CNIdding a mycophenolate compound or increasinghe dose adding corticosteroids to previously ste-oid-free regimens or addingsubstituting an mTORnhibitor More than 85 of patients are alreadysing MPA agents so the number available forwitching will be relatively small
DIGORecommendations inChapter 7reatment of ChronicAllograft Injury (CAI)
71 We recommend kidney allograft biopsy for allpatients with declining kidney function of unclearcause to detect potentially reversible causes (1C)
72 For patients with CAI and histological evidence ofCNI toxicity we suggest reducing withdrawing orreplacing the CNI (2C)721 For patients with CAI eGFR 40 mLmin
173 m2 and urine total protein excretion500 mgg creatinine (or equivalent protein-uria by other measures) we suggest replac-ing the CNI with a mTOR inhibitor (2D)
DOQIRationale andCommentary
We agree with the need for kidney transplantiopsy in patients with decreasing kidney function71) and again stress the importance of expertise inathologic interpretation Important causes ofhronic allograft injury (CAI) which include rejec-ion BK nephropathy CNI toxicity or recurrentisease require special histochemical stains for
iagnosis that are not readily available in all labora-
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ARTICLE IN PRESS
ories Therefore coordination with the transplantenter where these techniques are available is essen-ial For patients with CAI caused by CNI toxicityithdrawing the CNI should occur only after at-
empts at decreasing the dosage have failed Onelso must ensure that all other causes of CAI arexcluded to avoid inappropriate drug adjustmentsr missed treatment options Although our workroup thought that KDIGO suggestion 721 maye reasonable in some patients we also want tomphasize that the role of mTOR inhibitors in thereatment of CAICNI toxicity is poorly defined Its clear that switching from a CNI to an mTORnhibitor should be avoided in patients with se-erely decreased glomerular filtration rate (GFR)ndor the presence of proteinuria however the exactuidelines for when to switch are still evolving
SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
DIGORecommendations inChapter 8onitoringKidneyAllograft Function
81 We suggest measuring urine volume (2C)bull Every 1-2 hours for at least 24 hours after
transplantation (2D)
In the United States immunosuppressive protocolsused may vary from center to center based on theirparticular patient population organ source experienceand opinion of the transplant team ease of use and costof therapy Although data about the efficacy and safety ofsteroid-free regimens are still evolving it is clear that ifsteroids are to be eliminated this should be done in theearly transplant period and not late (after 1 year)Community nephrologists need to coordinate any alter-ations in immunosuppressive medications with the trans-plant center and be vigilant for potential drug interactionswith the addition of any new medications Drug monitor-ing is an essential monitoring tool throughout the post-transplant course but not always applicable to everyimmunosuppressive medication Transplant biopsies fre-quently are necessary to determine the cause of renaldysfunction and the interpretation must be performed bypathologists with resources and experience in handlingand reading the transplant biopsy specimen
bull Daily until graft function is stable (2D) c
82 We suggest measuring urine protein excretion (2C)at leastbull Once in the first month to determine a baseline
(2D)bull Every 3 months during the first year (2D)bull Annually thereafter (2D)
83 We recommend measuring serum creatinine (1B) atleastbull Daily for 7 days or until hospital discharge
whichever occurs sooner (2C)bull 2-3 times per week for weeks 2-4 (2C)bull Weekly for months 2 and 3 (2C)bull Every 2 weeks for months 4-6 (2C)bull Monthly for months 7-12 (2C)bull Every 2-3 months thereafter (2C)
831 We suggest estimating GFR whenever se-rum creatinine is measured (2D) usingbull One of several formulas validated for
adults (2C) orbull The Schwartz formula for children and
adolescents (2C)
84 We suggest including a kidney allograft ultrasoundexamination as part of the assessment of kidneyallograft dysfunction (2C)
DOQIRationale andCommentary
RoutineScreeningTestsandTimeandFrequencyofMonitoring
Regular surveillance and vigilant monitoring ofidney allograft function are important in improv-ng short- and long-term outcomes Early detectionf kidney allograft dysfunction will allow timelyiagnosis and treatment that may improve patientnd graft survival Frequency and types of routinecreening tests after kidney transplant are shown inig 2Although there is no standard protocol for therequency and type of monitoring recommenda-ions are guided by the likelihood of problemspecific to the particular transplant population Inhe early posttransplant period when rejection andomplications are the most likely testing is per-ormed more frequently Thereafter the follow-upnterval will depend in part on the patientrsquos generalondition and the development of additional prob-ems The AST recommended routine posttrans-lant 2-3 visits per week during month 1 every 1-3eeks during month 2-3 every 4-8 weeks duringonths 4-12 and every 2-4 months after therst year These early visits often are providedy the transplant physician or surgeon of theransplant center After 3-6 months monitor-ng may be performed by the transplant physi-
ian or community nephrologist15 In a recent
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KDOQI Commentary 9
ARTICLE IN PRESS
urvey of posttransplant outpatient visits inedicare beneficiaries in the United States
requency of visits to transplant centers variedy center and region most visits were toephrologists16
At each clinic visit education regardingedication adherence diet and healthy life-
tyle should be given Screening for tobaccose should be implemented before dischargend annually Although the work group did notgree that screening all adults for Epstein-Barrirus (EBV) was of value (see commentarynder Chapter 13 for EBV) screening for allther elements listed in Fig 2 including screen-ng for proteinuria is reasonable In additiono these tests monitoring for HLA antibodiesgainst the donor (donor-specific antibodies)hich is not described in the KDIGO guide-
ine is becoming more common in some USenters The optimal timing and frequency ofuch screening has yet to be determined1718
SerumCreatinineandEstimatedGFR
Serum creatinine measurement remains theost commonly used index of renal allograft
unction It is reliable for detecting acute changesn kidney function Furthermore serum creati-ine level at year 1 after transplant is a riskactor for subsequent outcomes19 and mayelp in the management of the frequency ofisits However it is less reliable for detecting
Figure 2 Routine screen-ng after kidney transplantomplete blood cell count in-ludes white blood cells hemo-lobin and platelets Screenor diabetes is by fasting bloodlucose level glucose toler-nce test or hemoglobin A1c
evel Lipid profile includes fast-ng cholesterol low-density li-oprotein cholesterol high-ensity lipoprotein cholesterolnd triglyceride levels Screensor BK polyoma virus (BKV)nd Epstein-Barr virus (EBV)se plasma nucleic acid test-
ng (NAT) EBV screen is foratients with no antibody toBV at transplant Adapted
rom the KDIGO transplantuideline3 with permission ofDIGO
ong-term changes in kidney function in the
idney transplant recipient Formulas to esti-ate GFR using serum creatinine values have
een tested in KTRs but no formula consis-ently has been shown to be superior to an-ther As with CKD considerable renal patho-ogic states can be present without dramatichanges in serum creatinine levels
In 2005 the definition of CKD was amendedo include all KTRs regardless of markers ofidney damage or GFR2021 Although the workroup agreed that CKD staging in KTRs isseful it must be noted that there is consider-ble difference in the rate of progression inhese 2 groups Progression is much slower inTRs in whom kidney half-life is longer at
very level of CKD Renal ultrasound is thereferred imaging study in KTRs (KDIGOuggestion 84)22
DIGORecommendations inChapter 9 Kidneyllograft Biopsy
91 We recommend kidney allograft biopsy whenthere is a persistent unexplained increase inserum creatinine (1C)
92 We suggest kidney allograft biopsy when serumcreatinine has not returned to baseline after treat-ment of acute rejection (2D)
93 We suggest kidney allograft biopsy every 7-10 daysduring delayed function (2C)
94 We suggest kidney allograft biopsy if expectedkidney function is not achieved within the first 1-2months after transplantation (2D)
95 We suggest kidney allograft biopsy when there is
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ARTICLE IN PRESS
bull New onset of proteinuria (2C)bull Unexplained proteinuria 30 g per gram creati-
nine or 30 g per 24 hours (2C)
DOQIRationale andCommentary
Biopsy
Renal allograft biopsy is the gold standard foriagnosing the cause of a change in renal allo-raft function It is useful in all clinical situationsescribed in KDIGO suggestions 91-94 Poten-ial causes of allograft dysfunction include vol-me depletion compromised renal blood flowrinary outflow obstruction parenchymal causesuch as acute rejection (cellular andor humoral)hronic allograft nephropathy recurrent or deovo disease or BK nephropathy Patients show-ng a 20-25 increase in creatinine level aboveaseline values warrant consideration for biopsyther indications for pursuing renal allograftiopsy would be a less-than-expected responseo treatment of acute rejection The expectedesponse would be dependent on the severity ofissue injury noted on the diagnostic biopsy speci-
en Delayed graft function lasting longer than-7 days warrants biopsy with repeated biopsieserformed every 7-10 days until graft functionecovers New-onset proteinuria protein 20g creatinine or 20 g24 h also merits aidney biopsy De novo and recurrent glomerulariseases are common causes of new-onset pro-einuria Patients with de novo or recurrent glo-erular diseases should be followed up closely
y transplant nephrologists or community neph-ologists with close communication with theransplant center because treatment of some recur-ent kidney diseases may prevent or delay thenset of graft failure2324
SafetyandAccuracy
The safety of kidney transplant biopsies haseen documented and the overall risk of compli-ations is low Most biopsies are performed inhe transplant center by transplant nephrologistsommunity nephrologists also may perform bi-psies of the kidney in KTRs more than a yearosttransplant It is prudent to obtain a diagnosticltrasound before biopsy to rule out unexpectedlterations in blood flow or urinary tract obstruc-ion It is imperative that a pathologist familiar
ith the transplant process interprets the pathol-
gy in consultation with the referring nephrolo-ist using appropriate stains and other studies
MolecularMarkers
In addition to conventional histopathologicxamination several US transplant centers aresing molecular markers as well as genomic orroteomic methods to enhance our understand-ng of the mechanism of immunologic and non-mmunologic pathway of injury As an exampleolymerase chain reaction (PCR) has been usedo detect messenger RNA for IL-2 and otheriomarkers in biopsy samples Using this ap-roach IL-2 upregulated during rejection coulde detected 2 days before rejection was apparentsing histologic or clinical criteria Such PCRpproaches have been used to detect other generoducts upregulated during acute rejection suchs granzyme B perforin transforming growthactor IL-10 and IL-1525-27 These newerethods are performed almost exclusively in
ransplant centers and may become a standardethod of transplant biopsy analysis in the fu-
ure
DIGORecommendations inChapter 10ecurrentDisease
101 We suggest screening KTRs with primary kidneydisease caused by FSGS for proteinuria (2C) atleastbull Daily for 1 week (2D)bull Weekly for 4 weeks (2D)bull Every 3 months for the first year (2D) Every
year thereafter (2D)
102 We suggest screening KTRs with potentially treat-able recurrence of primary kidney disease fromIgA nephropathy MPGN anti-GBM disease orANCA-associated vasculitis for microhematuria(2C) at leastbull Once in the first month to determine a baseline
(2D)bull Every 3 months during the first year (2D)
Annually thereafter (2D)
103 During episodes of graft dysfunction in patientswith primary HUS we suggest screening forthrombotic microangiopathy (eg with plateletcount peripheral smear for blood cell morphologyplasma haptoglobin and serum lactate dehydroge-nase) (2D)
104 When screening suggests possible treatable recur-rent disease we suggest obtaining an allograftbiopsy (2C)
105 Treatment of recurrent kidney disease1051 We suggest plasma exchange if a biopsy
shows minimal change disease or FSGS
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KDOQI Commentary 11
ARTICLE IN PRESS
in those with primary FSGS as theirprimary kidney disease (2D)
1052 We suggest high-dose corticosteroids andcyclophosphamide in patients with recur-rent ANCA-associated vasculitis or anti-GBM disease (2D)
1053 We suggest using an ACE-I [ACE inhibi-tor] or an ARB for patients with recurrentglomerulonephritis and proteinuria (2C)
1054 For KTRs with primary hyperoxaluriawe suggest appropriate measures to pre-vent oxalate deposition until plasma andurine oxalate levels are normal (2C)includingbull Pyridoxine (2C)bull High calcium and low oxalate diet
(2C)bull Increased oral fluid intake to enhance
urinary dilution of oxalate (2C)bull Potassium or sodium citrate to alkalin-
ize the urine (2C)bull Orthophosphate (2C)bull Magnesium oxide (2C)bull Intensive hemodialysis to remove ox-
alate (2C)
DOQIRationale andCommentary
Recurrent disease accounts for a substantialmount of graft loss after renal transplant It isifficult to assess the percentage of grafts lost toecurrent disease because many patients presentith end-stage renal disease without benefit of aiagnostic native renal biopsy The likelihood ofecurrent disease after transplant is dependent onhe disease with certain diseases at particularlyigh risk of recurrence28
Recurrent Focal SegmentalGlomerulosclerosis
We agree with recommendation 101 regard-ng frequent and regular screening for protein-ria in patients with primary focal segmentallomerulosclerosis (FSGS) as the cause of end-tage renal disease If the patient is still produc-ng urine at the time of transplant a preoperativerine protein-creatinine ratio can be a very help-ul baseline measure of proteinuria Early detec-ion of FSGS recurrence which can present withormal light microscopy but foot-process efface-ent on electron microscopy29 provides the best
pportunity for intervention and amelioration ofisease
IgANephropathy
Recurrence rates of immunoglobulin A (IgA)
ephropathy are variable We agree with recom- b
endation 102 for screening routinely for micro-ematuria Recurrent disease is confirmed with aenal allograft biopsy Histologic recurrence ofisease is much more common than is clinicalisease recurrence There is no proven therapyor treatment of recurrent disease30
MembranoproliferativeGlomerulonephritis
Recurrence of membranoproliferative glomer-lonephritis (MPGN) is common as high as 80ith MPGN type II (dense-deposit disease) Theost common cause of MPGN type I is hepatitisndashassociated immune complex formation Wegree with the proposed regularly scheduledcreening for microhematuria and proteinuria inecommendation 102 Patients with known hepa-itis Cndashassociated MPGN pretransplant also maye screened for cryoglobulins which are associ-ted with MPGN31
HemolyticUremic Syndrome
Hemolytic uremic syndrome (HUS) typicallys divided into diarrheal associated (D) andonndashdiarrheal associated (D) D disease oc-urs mostly in children and rarely recurs post-ransplant However D HUS is more commonn adults and can recur In HUS associated with aomplement abnormality such as factor H defi-iency or factor I mutation recurrence rates cane as high as 80 Screening for evidence ofecurrence allows for an earlier diagnosis whichill require biopsy in most cases and provides
n opportunity for earlier intervention There iso comment in the guideline regarding recur-ence of thrombotic thrombocytopenic purpuraut early detection of recurrence provides anpportunity for treatment with plasmapheresisnd intravenous immune globulin (IVIG)
BiopsyandTreatment
As stated kidney biopsy and interpretation bypathologist with expertise in transplant speci-en readings is critical in the diagnosis of dis-
ase recurrence Treatment for most recurrentisease in renal transplantation is based on aombination of case reports case cohorts andetrospective reviews Recurrent diseases post-ransplant are not common enough that random-zed controlled trials can be implemented there-ore most recommendations for treatment are
ased on a consensus of opinion Despite this we
at
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gree in general with the recommendations de-ailed in 105
DIGORecommendations inChapter 11reventingDetecting andTreatingonadherence
111 Consider providing all KTRs and family memberswith education prevention and treatment mea-sures to minimize nonadherence to immunosup-pressive medications (Not Graded)
112 Consider providing KTRs at increased risk fornonadherence with increased levels of screeningfor nonadherence (Not Graded)
DOQIRationale andCommentary
Noncompliance or nonadherence to diet andedication is a common problem in KTRs Nonad-
erence to medication is associated with a high riskf acute rejection and allograft loss We agree thatarly efforts should be made to identify KTRs atncreased risk of nonadherence and that these pa-ients should be monitored closely Prevention iden-ification and treatment of nonadherence are inte-ral to the monitoring of kidney allograft functionnd long-term care of KTRs Certain subgroup ofTRs younger patients African Americans and
hose with financial hardships have an enhancedisk of nonadherence3233
In addition to identifying patients at risk it ismportant to have a system for addressing patientonadherence This requires coordinated efforts ofocial workers transplant coordinators financialounselors pharmacists primary nephrologists andhe patientrsquos family34 A combination of educa-ional behavioral and social support interventionsrovides the best results Because there is no per-ect measure of adherence consideration should beiven to multiple approaches for adherence moni-oring Similar team approaches also are importantn other areas requiring adherence such as dietxercise tobacco alcohol and drug use
DIGORecommendations inChapter 12accination
121 We recommend giving all KTRs approvedinactivated vaccines according to recommendedschedules for the general population except forHBV vaccination (1D)1211 We suggest HBV vaccination (ideally
prior to transplantation) and HBsAb titers6-12 weeks after completing the vaccina-
tion series (2D) h
12111 We suggest annual HBsAb[antibody to hepatitis B sur-face antigen] titers (2D)
12112 We suggest revaccination ifthe antibody titer falls below10 mIUmL (2D)
122 We suggest avoiding live vaccines in KTRs (2C)123 We suggest avoiding vaccinations except influ-
enza vaccination in the first 6 months followingkidney transplantation (2C)1231 We suggest resuming immunizations once
patients are receiving minimal mainte-nance doses of immunosuppressive medi-cations (2C)
1232 We recommend giving all KTRs whoare at least 1-month post-transplantinfluenza vaccination prior to the onsetof the annual influenza season regard-less of status of immunosuppression(1C)
124 We suggest giving the following vaccines to KTRswho due to age direct exposure residence ortravel to endemic areas or other epidemiologicalrisk factors are at increased risk for the specificdiseasesbull rabies (2D)bull tick-borne meningoencephalitis (2D)bull Japanese B encephalitismdashinactivated (2D)bull Meningococcus (2D)bull Pneumococcus (2D)bull Salmonella typhimdashinactivated (2D)1241 Consult an infectious disease specialist a
travel clinic or public health official forguidance on whether specific cases war-rant these vaccinations (Not Graded)
DOQIRationale andCommentary
KTRs are at particular risk of viral infectionsecause of the preferential suppression of T lympho-ytes by both induction and maintenance immuno-uppression The risk and consequence of develop-ng a viral infection warrant use of selected vaccineshe suggestions regarding which vaccines are safend which are contraindicated are based on whetherhe vaccine contains live or killed virus Live virusaccines are contraindicated in immunosuppressedTRs The KDIGO recommendations for vaccina-
ions agree with updated guidelines recently pub-ished by the AST35 Specific comments on theDIGO suggestions regarding vaccinations are
isted in the following sections
Hepatitis B
The work group did not concur with KDIGOuggestion 1211 Neither revaccination against
epatitis after transplant nor following up hepa-
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KDOQI Commentary 13
ARTICLE IN PRESS
itis B antibody titers annually is a commonractice in the United States Hepatitis B is nots prevalent in the United States as in otherarts of the world and evidence supportingcreening in all patients posttransplant is lack-ng However screening for seroconversion inatients at risk (receiving a hepatitis B corentibodyndashpositive kidney) is appropriate Theseatients may benefit from lamivudine or ente-avir therapy36
LiveVaccineandTimingofVaccine
There is no particular reason for a 6-monthag between transplant and vaccination Theheory is that vaccines are less likely to beffective in the period when immunosuppres-ion is high In the United States most individu-ls are on their baseline maintenance immuno-uppression therapy by 3 months posttransplantecisions regarding the timing of vaccines areade based on immunosuppression exposure
nd risk of infection Recipients also shouldvoid intimate contact with individuals whoave received live vaccines37 This includesvoiding close contact with children who haveeceived oral polio vaccine for 3 weeks anday include close contact with adults receiv-
ng the attenuated varicella vaccine to preventoster Immunosuppressed individuals are ad-ised to avoid contact for 7 days with individu-ls who have received live virus nasal spraysor influenza We concur with the recommenda-ion for flu vaccine but common practice inhe United States is to wait 3-6 months afterransplant before it is administered
DIGORecommendations inChapter 13 Viraliseases
131 BK POLYOMA VIRUS1311 We suggest screening all KTRs for BKV
with quantitative plasma NAT (2C) atleastbull monthly for the first 3-6 months after
transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull whenever there is an unexplained rise
in serum creatinine (2D)bull and after treatment for acute rejection
(2D)1312 We suggest reducing immunosuppressive
medications when BKV plasma NAT is
persistently greater than 10 000 cop-iesmL (107 copiesL) (2D)
132 CYTOMEGALOVIRUS1321 CMV prophylaxis We recommend that
KTRs (except when donor and recipi-ent both have negative CMV serolo-gies) receive chemoprophylaxis forCMV infection with oral ganciclovir orvalganciclovir for at least 3 monthsafter transplantation (1B) and for 6weeks after treatment with a T-cellndashdepleting antibody (1C)
1322 In patients with CMV disease we suggestweekly monitoring of CMV by NAT orpp65 antigenemia (2D)
1323 CMV treatment13231 We recommend that all pa-
tients with serious (includ-ing most patients with tissueinvasive) CMV disease betreated with intravenousganciclovir (1D)
13232 We recommend that CMVdisease in adult KTRs that isnot serious (eg episodes thatare associated with mildclinical symptoms) be treatedwith either intravenous gan-ciclovir or oral valganciclo-vir (1D)
13233 We recommend that allCMV disease in pediatricKTRs be treated with intra-venous ganciclovir (1D)
13234 We suggest continuing therapyuntil CMV is no longer detect-able by plasma NAT or pp65antigenemia (2D)
1324 We suggest reducing immunosuppressivemedication in life-threatening CMV dis-ease and CMV disease that persists in theface of treatment until CMV disease hasresolved (2D)13241 We suggest monitoring graft
function closely during CMVdisease (2D)
133 EPSTEIN-BARR VIRUS AND POST-TRANS-PLANT LYMPHOPROLIFERATIVE DISEASE1331 We suggest monitoring high-risk (donor
EBV seropositiverecipient seronegative)KTRs for EBV by NAT (2C)bull once in the first week after transplanta-
tion (2D)bull then at least monthly for the first 3-6
months after transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull and additionally after treatment for
acute rejection (2D)
Bia et al14
ARTICLE IN PRESS
1332 We suggest that EBV-seronegative pa-tients with an increasing EBV load haveimmunosuppressive medication reduced(2D)
1333 We recommend that patients with EBVdisease including PTLD have a reduc-tion or cessation of immunosuppres-sive medication (1C)
134 HERPES SIMPLEX VIRUS 1 2 AND VARI-CELLA ZOSTER VIRUS1341 We recommend that KTRs who de-
velop a superficial HSV 1 2 infectionbe treated (1B) with an appropriateoral antiviral agent (eg acyclovir vala-cyclovir or famciclovir) until all le-sions have resolved (1D)
1342 We recommend that KTRs with sys-temic HSV 1 2 infection be treated(1B) with intravenous acyclovir and areduction in immunosuppressive medi-cation (1D)13421 We recommend that intrave-
nous acyclovir continue un-til the patient has a clinicalresponse (1B) then switch toan appropriate oral antiviralagent (eg acyclovir valacy-clovir or famciclovir) to com-plete a total treatment durationof 14-21 days (2D)
1343 We suggest using a prophylactic antiviralagent for KTRs experiencing frequentrecurrences of HSV 12 infection (2D)
1344 We recommend that primary VZV infec-tion (chicken pox) in KTRs be treated(1C) with either intravenous or oral acy-clovir or valacyclovir and a temporaryreduction in amount of immunosuppres-sive medication (2D)
135 HEPATITIS C VIRUS1351 We suggest that HCV-infected KTRs be
treated only when the benefits of treat-ment clearly outweigh the risk of allo-graft rejection due to interferon-basedtherapy (eg fibrosing cholestatic hepati-tis life-threatening vasculitis) (2D)[Based on KDIGO Hepatitis C Recom-mendation 215]
1352 We suggest monotherapy with standardinterferon for HCV-infected KTRs inwhom the benefits of antiviral treatmentclearly outweigh the risks (2D) [Basedon KDIGO Hepatitis C Recommenda-tions 224 and 442]
1353 We suggest that all conventional currentinduction and maintenance immunosup-pressive regimens can be used in HCVinfected patients (2D) [Based on KDIGO
Hepatitis C Recommendation 43]
1354 Measure ALT in HCV-infected patientsmonthly for the first 6 months and every3-6 months thereafter Perform imagingannually to look for cirrhosis and hepato-cellular carcinoma (Not Graded) [Basedon KDIGO Hepatitis C Recommendation441] (See Recommendation 193)
1355 Test HCV-infected patients at least every3-6 months for proteinuria (Not Graded)[Based on KDIGO Hepatitis C Recom-mendation 444]13551 For patients who develop new
onset proteinuria (either urineproteincreatinine ratio 1 or24-hour urine protein 1 g ontwo or more occasions) per-form an allograft biopsy withimmunofluorescence and elec-tron microscopy (Not Graded)[Based on KDIGO Hepatitis CRecommendation 444]
1356 We suggest that patients with HCV asso-ciated glomerulopathy not receive inter-feron (2D) [Based on KDIGO HepatitisC Recommendation 445]
136 HEPATITIS B VIRUS1361 We suggest that any currently available
induction and maintenance immunosup-pressive medication can be used in HBV-infected KTRs (2D)
1362 We suggest that interferon treatmentshould generally be avoided in HBVinfected KTRs (2C)
1363 We suggest that all HBsAg-positive KTRsreceive prophylaxis with tenofovir ente-cavir or lamivudine (2B)13631 Tenofovir or entecavir are pref-
erable to lamivudine to mini-mize development of potentialdrug resistance unless medica-tion cost requires that lami-vudinebe used (Not Graded)
13632 During therapy with antivi-rals measure HBV DNA andALT levels every 3 months tomonitor efficacy and to detectdrug resistance (Not Graded)
1364 We suggest treatment with adefovir ortenofovir for KTRs with lamivudine resis-tance (5 log10 copiesmL rebound ofHBV-DNA) (2D)
1365 Screen HBsAg-positive patients with cir-rhosis for hepatocellular carcinoma every12 months with liver ultrasound andalpha feto-protein (Not Graded) (SeeRecommendation 193)
1366 We suggest that patients who are negativefor HBsAg and have HBsAb titer 10mIUmL receive booster vaccination to
raise the titer to 100 mIUmL (2D)
K
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KDOQI Commentary 15
ARTICLE IN PRESS
137 HUMAN IMMUNODEFICIENCY VIRUS1371 If not already done screen for HIV
infection (Not Graded)1372 To determine antiretroviral therapy refer
HIV-infected KTRs to an HIV specialistwho should pay special attention to drugndashdrug interactions and appropriate dosingof medications (Not Graded)
DOQIRationale andCommentary
Viral infections are particularly problematic inransplant recipients because of the preferentialnhibition of T-lymphocyte function by both induc-ion and maintenance immunosuppression Use ofnduction immunosuppression with lymphocyte-epleting agents (thymoglobulin or alemtuzumab)s associated with a greater risk of viral infectionosttransplant In general the greater the cumula-ive exposure to immunosuppression the greaterhe risk of infectious complications The presenta-ion of viral infections can be asymptomatic vaguend nonspecific or life-threatening acute illnessany viral infections seen in KTRs are rarely seen
n immunocompetent patients and therefore do notnter into the differential diagnosis for physiciansnfamiliar with transplant recipients Close commu-ication with the transplant center is crucial inaring for the transplant population Early detectionnd institution of therapy provide the best chanceor viral eradication
BKVirus
Although the work group agreed with KDIGOuggestions for BK virus screening posttransplante did not think it was practical to require screen-
ng exclusively with quantitative plasma nucleiccid testing (NAT) because many US centers usenitial urinary screening and then test plasma onlyf urine screening results are positive Howeverhere is no disagreement that some type of screen-ng for BK virus is critical to avoid BK nephropa-hy for which there is no specific treatment when its established Complicating screening for BK vi-us is the variability in results between laboratoriesnd uncertainty about the level of viremia thathould trigger a response to decrease in immunosup-ression In the presence of viremia and increase inerum creatinine level a renal allograft biopsy isndicated to confirm the presence of BK nephropa-
hy Because BK viremia and viruria certainly can b
e detected beyond the first year it is not clear howong screening should be continued posttransplantlthough most centers screen for the first year onlyngoing clinical trials are exploring effective treat-ent for BK nephropathy3839 Decisions about
ecreases in immunosuppression currently theainstay of BK viremia management always
hould be made in consultation with the transplantenter
Cytomegalovirus
KDIGO recommendation 1321 regarding cyto-egalovirus (CMV) prophylaxis is reasonable and
pplicable to the US population Universal prophy-axis for CMV now is recommended over initiatingre-emptive treatment after CMV develops40 Aajor concern for US patients is the cost of CMV
rophylaxis with oral valgancyclovir Leukopeniaan be observed in patients using mycophenolatereparations when prophylaxis with valgancyclo-ir is used Screening for CMV is best performedsing NAT methods (1322) CMV antigenemiassays are still in use in many facilities but are nots sensitive as PCR assays41 There is no utility inhecking for serologic response to CMV with IgGr IgM titers posttransplant because the immuneesponse is not predictable Patients with CMVisease should be cared for by clinicians familiarith treating this disease It is recommended that
reatment be continued until viral load is undetect-ble followed by prophylactic doses of valgancy-lovir for an additional 3 months35
Epstein-BarrVirus
Current practice regarding EBV screening variesmong centers in the United States and many doot routinely screen for EBV posttransplant evenn recipient-negative donor-positive cases In con-rast to KDIGO recommendation 1311 routineBV screening is not recommended in AST infec-
ious disease guidelines35 In many centers EBVcreening is reserved for children who are muchore commonly EBV negative pretransplant than
dults EBV-induced posttransplant lymphoprolif-rative disorder (PTLD) affects many more pediat-ic than adult KTRs If screening is someday to beoutinely implemented in US centers details regard-ng the best method of screening and levels ofiremia above which a clinical intervention should
e triggered need to be better defined
ttattt
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ARTICLE IN PRESS
HerpesandVaricella
Systemic herpesvirus infections can be lifehreatening in transplant recipients and should bereated aggressively with intravenous antiviralgents as described in the KDIGO recommenda-ions Less aggressive cutaneous infection can bereated with oral antiviral agents as outlined inhe KDIGO guidelines
Varicella exposure is particularly concerning inransplant recipients The work group disputes theecommended dosing of acyclovir for varicellaxposure Acyclovir at a dose of 10 mgkg or about00 mg 4 times daily of oral acyclovir would betandard dosing We agree with the use of varicellammune globulin and emphasize the need to avoidhe varicella vaccine because it is a live virushould a transplant recipient develop a systemicaricella infection hospitalization and high-dosentravenous acyclovir therapy are warranted
Hepatitis C
Hepatitis C management posttransplant is ahallenge The KDIGO guidelines cited hereere based on the recently published KDIGOuideline for hepatitis C in CKD4 Hepatitis Cypically is not treated posttransplant because ofhe risk (50) of rejection precipitated bynterferon therapy particularly in US KTRs inhom hepatitis C commonly is genotype 1 which
s more resistant to treatment with interferon42
owever should hepatitis Cndashrelated glomerulo-ephritis develop the risk-benefit ratio may fa-or treatment in selected patients Such decisionslways should be made in consultation withepatology and infectious disease experts andhe transplant center Monitoring liver enzymeevels specifically alanine aminotransferaseALT) may reflect a change in hepatitis activityut monitoring hepatitis C viral load is not recom-ended because it does not seem to correlateith outcome Annual monitoring for hepatocel-
ular carcinoma using -fetoprotein and imagings encouraged but not often practiced
Hepatitis B
KDIGO recommendations for hepatitis B areeasonable and currently are followed in mostS centers except for recommendation 1366
see previous recommendation under vaccina-ions) KTRs with hepatitis C or hepatitis B also
hould be followed up by a hepatologist
Human ImmunodeficiencyVirus
Human immunodeficiency virus (HIV)-posi-ive individuals are now acceptable for transplantf CD4 count is 200 cellsL and viral loadVL) is undetectable3543 Transplant should beerformed at centers with expertise in managingIV-positive individuals and care should be co-rdinated carefully with HIV specialists Somentiretroviral agents in particular the proteasenhibitors have potentially serious drug interac-ions with immunosuppressive agents35
DIGORecommendations inChapter 14Othernfections
141 URINARY TRACT INFECTION1411 We suggest that all KTRs receive UTI
prophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 monthsafter transplantation (2B)
1412 For allograft pyelonephritis we suggestinitial hospitalization and treatment withintravenous antibiotics (2C)
142 PNEUMOCYSTIS JIROVECII PNEUMONIA1421 We recommend that all KTRs receive
PCP prophylaxis with daily tri-methoprimndashsulfamethoxazole for 3-6months after transplantation (1B)
1422 We suggest that all KTRs receive PCPprophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 weeksduring and after treatment for acute rejec-tion (2C)
1423 We recommend that KTRs with PCPdiagnosed by bronchial alveolar lavageandor lung biopsy be treated withhigh-dose intravenous trimethoprimndashsulfamethoxazole corticosteroids anda reduction in immunosuppressivemedication (1C)
1424 We recommend treatment with cortico-steroids for KTRs with moderate tosevere PCP (as defined by PaO2 lt70mm Hg in room air or an alveolargradient of gt35 mm Hg) (1C)
143 TUBERCULOSIS1431 We suggest that TB prophylaxis and
treatment regimens be the same in KTRsas would be used in the local generalpopulation who require therapy (2D)
1432 We recommend monitoring CNI andmTORi [mTOR inhibitor] blood levels inpatients receiving rifampin (1C)14321 Consider substituting rifabu-
tin for rifampin to minimize
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KDOQI Commentary 17
ARTICLE IN PRESS
interactions with CNIs andmTORi (Not Graded)
144 CANDIDA PROPHYLAXIS1441 We suggest oral and esophageal Candida
prophylaxis with oral clotrimazole loz-enges nystatin or fluconazole for 1-3months after transplantation and for 1month after treatment with an antilympho-cyte antibody (2C)
DOQIRationale andCommentary
UrinaryTract Infection
Urinary tract infections (UTIs) after kidneyransplant are very common and account for aarge percentage of readmissions posttransplantTIs are common because of multiple factors
ncluding the disrupted anatomy of the urinaryract with a ureteroneocystotomy incompleteladder emptying because of diabetes or pros-atic hypertrophy and impaired immune re-ponses Prophylaxis of UTIs usually is under-aken with trimethoprim-sulfamethoxazole for 6onths posttransplant although infections often
ccur despite therapy because of the develop-ent of drug resistance Although native kidney
yelonephritis does not always require hospital-zation it is recommended that all KTRs withhis diagnosis be hospitalized because the graftysfunction that usually accompanies transplantyelonephritis requires aggressive investigationnd treatment Individuals with recurrent UTIsarrant evaluation with urologic assessment Pa-
ients with recurrent UTIs may benefit fromong-term suppressive therapy
Pneumocystic Pneumonia
We agree that Pneumocystis jirovecii pneumoniaPCP) prophylaxis is important for the first 3-6onths posttransplant (1421)After the first month
very-other-day dosing of trimethoprim-sulfame-hoxazole or atovaquone is believed to be adequaterophylaxis In cases in which neither of thesegents can be used an individual may be treatedrophylactically with inhaled pentamidine OurDOQI work group emphasized that patients whoevelop PCP should be transferred to the transplantenter promptly for management and adjustmentsn immunosuppression
Tuberculosis
Monitoring for latent tuberculosis has posed a
hallenge in the immunosuppressed population be-
ause of the unreliable nature of skin testing Newerechniques involving interferon release assays aremerging as the new gold standard for detection ofatent tuberculosis4445
CandidaProphylaxis
Oral candidiasis must be screened for usingral mucosa examination on follow-up visitsn KTRs This is especially true in the earlyosttransplant period when immunosuppres-ive medication dosage is the highest Wegree with these recommendations and empha-ize that if fluconazole is used there is aotential for serious drug interactions becausef cytochrome P-450 3A4 inhibition
SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
Improvement in short-term outcomes has not trans-lated into significant improvements in long-term out-comes in KTRs The lack of significant improvement inlong-term survival may be related to post-transplantcomplications Frequent posttransplant monitoring mayimprove long-term outcomes by decreasing chronic graftfailure or death with a functioning graft Our work groupconcurred with the recommendation and schedules ofroutine screening in monitoring kidney allograft functionafter kidney transplant with a low threshold for perform-ing kidney biopsy in cases of graft dysfunction or protein-uria Expert tissue processing and interpretation of trans-plant biopsy specimens by pathologists with transplantexperience are critical Regular surveillance of the pa-tientrsquos kidney function at the transplant center or in thenephrologistrsquos office offers an opportunity to enhancepatient adherence to medication diet and healthy life-style Although CKD in KTRs progresses more slowlythan CKD in other patients the work group agreed thatthe KDIGO guidelines on CKD should be followed inKTRs
Opportunistic infections are common in KTRs al-though advances in diagnosis and treatment have led toimproved survival in KTRs with infection It is nowstandard of care to use vaccinations in KTRs as long asthe vaccine does not contain live or attenuated virus Italso is routine to screen for or use prophylaxis to preventseveral posttransplant viral infections With few excep-tions (related to EBV and BK virus screening andhepatitis B vaccination posttransplant) we concurredwith KDIGO guidelines for vaccination screening and
treatment of infection posttransplant
KD
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ARTICLE IN PRESS
COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULAR
DISEASE
DIGORecommendations inChapter 15iabetesMellitus
151 Screening for New-Onset Diabetes after Transplan-tation1511 We recommend screening all nondia-
betic KTRs with fasting plasma glu-cose oral glucose tolerance testingandor HbA1c (1C) at leastbull weekly for 4 weeks (2D)bull every 3 months for 1 year (2D)bull and annually thereafter (2D)
1512 We suggest screening for NODAT withfasting glucose oral glucose tolerancetesting andor after starting or substan-tially increasing the dose of CNIsmTORi or corticosteroids (2D)
152 Managing NODAT or Diabetes Present at Trans-plantation1521 If NODAT develops consider modifying
the immunosuppressive drug regimen toreverse or ameliorate diabetes afterweighing the risk of rejection and otherpotential adverse effects (Not Graded)
1522 Consider targeting HbA1c 70-75and avoid targeting HbA1c 60 espe-cially if hypoglycemic reactions are com-mon (Not Graded)
1523 We suggest that in patients with diabetesaspirin (65-100 mgd) use for the primaryprevention of CVD be based on patientpreferences and values balancing the riskfor ischemic events to that of bleeding(2D)
DOQIRationale andCommentary
Diabetic Screening
We agree with screening for new-onset diabetesfter transplantation (NODAT) as outlined by theDIGO work group Definitions used are similar
o those of the American Diabetes AssociationADA) The greater frequency of testing initially isustified by the high risk of NODAT in the earlyosttransplant period however ongoing screenings required because the risk of the development ofODAT continues to increase over time4647 We
lso point out that prediabetic states (impairedasting glucose level and impaired glucose toler-nce) occur even more commonly than overt diabe-es48 and may be associated with metabolic syn-rome as well as with increased cardiovascular
ortality49-51 Potential implications of these predia-
etic states emphasize the importance of perform-ng blood tests under fasting conditions For pa-ients with fasting hyperglycemia an oral glucoseolerance test or hemoglobinA1c (HbA1c) test shoulde performed Although more cumbersome to per-orm data suggest that an oral glucose toleranceest is a more sensitive indicator of NODAT inyperglycemic KTRs52 This may allow earlieretection of overt diabetes and more prompt institu-ion of treatment
DiabetesManagement
Data supporting a substantial benefit in themelioration or reversal of NODAT using immu-osuppression modification in KTRs are veryimited There was consensus in our work grouphat considering the paucity of data for reversingODAT by changing immunosuppression and
he potential risk of an adverse outcome withuch a maneuver KDIGO suggestion 1521 couldot be supported Certainly if such a step waseing considered it should be done in conjunc-ion with the transplant center Targeting an HbA1c
evel of 7-75 and avoiding levels 6 isased on data showing increased cardiovascularvents with the lower HbA1c target5354
DIGORecommendations inChapter 16ypertensionDyslipidemias TobaccoUse andbesity
161 Hypertension1611 We recommend measuring blood pres-
sure at each clinic visit (1C)1612 We suggest maintaining blood pressure at
130 mm Hg systolic and 80 mm Hgdiastolic if 18 years of age and 90th
percentile for sex age and height if 18years old (2C)
1613 To treat hypertension (Not Graded)bull Use any class of antihypertensive
agentbull Monitor closely for adverse effects
and drug-drug interactions and whenurine protein excretion 1 gd for18 years old and 600 mgm224 hfor 18 years old consider an ACE-Ior an ARB as first-line therapy
162 Dyslipidemias (These recommendations are basedon KDOQI Dyslipidemia Guidelines and are thusnot graded)1621 Measure a complete lipid profile in all
adult (18 years old) and adolescent
(puberty to 18 years old) KTRs [Based on
K
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KDOQI Commentary 19
ARTICLE IN PRESS
KDOQI Dyslipidemia Recommendation1]bull 2-3 months after transplantationbull 2-3 months after a change in treatment
or other conditions known to causedyslipidemias
bull at least annually thereafter1622 Evaluate KTRs with dyslipidemias for
secondary causes [Based on KDOQI Dys-lipidemia Recommendation 3]16221 For KTRs with fasting triglyc-
erides 500 mgdL (565mmolL) that cannot be cor-rected by removing an under-lying cause treat withbull Adults therapeutic lifestyle
changes and a triglyceride-lowering agent [Based onKDOQI Recommendation41]
bull Adolescents therapeutic life-style changes [Based onKDOQI Recommendation51]
16222 For KTRs with elevatedLDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)treat to reduce LDL-C to100 mgdL (259mmolL) [Based on KDOQIGuideline 42]
bull Adolescents If LDL-C130 mgdL (336 mmolL) treat to reduce LDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 52]
16223 For KTRs with normalLDL-C elevated triglyceridesand elevated non-HDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)fasting triglycerides 200mgdL (226 mmolL)and non-HDL-C 130mgdL (336 mmolL)treat to reduce non-HDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 43]
bull Adolescents If LDL-C130 mgdL (336 mmolL) fasting triglycerides200 mgdL (226 mmolL) and non-HDL-C 160mgdL (414 mmolL)treat to reduce non-HDL-C
to 160 mgdL (414 i
mmolL) [Based on KDOQIGuideline 53]
163 Tobacco Use1631 Screen and counsel all KTRs including
adolescents and children for tobacco useand record the results in the medicalrecord (Not Graded)bull Screen during initial transplant hospi-
talizationbull Screen at least annually thereafter
1632 Offer treatment to all patients who usetobacco (Not Graded)
164 Obesity1641 Assess obesity at each visit (Not Graded)
bull Measure height and weight at eachvisit in adults and children
bull Calculate BMI at each visitbull Measure waist circumference when
weight and physical appearance sug-gest obesity but BMI is 35 kgm2
1642 Offer a weight-reduction program to allobese KTRs (Not Graded)
DOQIRationale andCommentary
Hypertension
The KDIGO work group adapted the KDOQI004 recommendations for target blood pres-ure in KTRs55 Self measurement is useful inssessing response to therapy and enhancesdherence56 In general we agree that the classf antihypertensive agent does not matter inhe treatment of blood pressure elevation inhis population and that attention should beiven to potential side effects of antihyperten-ive agents as well as possible interactionsith the immunosuppressive regimen (eg non-ihydropyridine calcium channel blockers andNIs) In the absence of adequate randomizedontrolled trials it is not known whether angio-ensin-converting enzyme (ACE) inhibitors andngiotensin receptor blockers (ARBs) prolongecipient or allograft survival Some but notll retrospective studies suggest a benefitowever all these studies are limited by selec-ion bias5758 Although ACE inhibitors andRBs commonly lead to some decrease inFR treatment with these drugs should be
ontinued unless serum creatinine level in-reases by 25 to 30 in keeping withDOQI recommendations55 In KTRs receiv-
ng ACE inhibitors or ARBs it is important toducate patients to maintain adequate fluid
ntake during illness to prevent a prerenal
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ARTICLE IN PRESS
nsult to the allograft Similarly awareness isecessary when using diuretics in conjunctionith therapies that block the renin-angiotensin-
ldosterone-system59
Dyslipidemia
The KDIGO work group based their recom-endations for evaluation and treatment of
yperlipidemia on the KDOQI dyslipidemiauidelines for KTRs60 We agree with theseecommendations CNIs potentiate the toxicityf statins by slowing their metabolism throughhe cytochrome P-450 system This interactionccurs more commonly with cyclosporine61
han with tacrolimus Dyslipidemia especiallyypertriglyceridemia frequently complicatesTOR-inhibitor use and lipid-lowering therapy
s required in most patients using these agents
TobaccoUse
Not surprisingly tobacco use at the time ofransplant is associated with decreased patientnd graft survival as well as increased risk ofosttransplant cardiovascular disease (CVD)lthough the KDIGO work group recom-ends initial screening and intervention dur-
ng the hospitalization for transplant we be-ieve there may be benefit gained by startingounseling in the pretransplant period duringhe evaluation phase Unfortunately this doesot occur often because of time and personnelonstraints in transplant centers Ideally allransplant centers should have smoking-cessa-ion programs available to patients either in-ouse or through referral Ideally systemshould be created to continue to screen andonitor for smoking cessation at yearly inter-
als after transplant because there is a highate of relapse with this addiction As outlinedn KDIGO Table 253 although all pharmaco-ogic therapies for smoking cessation can besed in KTRs the starting dose of vareniclinehould be decreased in patients with GFR 30Lmin
Obesity
Obesity is an epidemic in the United Statesnd the proportion of obese kidney transplantandidates continues to grow In additioneight gain after transplant is very commonly
bserved Obesity in KTRs is associated with w
ncreased risks of wound complications de-ayed graft function acute rejection and NO-AT resulting in inferior patient and graftutcomes Attention to this potential complica-ion and counseling should be initiated duringhe pretransplant evaluation phase Informa-ion regarding pharmacologic therapies foreight loss in KTRs is not available and we
gree with the KDIGO work group that thera-eutic lifestyle measures should be encour-ged Data regarding steroid therapy with-rawal and weight gain are controversial Aecent double-blind randomized controlled trialxamining early steroid therapy withdrawalid not show a difference in weight gain at 5ears posttransplant compared with the cohortemaining on standard maintenance corticoste-oid therapy62
DIGORecommendations inChapter 17ardiovascularManagement
171 Consider managing CVD at least as intensively inKTRs as in the general population with appropri-ate diagnostic tests and treatments (Not Graded)
172 We suggest using aspirin (65-100 mgd) in allpatients with atherosclerotic CVD unless there arecontraindications (2B)
DOQIRationale andCommentary
Although outcomes are favorable comparedith remaining on the waiting list the risk of
ardiovascular mortality in KTRs is several-foldigher than observed in the general population63
specially in younger age groups and patientsith decreasing allograft function64 CVD is aajor cause of graft loss after the first post-
ransplant year In this context we strongly agreehat CVD should be managed in KTRs at least asntensively as in the general population Ideallyecreasing CVD risk in KTRs requires a multifac-ted and multidisciplinary approach Based onurrent practice models in the United States theransplant and nephrology community has notet been able to achieve these desirable goals65
his clearly deserves more attention becauseontrol of CVD has the potential to contributeore to long-term kidney graft survival than the
iscovery of newer drugs that decrease the ratef allograft rejection Our KDOQI working groupgreed with the use of low-dose aspirin in KTRs
ith evidence of atherosclerosis
Ko
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KDOQI Commentary 21
ARTICLE IN PRESS
SUMMARY OF COMMENTARY ONSECTION III CVD
COMMENTARY ON SECTION IV OF KDIGO
TRANSPLANT GUIDELINE MALIGNANCY
DIGORecommendations inChapter 18 Cancerf the Skin andLip
181 We recommend that KTRs especially thosewho have fair skin live in high sun-exposureclimates have occupations requiring sun expo-sure have had significant sun exposure as achild or have a history of skin cancer be toldthat their risk of skin and lip cancer is veryhigh (1C)
182 We recommend that KTRs minimize life-longsun exposure and use appropriate ultravioletlight blocking agents (1D)
183 We suggest that adult KTRs perform skin andlip self-examinations and report new lesions toa health-care provider (2D)
184 For adult KTRs we suggest that a qualified healthprofessional with experience in diagnosing skincancer perform annual skin and lip examinationon KTRs except possibly for KTRs with dark skinpigmentation (2D)
185 We suggest that patients with a history of skin orlip cancer or premalignant lesions be referred to andfollowed by a qualified health professional withexperience in diagnosing and treating skin cancer
With the decrease in acute rejection during the pastdecade in association with improved immunosuppres-sion regimens patient death now rivals chronic graftdysfunction as one of the leading causes of long-termgraft loss Because CVD is the most common cause ofpatient death in KTRs a concerted effort at minimizingrisk factors for heart disease likely will have as great oreven greater impact on optimizing patient and graftoutcomes than the discovery of new antirejection thera-pies CVD risk reduction strategies should include regularscreening for new-onset diabetes (using ADA-based defini-tions) in the posttransplant period in previously nondiabeticpatients good glycemic regulation for diabetic patients accord-ing to current ADA guidelines and lipid management andblood pressure control according to KDOQI recommenda-tions In addition promotion of a healthy lifestyle throughweight control exercise and smoking cessation should be acentral part of posttransplant counseling and care Whenimmunosuppression modification is being considered to miti-gate cardiovascular risk we recommend that this be inconjunction with the transplant center In summary we gener-ally concurred with the suggestions of the work group in thissection but based on current practice standards in the UnitedStateschallengesremainwith implementationof thisguideline
(2D) s
186 We suggest that patients with a history of skincancer be offered treatment with oral acitretin ifthere are no contraindications (2B)
DOQIRationale andCommentary
CounselingandSunscreen
We concur with recommendations 181 and82 because skin cancer is a major source oforbidity and sometimes mortality in KTRsarning patients at risk of the high danger of
kin cancer a 1C recommendation is reinforcedy a recent prospective case-control study ofrgan transplant recipients that showed that regu-ar use of broad-spectrum sunscreens that pro-ide UVA and UVB protection may prevent theevelopment of actinic keratosis invasive squa-ous cell carcinoma and to a lesser extent
asal cell carcinoma66 Most cancer-causing ra-iation is thought to come from the UVB spec-rum and newer broad-spectrum sunscreens pro-ide protection against UVA and UVB radiationounseling about sunscreen and the need for sunvoidance needs to be incorporated into routineffice visits although it may not always beuccessful In a recent study of KTRs in which1 of patients had been informed about theeed for sun protection only 46 used morehan a tube of sunscreen per year67
Dermatology Involvement
There is increased evidence to suggest thatpecialty dermatology clinics for organ trans-lant recipients improve outcome measures in-luding compliance with photoprotection andncreased awareness of skin cancer68 The re-ources required for these specialty clinics makemplementation difficult for community nephrol-gy groups that do not have direct access to aransplant center Transplant patients should bencouraged to have annual visits with their trans-lant center and if dermatology specialty clinicsre available attempt to coordinate a skin cancervaluation annually
UseofRetinoid-likeCompounds
There is a limited scientific basis for KDIGOuggestion recommendation 186 Although reti-oids now are used routinely in KTRs with aigh skin cancer burden our KDOQI work groupelieves that more data are needed before this
uggestion should be accepted as a guideline In
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ow-immunologic-risk groups and particularlyifficult cases some data suggest that switchingrom CNI to sirolimus therapy may decrease thencidence of skin cancer69 however the riskersus benefit of this maneuver has not been welltudied
DIGORecommendations inChapter 19on-SkinMalignancies
191 Develop an individualized screening plan for eachKTR that takes into account the patientrsquos pastmedical and family history tobacco use compet-ing risks for death and the performance of thescreening methodology (Not Graded)
192 Screen for the following cancers as per localguidelines for the general population (Not Graded)Women cervical breast and colon cancer Menprostate and colon cancer
193 Obtain hepatic ultrasound and alpha feto-proteinevery 12 months in patients with compensatedcirrhosis (Not Graded) [See Recommendations1354 (HCV) and 1365 (HBV)]
DOQIRationale andCommentary
Screening
It is recognized that KTRs have a higher inci-ence of malignancy particularly those associatedith specific viral infections Although cancer
creening may have benefits in this higher riskopulation it should be reinforced that some meth-ds of screening have significant risks which shoulde considered on an individualized basis particu-arly in patients who have projected survival lesshan 5 years
Screening forCancer inPatientsWithHepatitis
Many patients who have underlying cirrhosisn the United States will be followed up by arofessional specializing in liver disease whoay provide additional insight into this cancer
creening recommendation Based on a recentuestionnaire of US gastroenterologists only 50creen patients for hepatocellular carcinoma70
herefore implementation of this guideline byS clinicians is unlikely to be widespread
DIGORecommendations inChapter 20anagingCancerwithReductionof
mmunosuppressiveMedication
201 We suggest consideration be given to reducingimmunosuppressive medications for KTRs with can-
cer (2C)
2011 Important factors for consideration in-clude (Not Graded)bull The stage of cancer at diagnosisbull Whether the cancer is likely to be
exacerbated by immunosuppressionbull The therapies available for the can-
cerbull Whether immunosuppressive medica-
tions interfere with ability to admin-ister the standard chemotherapy
202 For patients with Kaposi sarcoma we suggestusing mTORi along with a reduction in overallimmunosuppression (2C)
DOQIRationale andCommentary
Table 1 (Table 29 in the KDIGO report3 andxcerpted from Grulich et al71) lists cancershat are increased most in immunosuppressedTRs based on standardized incidence ratios
SIRs) which compare the incidence toatched populations Cancers with the highestIRs may be those most likely to respond to aecrease in immunosuppression Except foraposi sarcoma limited evidence is available
or a decrease in immunosuppression in theseettings A strategy to change immunosuppres-ion therapy must occur in consultation withhe transplant center Switching to sirolimusherapy and decreasing immunosuppression inatients who develop Kaposi sarcoma is basedn sound scientific rationale7273
SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
The incidence of cancer posttransplant is 2-20times higher than that in the general population andKDIGO guidelines have been written to outline stepsfor prevention and screening With few exceptions weagree with the recommendations as outlined Skincancer is common in US transplant patients andscreening and prevention are critical However imple-mentation of guidelines for doing so including theKDIGO guidelines is a challenge because of patientpreferences against the routine use of sunscreen aswell as time constraints during office visits Althoughmany posttransplant cancers are viral mediated andrelated to immunosuppression it is less clear how toalter immunosuppression after malignancy has oc-curred We agree that although age-specific screeningfor malignancy should be incorporated into care con-sideration must be given to the risk of screening inpatients with limited life spans (5 years) because of
comorbid conditions
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
ommonPopu
i sarco-Hodgmelanise sm
sophaemia
estima standa10 c
ut esti
0 case
alized t
to guide treatment specifically before the
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
REFERENCES1 McCullough KP Keith DS Meyer KH et al Kidney
nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
o2
Tf2
Tfh2
TfcM
CU1
dt
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tdp
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op
Mpp
apt
pI
ar
ti2
mi2
i2
uap
ba5
ra2
cJ
sir
ml
gt1
p2
ps2
c2
p2
sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
ation Transpl Rev 200923191-19815 Abbud-Filho M Adams PL Alberuacute J et al A report
f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
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ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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KDOQI Commentary 7
ARTICLE IN PRESS
e appreciated that therapeutic levels of thisgent have yet to be defined in controlled studies
DIGORecommendations inChapter 6reatment ofAcuteRejection
61 We recommend biopsy before treating acuterejection unless the biopsy will substantiallydelay treatment (1C)
62 We suggest treating subclinical and borderline acuterejection (2D)
63 We recommend corticosteroids for the initialtreatment of acute cellular rejection (1D)631 We suggest adding or restoring maintenance
prednisone in patients not on steroids whohave a rejection episode (2D)
632 We suggest using lymphocyte-depleting anti-bodies or OKT3 [muromonab-CD3] for acutecellular rejections that do not respond tocorticosteroids and for recurrent acute cellu-lar rejections (2C)
64 We suggest treating antibody-mediated acute rejec-tion with one or more of the following alternativeswith or without corticosteroids (2C)bull plasma exchangebull intravenous immunoglobulinbull anti-CD20 antibodybull lymphocyte-depleting antibody
65 For patients who have a rejection episode wesuggest adding mycophenolate if the patient is notreceiving mycophenolate or azathioprine or switch-ing azathioprine to mycophenolate (2D)
DOQIRationale andCommentary
We concur that biopsies should be performed onll KTRs suspected of having an acute rejectionrecommendation 61) Expert interpretation of theiopsy specimen by pathologists accustomed toeading kidney transplant biopsies is as importants expertise in performing the biopsy It is contro-ersial whether subclinical and borderline rejec-ions should be treated (recommendation 62 sup-orted by low evidence [2D]) Subclinical rejectionsre diagnosed in patients who have protocol biop-ies performed by design not for deterioration inidney function Recent data suggest that the riskf subclinical rejection in patients on tacrolimusnd mycophenolate compound therapy is so lowhat protocol biopsies may no longer be indi-ated13 Whether this is true in patients with highmmunologic risk or patients on minimization pro-ocols (ie steroid-free protocols or lower CNI doses)s uncertain Whether borderline rejection shoulde treated or some infiltrates may be protective also
s uncertain In most US centers steroids are used d
ost frequently as first-line treatment for acuteejection followed by lymphocyte-depleting anti-odies in steroid-resistant rejection but there maye exceptions to this approach Decision makingegarding appropriate initial treatment for acuteejection should be based on clinical and patho-ogic information Timing of the rejection episodeosttransplant type of induction agent used beforeejection degree of deterioration in kidney functiont the time of rejection and histologic grade of theejection may influence selection of the appropriatenitial antirejection therapy There is increasingecognition of the role of antibody-mediated mecha-isms in acute rejection This process requirespecial blood tests (to detect donor-specific antibod-es) and histochemical stains (immunofluorescenceor C4d) for diagnosis14 Coordination with theransplant center is critical to ensure that all appro-riate testing is performed and specific treatment isnitiated After treatment of an acute episode opti-
izing overall immunosuppression is requiredonsiderations should include changing the CNIdding a mycophenolate compound or increasinghe dose adding corticosteroids to previously ste-oid-free regimens or addingsubstituting an mTORnhibitor More than 85 of patients are alreadysing MPA agents so the number available forwitching will be relatively small
DIGORecommendations inChapter 7reatment of ChronicAllograft Injury (CAI)
71 We recommend kidney allograft biopsy for allpatients with declining kidney function of unclearcause to detect potentially reversible causes (1C)
72 For patients with CAI and histological evidence ofCNI toxicity we suggest reducing withdrawing orreplacing the CNI (2C)721 For patients with CAI eGFR 40 mLmin
173 m2 and urine total protein excretion500 mgg creatinine (or equivalent protein-uria by other measures) we suggest replac-ing the CNI with a mTOR inhibitor (2D)
DOQIRationale andCommentary
We agree with the need for kidney transplantiopsy in patients with decreasing kidney function71) and again stress the importance of expertise inathologic interpretation Important causes ofhronic allograft injury (CAI) which include rejec-ion BK nephropathy CNI toxicity or recurrentisease require special histochemical stains for
iagnosis that are not readily available in all labora-
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ories Therefore coordination with the transplantenter where these techniques are available is essen-ial For patients with CAI caused by CNI toxicityithdrawing the CNI should occur only after at-
empts at decreasing the dosage have failed Onelso must ensure that all other causes of CAI arexcluded to avoid inappropriate drug adjustmentsr missed treatment options Although our workroup thought that KDIGO suggestion 721 maye reasonable in some patients we also want tomphasize that the role of mTOR inhibitors in thereatment of CAICNI toxicity is poorly defined Its clear that switching from a CNI to an mTORnhibitor should be avoided in patients with se-erely decreased glomerular filtration rate (GFR)ndor the presence of proteinuria however the exactuidelines for when to switch are still evolving
SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
DIGORecommendations inChapter 8onitoringKidneyAllograft Function
81 We suggest measuring urine volume (2C)bull Every 1-2 hours for at least 24 hours after
transplantation (2D)
In the United States immunosuppressive protocolsused may vary from center to center based on theirparticular patient population organ source experienceand opinion of the transplant team ease of use and costof therapy Although data about the efficacy and safety ofsteroid-free regimens are still evolving it is clear that ifsteroids are to be eliminated this should be done in theearly transplant period and not late (after 1 year)Community nephrologists need to coordinate any alter-ations in immunosuppressive medications with the trans-plant center and be vigilant for potential drug interactionswith the addition of any new medications Drug monitor-ing is an essential monitoring tool throughout the post-transplant course but not always applicable to everyimmunosuppressive medication Transplant biopsies fre-quently are necessary to determine the cause of renaldysfunction and the interpretation must be performed bypathologists with resources and experience in handlingand reading the transplant biopsy specimen
bull Daily until graft function is stable (2D) c
82 We suggest measuring urine protein excretion (2C)at leastbull Once in the first month to determine a baseline
(2D)bull Every 3 months during the first year (2D)bull Annually thereafter (2D)
83 We recommend measuring serum creatinine (1B) atleastbull Daily for 7 days or until hospital discharge
whichever occurs sooner (2C)bull 2-3 times per week for weeks 2-4 (2C)bull Weekly for months 2 and 3 (2C)bull Every 2 weeks for months 4-6 (2C)bull Monthly for months 7-12 (2C)bull Every 2-3 months thereafter (2C)
831 We suggest estimating GFR whenever se-rum creatinine is measured (2D) usingbull One of several formulas validated for
adults (2C) orbull The Schwartz formula for children and
adolescents (2C)
84 We suggest including a kidney allograft ultrasoundexamination as part of the assessment of kidneyallograft dysfunction (2C)
DOQIRationale andCommentary
RoutineScreeningTestsandTimeandFrequencyofMonitoring
Regular surveillance and vigilant monitoring ofidney allograft function are important in improv-ng short- and long-term outcomes Early detectionf kidney allograft dysfunction will allow timelyiagnosis and treatment that may improve patientnd graft survival Frequency and types of routinecreening tests after kidney transplant are shown inig 2Although there is no standard protocol for therequency and type of monitoring recommenda-ions are guided by the likelihood of problemspecific to the particular transplant population Inhe early posttransplant period when rejection andomplications are the most likely testing is per-ormed more frequently Thereafter the follow-upnterval will depend in part on the patientrsquos generalondition and the development of additional prob-ems The AST recommended routine posttrans-lant 2-3 visits per week during month 1 every 1-3eeks during month 2-3 every 4-8 weeks duringonths 4-12 and every 2-4 months after therst year These early visits often are providedy the transplant physician or surgeon of theransplant center After 3-6 months monitor-ng may be performed by the transplant physi-
ian or community nephrologist15 In a recent
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ARTICLE IN PRESS
urvey of posttransplant outpatient visits inedicare beneficiaries in the United States
requency of visits to transplant centers variedy center and region most visits were toephrologists16
At each clinic visit education regardingedication adherence diet and healthy life-
tyle should be given Screening for tobaccose should be implemented before dischargend annually Although the work group did notgree that screening all adults for Epstein-Barrirus (EBV) was of value (see commentarynder Chapter 13 for EBV) screening for allther elements listed in Fig 2 including screen-ng for proteinuria is reasonable In additiono these tests monitoring for HLA antibodiesgainst the donor (donor-specific antibodies)hich is not described in the KDIGO guide-
ine is becoming more common in some USenters The optimal timing and frequency ofuch screening has yet to be determined1718
SerumCreatinineandEstimatedGFR
Serum creatinine measurement remains theost commonly used index of renal allograft
unction It is reliable for detecting acute changesn kidney function Furthermore serum creati-ine level at year 1 after transplant is a riskactor for subsequent outcomes19 and mayelp in the management of the frequency ofisits However it is less reliable for detecting
Figure 2 Routine screen-ng after kidney transplantomplete blood cell count in-ludes white blood cells hemo-lobin and platelets Screenor diabetes is by fasting bloodlucose level glucose toler-nce test or hemoglobin A1c
evel Lipid profile includes fast-ng cholesterol low-density li-oprotein cholesterol high-ensity lipoprotein cholesterolnd triglyceride levels Screensor BK polyoma virus (BKV)nd Epstein-Barr virus (EBV)se plasma nucleic acid test-
ng (NAT) EBV screen is foratients with no antibody toBV at transplant Adapted
rom the KDIGO transplantuideline3 with permission ofDIGO
ong-term changes in kidney function in the
idney transplant recipient Formulas to esti-ate GFR using serum creatinine values have
een tested in KTRs but no formula consis-ently has been shown to be superior to an-ther As with CKD considerable renal patho-ogic states can be present without dramatichanges in serum creatinine levels
In 2005 the definition of CKD was amendedo include all KTRs regardless of markers ofidney damage or GFR2021 Although the workroup agreed that CKD staging in KTRs isseful it must be noted that there is consider-ble difference in the rate of progression inhese 2 groups Progression is much slower inTRs in whom kidney half-life is longer at
very level of CKD Renal ultrasound is thereferred imaging study in KTRs (KDIGOuggestion 84)22
DIGORecommendations inChapter 9 Kidneyllograft Biopsy
91 We recommend kidney allograft biopsy whenthere is a persistent unexplained increase inserum creatinine (1C)
92 We suggest kidney allograft biopsy when serumcreatinine has not returned to baseline after treat-ment of acute rejection (2D)
93 We suggest kidney allograft biopsy every 7-10 daysduring delayed function (2C)
94 We suggest kidney allograft biopsy if expectedkidney function is not achieved within the first 1-2months after transplantation (2D)
95 We suggest kidney allograft biopsy when there is
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ARTICLE IN PRESS
bull New onset of proteinuria (2C)bull Unexplained proteinuria 30 g per gram creati-
nine or 30 g per 24 hours (2C)
DOQIRationale andCommentary
Biopsy
Renal allograft biopsy is the gold standard foriagnosing the cause of a change in renal allo-raft function It is useful in all clinical situationsescribed in KDIGO suggestions 91-94 Poten-ial causes of allograft dysfunction include vol-me depletion compromised renal blood flowrinary outflow obstruction parenchymal causesuch as acute rejection (cellular andor humoral)hronic allograft nephropathy recurrent or deovo disease or BK nephropathy Patients show-ng a 20-25 increase in creatinine level aboveaseline values warrant consideration for biopsyther indications for pursuing renal allograftiopsy would be a less-than-expected responseo treatment of acute rejection The expectedesponse would be dependent on the severity ofissue injury noted on the diagnostic biopsy speci-
en Delayed graft function lasting longer than-7 days warrants biopsy with repeated biopsieserformed every 7-10 days until graft functionecovers New-onset proteinuria protein 20g creatinine or 20 g24 h also merits aidney biopsy De novo and recurrent glomerulariseases are common causes of new-onset pro-einuria Patients with de novo or recurrent glo-erular diseases should be followed up closely
y transplant nephrologists or community neph-ologists with close communication with theransplant center because treatment of some recur-ent kidney diseases may prevent or delay thenset of graft failure2324
SafetyandAccuracy
The safety of kidney transplant biopsies haseen documented and the overall risk of compli-ations is low Most biopsies are performed inhe transplant center by transplant nephrologistsommunity nephrologists also may perform bi-psies of the kidney in KTRs more than a yearosttransplant It is prudent to obtain a diagnosticltrasound before biopsy to rule out unexpectedlterations in blood flow or urinary tract obstruc-ion It is imperative that a pathologist familiar
ith the transplant process interprets the pathol-
gy in consultation with the referring nephrolo-ist using appropriate stains and other studies
MolecularMarkers
In addition to conventional histopathologicxamination several US transplant centers aresing molecular markers as well as genomic orroteomic methods to enhance our understand-ng of the mechanism of immunologic and non-mmunologic pathway of injury As an exampleolymerase chain reaction (PCR) has been usedo detect messenger RNA for IL-2 and otheriomarkers in biopsy samples Using this ap-roach IL-2 upregulated during rejection coulde detected 2 days before rejection was apparentsing histologic or clinical criteria Such PCRpproaches have been used to detect other generoducts upregulated during acute rejection suchs granzyme B perforin transforming growthactor IL-10 and IL-1525-27 These newerethods are performed almost exclusively in
ransplant centers and may become a standardethod of transplant biopsy analysis in the fu-
ure
DIGORecommendations inChapter 10ecurrentDisease
101 We suggest screening KTRs with primary kidneydisease caused by FSGS for proteinuria (2C) atleastbull Daily for 1 week (2D)bull Weekly for 4 weeks (2D)bull Every 3 months for the first year (2D) Every
year thereafter (2D)
102 We suggest screening KTRs with potentially treat-able recurrence of primary kidney disease fromIgA nephropathy MPGN anti-GBM disease orANCA-associated vasculitis for microhematuria(2C) at leastbull Once in the first month to determine a baseline
(2D)bull Every 3 months during the first year (2D)
Annually thereafter (2D)
103 During episodes of graft dysfunction in patientswith primary HUS we suggest screening forthrombotic microangiopathy (eg with plateletcount peripheral smear for blood cell morphologyplasma haptoglobin and serum lactate dehydroge-nase) (2D)
104 When screening suggests possible treatable recur-rent disease we suggest obtaining an allograftbiopsy (2C)
105 Treatment of recurrent kidney disease1051 We suggest plasma exchange if a biopsy
shows minimal change disease or FSGS
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KDOQI Commentary 11
ARTICLE IN PRESS
in those with primary FSGS as theirprimary kidney disease (2D)
1052 We suggest high-dose corticosteroids andcyclophosphamide in patients with recur-rent ANCA-associated vasculitis or anti-GBM disease (2D)
1053 We suggest using an ACE-I [ACE inhibi-tor] or an ARB for patients with recurrentglomerulonephritis and proteinuria (2C)
1054 For KTRs with primary hyperoxaluriawe suggest appropriate measures to pre-vent oxalate deposition until plasma andurine oxalate levels are normal (2C)includingbull Pyridoxine (2C)bull High calcium and low oxalate diet
(2C)bull Increased oral fluid intake to enhance
urinary dilution of oxalate (2C)bull Potassium or sodium citrate to alkalin-
ize the urine (2C)bull Orthophosphate (2C)bull Magnesium oxide (2C)bull Intensive hemodialysis to remove ox-
alate (2C)
DOQIRationale andCommentary
Recurrent disease accounts for a substantialmount of graft loss after renal transplant It isifficult to assess the percentage of grafts lost toecurrent disease because many patients presentith end-stage renal disease without benefit of aiagnostic native renal biopsy The likelihood ofecurrent disease after transplant is dependent onhe disease with certain diseases at particularlyigh risk of recurrence28
Recurrent Focal SegmentalGlomerulosclerosis
We agree with recommendation 101 regard-ng frequent and regular screening for protein-ria in patients with primary focal segmentallomerulosclerosis (FSGS) as the cause of end-tage renal disease If the patient is still produc-ng urine at the time of transplant a preoperativerine protein-creatinine ratio can be a very help-ul baseline measure of proteinuria Early detec-ion of FSGS recurrence which can present withormal light microscopy but foot-process efface-ent on electron microscopy29 provides the best
pportunity for intervention and amelioration ofisease
IgANephropathy
Recurrence rates of immunoglobulin A (IgA)
ephropathy are variable We agree with recom- b
endation 102 for screening routinely for micro-ematuria Recurrent disease is confirmed with aenal allograft biopsy Histologic recurrence ofisease is much more common than is clinicalisease recurrence There is no proven therapyor treatment of recurrent disease30
MembranoproliferativeGlomerulonephritis
Recurrence of membranoproliferative glomer-lonephritis (MPGN) is common as high as 80ith MPGN type II (dense-deposit disease) Theost common cause of MPGN type I is hepatitisndashassociated immune complex formation Wegree with the proposed regularly scheduledcreening for microhematuria and proteinuria inecommendation 102 Patients with known hepa-itis Cndashassociated MPGN pretransplant also maye screened for cryoglobulins which are associ-ted with MPGN31
HemolyticUremic Syndrome
Hemolytic uremic syndrome (HUS) typicallys divided into diarrheal associated (D) andonndashdiarrheal associated (D) D disease oc-urs mostly in children and rarely recurs post-ransplant However D HUS is more commonn adults and can recur In HUS associated with aomplement abnormality such as factor H defi-iency or factor I mutation recurrence rates cane as high as 80 Screening for evidence ofecurrence allows for an earlier diagnosis whichill require biopsy in most cases and provides
n opportunity for earlier intervention There iso comment in the guideline regarding recur-ence of thrombotic thrombocytopenic purpuraut early detection of recurrence provides anpportunity for treatment with plasmapheresisnd intravenous immune globulin (IVIG)
BiopsyandTreatment
As stated kidney biopsy and interpretation bypathologist with expertise in transplant speci-en readings is critical in the diagnosis of dis-
ase recurrence Treatment for most recurrentisease in renal transplantation is based on aombination of case reports case cohorts andetrospective reviews Recurrent diseases post-ransplant are not common enough that random-zed controlled trials can be implemented there-ore most recommendations for treatment are
ased on a consensus of opinion Despite this we
at
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Bia et al12
ARTICLE IN PRESS
gree in general with the recommendations de-ailed in 105
DIGORecommendations inChapter 11reventingDetecting andTreatingonadherence
111 Consider providing all KTRs and family memberswith education prevention and treatment mea-sures to minimize nonadherence to immunosup-pressive medications (Not Graded)
112 Consider providing KTRs at increased risk fornonadherence with increased levels of screeningfor nonadherence (Not Graded)
DOQIRationale andCommentary
Noncompliance or nonadherence to diet andedication is a common problem in KTRs Nonad-
erence to medication is associated with a high riskf acute rejection and allograft loss We agree thatarly efforts should be made to identify KTRs atncreased risk of nonadherence and that these pa-ients should be monitored closely Prevention iden-ification and treatment of nonadherence are inte-ral to the monitoring of kidney allograft functionnd long-term care of KTRs Certain subgroup ofTRs younger patients African Americans and
hose with financial hardships have an enhancedisk of nonadherence3233
In addition to identifying patients at risk it ismportant to have a system for addressing patientonadherence This requires coordinated efforts ofocial workers transplant coordinators financialounselors pharmacists primary nephrologists andhe patientrsquos family34 A combination of educa-ional behavioral and social support interventionsrovides the best results Because there is no per-ect measure of adherence consideration should beiven to multiple approaches for adherence moni-oring Similar team approaches also are importantn other areas requiring adherence such as dietxercise tobacco alcohol and drug use
DIGORecommendations inChapter 12accination
121 We recommend giving all KTRs approvedinactivated vaccines according to recommendedschedules for the general population except forHBV vaccination (1D)1211 We suggest HBV vaccination (ideally
prior to transplantation) and HBsAb titers6-12 weeks after completing the vaccina-
tion series (2D) h
12111 We suggest annual HBsAb[antibody to hepatitis B sur-face antigen] titers (2D)
12112 We suggest revaccination ifthe antibody titer falls below10 mIUmL (2D)
122 We suggest avoiding live vaccines in KTRs (2C)123 We suggest avoiding vaccinations except influ-
enza vaccination in the first 6 months followingkidney transplantation (2C)1231 We suggest resuming immunizations once
patients are receiving minimal mainte-nance doses of immunosuppressive medi-cations (2C)
1232 We recommend giving all KTRs whoare at least 1-month post-transplantinfluenza vaccination prior to the onsetof the annual influenza season regard-less of status of immunosuppression(1C)
124 We suggest giving the following vaccines to KTRswho due to age direct exposure residence ortravel to endemic areas or other epidemiologicalrisk factors are at increased risk for the specificdiseasesbull rabies (2D)bull tick-borne meningoencephalitis (2D)bull Japanese B encephalitismdashinactivated (2D)bull Meningococcus (2D)bull Pneumococcus (2D)bull Salmonella typhimdashinactivated (2D)1241 Consult an infectious disease specialist a
travel clinic or public health official forguidance on whether specific cases war-rant these vaccinations (Not Graded)
DOQIRationale andCommentary
KTRs are at particular risk of viral infectionsecause of the preferential suppression of T lympho-ytes by both induction and maintenance immuno-uppression The risk and consequence of develop-ng a viral infection warrant use of selected vaccineshe suggestions regarding which vaccines are safend which are contraindicated are based on whetherhe vaccine contains live or killed virus Live virusaccines are contraindicated in immunosuppressedTRs The KDIGO recommendations for vaccina-
ions agree with updated guidelines recently pub-ished by the AST35 Specific comments on theDIGO suggestions regarding vaccinations are
isted in the following sections
Hepatitis B
The work group did not concur with KDIGOuggestion 1211 Neither revaccination against
epatitis after transplant nor following up hepa-
tpapsipapc
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KDOQI Commentary 13
ARTICLE IN PRESS
itis B antibody titers annually is a commonractice in the United States Hepatitis B is nots prevalent in the United States as in otherarts of the world and evidence supportingcreening in all patients posttransplant is lack-ng However screening for seroconversion inatients at risk (receiving a hepatitis B corentibodyndashpositive kidney) is appropriate Theseatients may benefit from lamivudine or ente-avir therapy36
LiveVaccineandTimingofVaccine
There is no particular reason for a 6-monthag between transplant and vaccination Theheory is that vaccines are less likely to beffective in the period when immunosuppres-ion is high In the United States most individu-ls are on their baseline maintenance immuno-uppression therapy by 3 months posttransplantecisions regarding the timing of vaccines areade based on immunosuppression exposure
nd risk of infection Recipients also shouldvoid intimate contact with individuals whoave received live vaccines37 This includesvoiding close contact with children who haveeceived oral polio vaccine for 3 weeks anday include close contact with adults receiv-
ng the attenuated varicella vaccine to preventoster Immunosuppressed individuals are ad-ised to avoid contact for 7 days with individu-ls who have received live virus nasal spraysor influenza We concur with the recommenda-ion for flu vaccine but common practice inhe United States is to wait 3-6 months afterransplant before it is administered
DIGORecommendations inChapter 13 Viraliseases
131 BK POLYOMA VIRUS1311 We suggest screening all KTRs for BKV
with quantitative plasma NAT (2C) atleastbull monthly for the first 3-6 months after
transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull whenever there is an unexplained rise
in serum creatinine (2D)bull and after treatment for acute rejection
(2D)1312 We suggest reducing immunosuppressive
medications when BKV plasma NAT is
persistently greater than 10 000 cop-iesmL (107 copiesL) (2D)
132 CYTOMEGALOVIRUS1321 CMV prophylaxis We recommend that
KTRs (except when donor and recipi-ent both have negative CMV serolo-gies) receive chemoprophylaxis forCMV infection with oral ganciclovir orvalganciclovir for at least 3 monthsafter transplantation (1B) and for 6weeks after treatment with a T-cellndashdepleting antibody (1C)
1322 In patients with CMV disease we suggestweekly monitoring of CMV by NAT orpp65 antigenemia (2D)
1323 CMV treatment13231 We recommend that all pa-
tients with serious (includ-ing most patients with tissueinvasive) CMV disease betreated with intravenousganciclovir (1D)
13232 We recommend that CMVdisease in adult KTRs that isnot serious (eg episodes thatare associated with mildclinical symptoms) be treatedwith either intravenous gan-ciclovir or oral valganciclo-vir (1D)
13233 We recommend that allCMV disease in pediatricKTRs be treated with intra-venous ganciclovir (1D)
13234 We suggest continuing therapyuntil CMV is no longer detect-able by plasma NAT or pp65antigenemia (2D)
1324 We suggest reducing immunosuppressivemedication in life-threatening CMV dis-ease and CMV disease that persists in theface of treatment until CMV disease hasresolved (2D)13241 We suggest monitoring graft
function closely during CMVdisease (2D)
133 EPSTEIN-BARR VIRUS AND POST-TRANS-PLANT LYMPHOPROLIFERATIVE DISEASE1331 We suggest monitoring high-risk (donor
EBV seropositiverecipient seronegative)KTRs for EBV by NAT (2C)bull once in the first week after transplanta-
tion (2D)bull then at least monthly for the first 3-6
months after transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull and additionally after treatment for
acute rejection (2D)
Bia et al14
ARTICLE IN PRESS
1332 We suggest that EBV-seronegative pa-tients with an increasing EBV load haveimmunosuppressive medication reduced(2D)
1333 We recommend that patients with EBVdisease including PTLD have a reduc-tion or cessation of immunosuppres-sive medication (1C)
134 HERPES SIMPLEX VIRUS 1 2 AND VARI-CELLA ZOSTER VIRUS1341 We recommend that KTRs who de-
velop a superficial HSV 1 2 infectionbe treated (1B) with an appropriateoral antiviral agent (eg acyclovir vala-cyclovir or famciclovir) until all le-sions have resolved (1D)
1342 We recommend that KTRs with sys-temic HSV 1 2 infection be treated(1B) with intravenous acyclovir and areduction in immunosuppressive medi-cation (1D)13421 We recommend that intrave-
nous acyclovir continue un-til the patient has a clinicalresponse (1B) then switch toan appropriate oral antiviralagent (eg acyclovir valacy-clovir or famciclovir) to com-plete a total treatment durationof 14-21 days (2D)
1343 We suggest using a prophylactic antiviralagent for KTRs experiencing frequentrecurrences of HSV 12 infection (2D)
1344 We recommend that primary VZV infec-tion (chicken pox) in KTRs be treated(1C) with either intravenous or oral acy-clovir or valacyclovir and a temporaryreduction in amount of immunosuppres-sive medication (2D)
135 HEPATITIS C VIRUS1351 We suggest that HCV-infected KTRs be
treated only when the benefits of treat-ment clearly outweigh the risk of allo-graft rejection due to interferon-basedtherapy (eg fibrosing cholestatic hepati-tis life-threatening vasculitis) (2D)[Based on KDIGO Hepatitis C Recom-mendation 215]
1352 We suggest monotherapy with standardinterferon for HCV-infected KTRs inwhom the benefits of antiviral treatmentclearly outweigh the risks (2D) [Basedon KDIGO Hepatitis C Recommenda-tions 224 and 442]
1353 We suggest that all conventional currentinduction and maintenance immunosup-pressive regimens can be used in HCVinfected patients (2D) [Based on KDIGO
Hepatitis C Recommendation 43]
1354 Measure ALT in HCV-infected patientsmonthly for the first 6 months and every3-6 months thereafter Perform imagingannually to look for cirrhosis and hepato-cellular carcinoma (Not Graded) [Basedon KDIGO Hepatitis C Recommendation441] (See Recommendation 193)
1355 Test HCV-infected patients at least every3-6 months for proteinuria (Not Graded)[Based on KDIGO Hepatitis C Recom-mendation 444]13551 For patients who develop new
onset proteinuria (either urineproteincreatinine ratio 1 or24-hour urine protein 1 g ontwo or more occasions) per-form an allograft biopsy withimmunofluorescence and elec-tron microscopy (Not Graded)[Based on KDIGO Hepatitis CRecommendation 444]
1356 We suggest that patients with HCV asso-ciated glomerulopathy not receive inter-feron (2D) [Based on KDIGO HepatitisC Recommendation 445]
136 HEPATITIS B VIRUS1361 We suggest that any currently available
induction and maintenance immunosup-pressive medication can be used in HBV-infected KTRs (2D)
1362 We suggest that interferon treatmentshould generally be avoided in HBVinfected KTRs (2C)
1363 We suggest that all HBsAg-positive KTRsreceive prophylaxis with tenofovir ente-cavir or lamivudine (2B)13631 Tenofovir or entecavir are pref-
erable to lamivudine to mini-mize development of potentialdrug resistance unless medica-tion cost requires that lami-vudinebe used (Not Graded)
13632 During therapy with antivi-rals measure HBV DNA andALT levels every 3 months tomonitor efficacy and to detectdrug resistance (Not Graded)
1364 We suggest treatment with adefovir ortenofovir for KTRs with lamivudine resis-tance (5 log10 copiesmL rebound ofHBV-DNA) (2D)
1365 Screen HBsAg-positive patients with cir-rhosis for hepatocellular carcinoma every12 months with liver ultrasound andalpha feto-protein (Not Graded) (SeeRecommendation 193)
1366 We suggest that patients who are negativefor HBsAg and have HBsAb titer 10mIUmL receive booster vaccination to
raise the titer to 100 mIUmL (2D)
K
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KDOQI Commentary 15
ARTICLE IN PRESS
137 HUMAN IMMUNODEFICIENCY VIRUS1371 If not already done screen for HIV
infection (Not Graded)1372 To determine antiretroviral therapy refer
HIV-infected KTRs to an HIV specialistwho should pay special attention to drugndashdrug interactions and appropriate dosingof medications (Not Graded)
DOQIRationale andCommentary
Viral infections are particularly problematic inransplant recipients because of the preferentialnhibition of T-lymphocyte function by both induc-ion and maintenance immunosuppression Use ofnduction immunosuppression with lymphocyte-epleting agents (thymoglobulin or alemtuzumab)s associated with a greater risk of viral infectionosttransplant In general the greater the cumula-ive exposure to immunosuppression the greaterhe risk of infectious complications The presenta-ion of viral infections can be asymptomatic vaguend nonspecific or life-threatening acute illnessany viral infections seen in KTRs are rarely seen
n immunocompetent patients and therefore do notnter into the differential diagnosis for physiciansnfamiliar with transplant recipients Close commu-ication with the transplant center is crucial inaring for the transplant population Early detectionnd institution of therapy provide the best chanceor viral eradication
BKVirus
Although the work group agreed with KDIGOuggestions for BK virus screening posttransplante did not think it was practical to require screen-
ng exclusively with quantitative plasma nucleiccid testing (NAT) because many US centers usenitial urinary screening and then test plasma onlyf urine screening results are positive Howeverhere is no disagreement that some type of screen-ng for BK virus is critical to avoid BK nephropa-hy for which there is no specific treatment when its established Complicating screening for BK vi-us is the variability in results between laboratoriesnd uncertainty about the level of viremia thathould trigger a response to decrease in immunosup-ression In the presence of viremia and increase inerum creatinine level a renal allograft biopsy isndicated to confirm the presence of BK nephropa-
hy Because BK viremia and viruria certainly can b
e detected beyond the first year it is not clear howong screening should be continued posttransplantlthough most centers screen for the first year onlyngoing clinical trials are exploring effective treat-ent for BK nephropathy3839 Decisions about
ecreases in immunosuppression currently theainstay of BK viremia management always
hould be made in consultation with the transplantenter
Cytomegalovirus
KDIGO recommendation 1321 regarding cyto-egalovirus (CMV) prophylaxis is reasonable and
pplicable to the US population Universal prophy-axis for CMV now is recommended over initiatingre-emptive treatment after CMV develops40 Aajor concern for US patients is the cost of CMV
rophylaxis with oral valgancyclovir Leukopeniaan be observed in patients using mycophenolatereparations when prophylaxis with valgancyclo-ir is used Screening for CMV is best performedsing NAT methods (1322) CMV antigenemiassays are still in use in many facilities but are nots sensitive as PCR assays41 There is no utility inhecking for serologic response to CMV with IgGr IgM titers posttransplant because the immuneesponse is not predictable Patients with CMVisease should be cared for by clinicians familiarith treating this disease It is recommended that
reatment be continued until viral load is undetect-ble followed by prophylactic doses of valgancy-lovir for an additional 3 months35
Epstein-BarrVirus
Current practice regarding EBV screening variesmong centers in the United States and many doot routinely screen for EBV posttransplant evenn recipient-negative donor-positive cases In con-rast to KDIGO recommendation 1311 routineBV screening is not recommended in AST infec-
ious disease guidelines35 In many centers EBVcreening is reserved for children who are muchore commonly EBV negative pretransplant than
dults EBV-induced posttransplant lymphoprolif-rative disorder (PTLD) affects many more pediat-ic than adult KTRs If screening is someday to beoutinely implemented in US centers details regard-ng the best method of screening and levels ofiremia above which a clinical intervention should
e triggered need to be better defined
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ARTICLE IN PRESS
HerpesandVaricella
Systemic herpesvirus infections can be lifehreatening in transplant recipients and should bereated aggressively with intravenous antiviralgents as described in the KDIGO recommenda-ions Less aggressive cutaneous infection can bereated with oral antiviral agents as outlined inhe KDIGO guidelines
Varicella exposure is particularly concerning inransplant recipients The work group disputes theecommended dosing of acyclovir for varicellaxposure Acyclovir at a dose of 10 mgkg or about00 mg 4 times daily of oral acyclovir would betandard dosing We agree with the use of varicellammune globulin and emphasize the need to avoidhe varicella vaccine because it is a live virushould a transplant recipient develop a systemicaricella infection hospitalization and high-dosentravenous acyclovir therapy are warranted
Hepatitis C
Hepatitis C management posttransplant is ahallenge The KDIGO guidelines cited hereere based on the recently published KDIGOuideline for hepatitis C in CKD4 Hepatitis Cypically is not treated posttransplant because ofhe risk (50) of rejection precipitated bynterferon therapy particularly in US KTRs inhom hepatitis C commonly is genotype 1 which
s more resistant to treatment with interferon42
owever should hepatitis Cndashrelated glomerulo-ephritis develop the risk-benefit ratio may fa-or treatment in selected patients Such decisionslways should be made in consultation withepatology and infectious disease experts andhe transplant center Monitoring liver enzymeevels specifically alanine aminotransferaseALT) may reflect a change in hepatitis activityut monitoring hepatitis C viral load is not recom-ended because it does not seem to correlateith outcome Annual monitoring for hepatocel-
ular carcinoma using -fetoprotein and imagings encouraged but not often practiced
Hepatitis B
KDIGO recommendations for hepatitis B areeasonable and currently are followed in mostS centers except for recommendation 1366
see previous recommendation under vaccina-ions) KTRs with hepatitis C or hepatitis B also
hould be followed up by a hepatologist
Human ImmunodeficiencyVirus
Human immunodeficiency virus (HIV)-posi-ive individuals are now acceptable for transplantf CD4 count is 200 cellsL and viral loadVL) is undetectable3543 Transplant should beerformed at centers with expertise in managingIV-positive individuals and care should be co-rdinated carefully with HIV specialists Somentiretroviral agents in particular the proteasenhibitors have potentially serious drug interac-ions with immunosuppressive agents35
DIGORecommendations inChapter 14Othernfections
141 URINARY TRACT INFECTION1411 We suggest that all KTRs receive UTI
prophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 monthsafter transplantation (2B)
1412 For allograft pyelonephritis we suggestinitial hospitalization and treatment withintravenous antibiotics (2C)
142 PNEUMOCYSTIS JIROVECII PNEUMONIA1421 We recommend that all KTRs receive
PCP prophylaxis with daily tri-methoprimndashsulfamethoxazole for 3-6months after transplantation (1B)
1422 We suggest that all KTRs receive PCPprophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 weeksduring and after treatment for acute rejec-tion (2C)
1423 We recommend that KTRs with PCPdiagnosed by bronchial alveolar lavageandor lung biopsy be treated withhigh-dose intravenous trimethoprimndashsulfamethoxazole corticosteroids anda reduction in immunosuppressivemedication (1C)
1424 We recommend treatment with cortico-steroids for KTRs with moderate tosevere PCP (as defined by PaO2 lt70mm Hg in room air or an alveolargradient of gt35 mm Hg) (1C)
143 TUBERCULOSIS1431 We suggest that TB prophylaxis and
treatment regimens be the same in KTRsas would be used in the local generalpopulation who require therapy (2D)
1432 We recommend monitoring CNI andmTORi [mTOR inhibitor] blood levels inpatients receiving rifampin (1C)14321 Consider substituting rifabu-
tin for rifampin to minimize
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KDOQI Commentary 17
ARTICLE IN PRESS
interactions with CNIs andmTORi (Not Graded)
144 CANDIDA PROPHYLAXIS1441 We suggest oral and esophageal Candida
prophylaxis with oral clotrimazole loz-enges nystatin or fluconazole for 1-3months after transplantation and for 1month after treatment with an antilympho-cyte antibody (2C)
DOQIRationale andCommentary
UrinaryTract Infection
Urinary tract infections (UTIs) after kidneyransplant are very common and account for aarge percentage of readmissions posttransplantTIs are common because of multiple factors
ncluding the disrupted anatomy of the urinaryract with a ureteroneocystotomy incompleteladder emptying because of diabetes or pros-atic hypertrophy and impaired immune re-ponses Prophylaxis of UTIs usually is under-aken with trimethoprim-sulfamethoxazole for 6onths posttransplant although infections often
ccur despite therapy because of the develop-ent of drug resistance Although native kidney
yelonephritis does not always require hospital-zation it is recommended that all KTRs withhis diagnosis be hospitalized because the graftysfunction that usually accompanies transplantyelonephritis requires aggressive investigationnd treatment Individuals with recurrent UTIsarrant evaluation with urologic assessment Pa-
ients with recurrent UTIs may benefit fromong-term suppressive therapy
Pneumocystic Pneumonia
We agree that Pneumocystis jirovecii pneumoniaPCP) prophylaxis is important for the first 3-6onths posttransplant (1421)After the first month
very-other-day dosing of trimethoprim-sulfame-hoxazole or atovaquone is believed to be adequaterophylaxis In cases in which neither of thesegents can be used an individual may be treatedrophylactically with inhaled pentamidine OurDOQI work group emphasized that patients whoevelop PCP should be transferred to the transplantenter promptly for management and adjustmentsn immunosuppression
Tuberculosis
Monitoring for latent tuberculosis has posed a
hallenge in the immunosuppressed population be-
ause of the unreliable nature of skin testing Newerechniques involving interferon release assays aremerging as the new gold standard for detection ofatent tuberculosis4445
CandidaProphylaxis
Oral candidiasis must be screened for usingral mucosa examination on follow-up visitsn KTRs This is especially true in the earlyosttransplant period when immunosuppres-ive medication dosage is the highest Wegree with these recommendations and empha-ize that if fluconazole is used there is aotential for serious drug interactions becausef cytochrome P-450 3A4 inhibition
SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
Improvement in short-term outcomes has not trans-lated into significant improvements in long-term out-comes in KTRs The lack of significant improvement inlong-term survival may be related to post-transplantcomplications Frequent posttransplant monitoring mayimprove long-term outcomes by decreasing chronic graftfailure or death with a functioning graft Our work groupconcurred with the recommendation and schedules ofroutine screening in monitoring kidney allograft functionafter kidney transplant with a low threshold for perform-ing kidney biopsy in cases of graft dysfunction or protein-uria Expert tissue processing and interpretation of trans-plant biopsy specimens by pathologists with transplantexperience are critical Regular surveillance of the pa-tientrsquos kidney function at the transplant center or in thenephrologistrsquos office offers an opportunity to enhancepatient adherence to medication diet and healthy life-style Although CKD in KTRs progresses more slowlythan CKD in other patients the work group agreed thatthe KDIGO guidelines on CKD should be followed inKTRs
Opportunistic infections are common in KTRs al-though advances in diagnosis and treatment have led toimproved survival in KTRs with infection It is nowstandard of care to use vaccinations in KTRs as long asthe vaccine does not contain live or attenuated virus Italso is routine to screen for or use prophylaxis to preventseveral posttransplant viral infections With few excep-tions (related to EBV and BK virus screening andhepatitis B vaccination posttransplant) we concurredwith KDIGO guidelines for vaccination screening and
treatment of infection posttransplant
KD
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Bia et al18
ARTICLE IN PRESS
COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULAR
DISEASE
DIGORecommendations inChapter 15iabetesMellitus
151 Screening for New-Onset Diabetes after Transplan-tation1511 We recommend screening all nondia-
betic KTRs with fasting plasma glu-cose oral glucose tolerance testingandor HbA1c (1C) at leastbull weekly for 4 weeks (2D)bull every 3 months for 1 year (2D)bull and annually thereafter (2D)
1512 We suggest screening for NODAT withfasting glucose oral glucose tolerancetesting andor after starting or substan-tially increasing the dose of CNIsmTORi or corticosteroids (2D)
152 Managing NODAT or Diabetes Present at Trans-plantation1521 If NODAT develops consider modifying
the immunosuppressive drug regimen toreverse or ameliorate diabetes afterweighing the risk of rejection and otherpotential adverse effects (Not Graded)
1522 Consider targeting HbA1c 70-75and avoid targeting HbA1c 60 espe-cially if hypoglycemic reactions are com-mon (Not Graded)
1523 We suggest that in patients with diabetesaspirin (65-100 mgd) use for the primaryprevention of CVD be based on patientpreferences and values balancing the riskfor ischemic events to that of bleeding(2D)
DOQIRationale andCommentary
Diabetic Screening
We agree with screening for new-onset diabetesfter transplantation (NODAT) as outlined by theDIGO work group Definitions used are similar
o those of the American Diabetes AssociationADA) The greater frequency of testing initially isustified by the high risk of NODAT in the earlyosttransplant period however ongoing screenings required because the risk of the development ofODAT continues to increase over time4647 We
lso point out that prediabetic states (impairedasting glucose level and impaired glucose toler-nce) occur even more commonly than overt diabe-es48 and may be associated with metabolic syn-rome as well as with increased cardiovascular
ortality49-51 Potential implications of these predia-
etic states emphasize the importance of perform-ng blood tests under fasting conditions For pa-ients with fasting hyperglycemia an oral glucoseolerance test or hemoglobinA1c (HbA1c) test shoulde performed Although more cumbersome to per-orm data suggest that an oral glucose toleranceest is a more sensitive indicator of NODAT inyperglycemic KTRs52 This may allow earlieretection of overt diabetes and more prompt institu-ion of treatment
DiabetesManagement
Data supporting a substantial benefit in themelioration or reversal of NODAT using immu-osuppression modification in KTRs are veryimited There was consensus in our work grouphat considering the paucity of data for reversingODAT by changing immunosuppression and
he potential risk of an adverse outcome withuch a maneuver KDIGO suggestion 1521 couldot be supported Certainly if such a step waseing considered it should be done in conjunc-ion with the transplant center Targeting an HbA1c
evel of 7-75 and avoiding levels 6 isased on data showing increased cardiovascularvents with the lower HbA1c target5354
DIGORecommendations inChapter 16ypertensionDyslipidemias TobaccoUse andbesity
161 Hypertension1611 We recommend measuring blood pres-
sure at each clinic visit (1C)1612 We suggest maintaining blood pressure at
130 mm Hg systolic and 80 mm Hgdiastolic if 18 years of age and 90th
percentile for sex age and height if 18years old (2C)
1613 To treat hypertension (Not Graded)bull Use any class of antihypertensive
agentbull Monitor closely for adverse effects
and drug-drug interactions and whenurine protein excretion 1 gd for18 years old and 600 mgm224 hfor 18 years old consider an ACE-Ior an ARB as first-line therapy
162 Dyslipidemias (These recommendations are basedon KDOQI Dyslipidemia Guidelines and are thusnot graded)1621 Measure a complete lipid profile in all
adult (18 years old) and adolescent
(puberty to 18 years old) KTRs [Based on
K
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KDOQI Commentary 19
ARTICLE IN PRESS
KDOQI Dyslipidemia Recommendation1]bull 2-3 months after transplantationbull 2-3 months after a change in treatment
or other conditions known to causedyslipidemias
bull at least annually thereafter1622 Evaluate KTRs with dyslipidemias for
secondary causes [Based on KDOQI Dys-lipidemia Recommendation 3]16221 For KTRs with fasting triglyc-
erides 500 mgdL (565mmolL) that cannot be cor-rected by removing an under-lying cause treat withbull Adults therapeutic lifestyle
changes and a triglyceride-lowering agent [Based onKDOQI Recommendation41]
bull Adolescents therapeutic life-style changes [Based onKDOQI Recommendation51]
16222 For KTRs with elevatedLDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)treat to reduce LDL-C to100 mgdL (259mmolL) [Based on KDOQIGuideline 42]
bull Adolescents If LDL-C130 mgdL (336 mmolL) treat to reduce LDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 52]
16223 For KTRs with normalLDL-C elevated triglyceridesand elevated non-HDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)fasting triglycerides 200mgdL (226 mmolL)and non-HDL-C 130mgdL (336 mmolL)treat to reduce non-HDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 43]
bull Adolescents If LDL-C130 mgdL (336 mmolL) fasting triglycerides200 mgdL (226 mmolL) and non-HDL-C 160mgdL (414 mmolL)treat to reduce non-HDL-C
to 160 mgdL (414 i
mmolL) [Based on KDOQIGuideline 53]
163 Tobacco Use1631 Screen and counsel all KTRs including
adolescents and children for tobacco useand record the results in the medicalrecord (Not Graded)bull Screen during initial transplant hospi-
talizationbull Screen at least annually thereafter
1632 Offer treatment to all patients who usetobacco (Not Graded)
164 Obesity1641 Assess obesity at each visit (Not Graded)
bull Measure height and weight at eachvisit in adults and children
bull Calculate BMI at each visitbull Measure waist circumference when
weight and physical appearance sug-gest obesity but BMI is 35 kgm2
1642 Offer a weight-reduction program to allobese KTRs (Not Graded)
DOQIRationale andCommentary
Hypertension
The KDIGO work group adapted the KDOQI004 recommendations for target blood pres-ure in KTRs55 Self measurement is useful inssessing response to therapy and enhancesdherence56 In general we agree that the classf antihypertensive agent does not matter inhe treatment of blood pressure elevation inhis population and that attention should beiven to potential side effects of antihyperten-ive agents as well as possible interactionsith the immunosuppressive regimen (eg non-ihydropyridine calcium channel blockers andNIs) In the absence of adequate randomizedontrolled trials it is not known whether angio-ensin-converting enzyme (ACE) inhibitors andngiotensin receptor blockers (ARBs) prolongecipient or allograft survival Some but notll retrospective studies suggest a benefitowever all these studies are limited by selec-ion bias5758 Although ACE inhibitors andRBs commonly lead to some decrease inFR treatment with these drugs should be
ontinued unless serum creatinine level in-reases by 25 to 30 in keeping withDOQI recommendations55 In KTRs receiv-
ng ACE inhibitors or ARBs it is important toducate patients to maintain adequate fluid
ntake during illness to prevent a prerenal
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ARTICLE IN PRESS
nsult to the allograft Similarly awareness isecessary when using diuretics in conjunctionith therapies that block the renin-angiotensin-
ldosterone-system59
Dyslipidemia
The KDIGO work group based their recom-endations for evaluation and treatment of
yperlipidemia on the KDOQI dyslipidemiauidelines for KTRs60 We agree with theseecommendations CNIs potentiate the toxicityf statins by slowing their metabolism throughhe cytochrome P-450 system This interactionccurs more commonly with cyclosporine61
han with tacrolimus Dyslipidemia especiallyypertriglyceridemia frequently complicatesTOR-inhibitor use and lipid-lowering therapy
s required in most patients using these agents
TobaccoUse
Not surprisingly tobacco use at the time ofransplant is associated with decreased patientnd graft survival as well as increased risk ofosttransplant cardiovascular disease (CVD)lthough the KDIGO work group recom-ends initial screening and intervention dur-
ng the hospitalization for transplant we be-ieve there may be benefit gained by startingounseling in the pretransplant period duringhe evaluation phase Unfortunately this doesot occur often because of time and personnelonstraints in transplant centers Ideally allransplant centers should have smoking-cessa-ion programs available to patients either in-ouse or through referral Ideally systemshould be created to continue to screen andonitor for smoking cessation at yearly inter-
als after transplant because there is a highate of relapse with this addiction As outlinedn KDIGO Table 253 although all pharmaco-ogic therapies for smoking cessation can besed in KTRs the starting dose of vareniclinehould be decreased in patients with GFR 30Lmin
Obesity
Obesity is an epidemic in the United Statesnd the proportion of obese kidney transplantandidates continues to grow In additioneight gain after transplant is very commonly
bserved Obesity in KTRs is associated with w
ncreased risks of wound complications de-ayed graft function acute rejection and NO-AT resulting in inferior patient and graftutcomes Attention to this potential complica-ion and counseling should be initiated duringhe pretransplant evaluation phase Informa-ion regarding pharmacologic therapies foreight loss in KTRs is not available and we
gree with the KDIGO work group that thera-eutic lifestyle measures should be encour-ged Data regarding steroid therapy with-rawal and weight gain are controversial Aecent double-blind randomized controlled trialxamining early steroid therapy withdrawalid not show a difference in weight gain at 5ears posttransplant compared with the cohortemaining on standard maintenance corticoste-oid therapy62
DIGORecommendations inChapter 17ardiovascularManagement
171 Consider managing CVD at least as intensively inKTRs as in the general population with appropri-ate diagnostic tests and treatments (Not Graded)
172 We suggest using aspirin (65-100 mgd) in allpatients with atherosclerotic CVD unless there arecontraindications (2B)
DOQIRationale andCommentary
Although outcomes are favorable comparedith remaining on the waiting list the risk of
ardiovascular mortality in KTRs is several-foldigher than observed in the general population63
specially in younger age groups and patientsith decreasing allograft function64 CVD is aajor cause of graft loss after the first post-
ransplant year In this context we strongly agreehat CVD should be managed in KTRs at least asntensively as in the general population Ideallyecreasing CVD risk in KTRs requires a multifac-ted and multidisciplinary approach Based onurrent practice models in the United States theransplant and nephrology community has notet been able to achieve these desirable goals65
his clearly deserves more attention becauseontrol of CVD has the potential to contributeore to long-term kidney graft survival than the
iscovery of newer drugs that decrease the ratef allograft rejection Our KDOQI working groupgreed with the use of low-dose aspirin in KTRs
ith evidence of atherosclerosis
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KDOQI Commentary 21
ARTICLE IN PRESS
SUMMARY OF COMMENTARY ONSECTION III CVD
COMMENTARY ON SECTION IV OF KDIGO
TRANSPLANT GUIDELINE MALIGNANCY
DIGORecommendations inChapter 18 Cancerf the Skin andLip
181 We recommend that KTRs especially thosewho have fair skin live in high sun-exposureclimates have occupations requiring sun expo-sure have had significant sun exposure as achild or have a history of skin cancer be toldthat their risk of skin and lip cancer is veryhigh (1C)
182 We recommend that KTRs minimize life-longsun exposure and use appropriate ultravioletlight blocking agents (1D)
183 We suggest that adult KTRs perform skin andlip self-examinations and report new lesions toa health-care provider (2D)
184 For adult KTRs we suggest that a qualified healthprofessional with experience in diagnosing skincancer perform annual skin and lip examinationon KTRs except possibly for KTRs with dark skinpigmentation (2D)
185 We suggest that patients with a history of skin orlip cancer or premalignant lesions be referred to andfollowed by a qualified health professional withexperience in diagnosing and treating skin cancer
With the decrease in acute rejection during the pastdecade in association with improved immunosuppres-sion regimens patient death now rivals chronic graftdysfunction as one of the leading causes of long-termgraft loss Because CVD is the most common cause ofpatient death in KTRs a concerted effort at minimizingrisk factors for heart disease likely will have as great oreven greater impact on optimizing patient and graftoutcomes than the discovery of new antirejection thera-pies CVD risk reduction strategies should include regularscreening for new-onset diabetes (using ADA-based defini-tions) in the posttransplant period in previously nondiabeticpatients good glycemic regulation for diabetic patients accord-ing to current ADA guidelines and lipid management andblood pressure control according to KDOQI recommenda-tions In addition promotion of a healthy lifestyle throughweight control exercise and smoking cessation should be acentral part of posttransplant counseling and care Whenimmunosuppression modification is being considered to miti-gate cardiovascular risk we recommend that this be inconjunction with the transplant center In summary we gener-ally concurred with the suggestions of the work group in thissection but based on current practice standards in the UnitedStateschallengesremainwith implementationof thisguideline
(2D) s
186 We suggest that patients with a history of skincancer be offered treatment with oral acitretin ifthere are no contraindications (2B)
DOQIRationale andCommentary
CounselingandSunscreen
We concur with recommendations 181 and82 because skin cancer is a major source oforbidity and sometimes mortality in KTRsarning patients at risk of the high danger of
kin cancer a 1C recommendation is reinforcedy a recent prospective case-control study ofrgan transplant recipients that showed that regu-ar use of broad-spectrum sunscreens that pro-ide UVA and UVB protection may prevent theevelopment of actinic keratosis invasive squa-ous cell carcinoma and to a lesser extent
asal cell carcinoma66 Most cancer-causing ra-iation is thought to come from the UVB spec-rum and newer broad-spectrum sunscreens pro-ide protection against UVA and UVB radiationounseling about sunscreen and the need for sunvoidance needs to be incorporated into routineffice visits although it may not always beuccessful In a recent study of KTRs in which1 of patients had been informed about theeed for sun protection only 46 used morehan a tube of sunscreen per year67
Dermatology Involvement
There is increased evidence to suggest thatpecialty dermatology clinics for organ trans-lant recipients improve outcome measures in-luding compliance with photoprotection andncreased awareness of skin cancer68 The re-ources required for these specialty clinics makemplementation difficult for community nephrol-gy groups that do not have direct access to aransplant center Transplant patients should bencouraged to have annual visits with their trans-lant center and if dermatology specialty clinicsre available attempt to coordinate a skin cancervaluation annually
UseofRetinoid-likeCompounds
There is a limited scientific basis for KDIGOuggestion recommendation 186 Although reti-oids now are used routinely in KTRs with aigh skin cancer burden our KDOQI work groupelieves that more data are needed before this
uggestion should be accepted as a guideline In
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ARTICLE IN PRESS
ow-immunologic-risk groups and particularlyifficult cases some data suggest that switchingrom CNI to sirolimus therapy may decrease thencidence of skin cancer69 however the riskersus benefit of this maneuver has not been welltudied
DIGORecommendations inChapter 19on-SkinMalignancies
191 Develop an individualized screening plan for eachKTR that takes into account the patientrsquos pastmedical and family history tobacco use compet-ing risks for death and the performance of thescreening methodology (Not Graded)
192 Screen for the following cancers as per localguidelines for the general population (Not Graded)Women cervical breast and colon cancer Menprostate and colon cancer
193 Obtain hepatic ultrasound and alpha feto-proteinevery 12 months in patients with compensatedcirrhosis (Not Graded) [See Recommendations1354 (HCV) and 1365 (HBV)]
DOQIRationale andCommentary
Screening
It is recognized that KTRs have a higher inci-ence of malignancy particularly those associatedith specific viral infections Although cancer
creening may have benefits in this higher riskopulation it should be reinforced that some meth-ds of screening have significant risks which shoulde considered on an individualized basis particu-arly in patients who have projected survival lesshan 5 years
Screening forCancer inPatientsWithHepatitis
Many patients who have underlying cirrhosisn the United States will be followed up by arofessional specializing in liver disease whoay provide additional insight into this cancer
creening recommendation Based on a recentuestionnaire of US gastroenterologists only 50creen patients for hepatocellular carcinoma70
herefore implementation of this guideline byS clinicians is unlikely to be widespread
DIGORecommendations inChapter 20anagingCancerwithReductionof
mmunosuppressiveMedication
201 We suggest consideration be given to reducingimmunosuppressive medications for KTRs with can-
cer (2C)
2011 Important factors for consideration in-clude (Not Graded)bull The stage of cancer at diagnosisbull Whether the cancer is likely to be
exacerbated by immunosuppressionbull The therapies available for the can-
cerbull Whether immunosuppressive medica-
tions interfere with ability to admin-ister the standard chemotherapy
202 For patients with Kaposi sarcoma we suggestusing mTORi along with a reduction in overallimmunosuppression (2C)
DOQIRationale andCommentary
Table 1 (Table 29 in the KDIGO report3 andxcerpted from Grulich et al71) lists cancershat are increased most in immunosuppressedTRs based on standardized incidence ratios
SIRs) which compare the incidence toatched populations Cancers with the highestIRs may be those most likely to respond to aecrease in immunosuppression Except foraposi sarcoma limited evidence is available
or a decrease in immunosuppression in theseettings A strategy to change immunosuppres-ion therapy must occur in consultation withhe transplant center Switching to sirolimusherapy and decreasing immunosuppression inatients who develop Kaposi sarcoma is basedn sound scientific rationale7273
SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
The incidence of cancer posttransplant is 2-20times higher than that in the general population andKDIGO guidelines have been written to outline stepsfor prevention and screening With few exceptions weagree with the recommendations as outlined Skincancer is common in US transplant patients andscreening and prevention are critical However imple-mentation of guidelines for doing so including theKDIGO guidelines is a challenge because of patientpreferences against the routine use of sunscreen aswell as time constraints during office visits Althoughmany posttransplant cancers are viral mediated andrelated to immunosuppression it is less clear how toalter immunosuppression after malignancy has oc-curred We agree that although age-specific screeningfor malignancy should be incorporated into care con-sideration must be given to the risk of screening inpatients with limited life spans (5 years) because of
comorbid conditions
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
ommonPopu
i sarco-Hodgmelanise sm
sophaemia
estima standa10 c
ut esti
0 case
alized t
to guide treatment specifically before the
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
REFERENCES1 McCullough KP Keith DS Meyer KH et al Kidney
nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
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sw
Bia et al28
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2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
ation Transpl Rev 200923191-19815 Abbud-Filho M Adams PL Alberuacute J et al A report
f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
A
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
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Iwa
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mi8
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Bia et al30
ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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ARTICLE IN PRESS
ories Therefore coordination with the transplantenter where these techniques are available is essen-ial For patients with CAI caused by CNI toxicityithdrawing the CNI should occur only after at-
empts at decreasing the dosage have failed Onelso must ensure that all other causes of CAI arexcluded to avoid inappropriate drug adjustmentsr missed treatment options Although our workroup thought that KDIGO suggestion 721 maye reasonable in some patients we also want tomphasize that the role of mTOR inhibitors in thereatment of CAICNI toxicity is poorly defined Its clear that switching from a CNI to an mTORnhibitor should be avoided in patients with se-erely decreased glomerular filtration rate (GFR)ndor the presence of proteinuria however the exactuidelines for when to switch are still evolving
SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
DIGORecommendations inChapter 8onitoringKidneyAllograft Function
81 We suggest measuring urine volume (2C)bull Every 1-2 hours for at least 24 hours after
transplantation (2D)
In the United States immunosuppressive protocolsused may vary from center to center based on theirparticular patient population organ source experienceand opinion of the transplant team ease of use and costof therapy Although data about the efficacy and safety ofsteroid-free regimens are still evolving it is clear that ifsteroids are to be eliminated this should be done in theearly transplant period and not late (after 1 year)Community nephrologists need to coordinate any alter-ations in immunosuppressive medications with the trans-plant center and be vigilant for potential drug interactionswith the addition of any new medications Drug monitor-ing is an essential monitoring tool throughout the post-transplant course but not always applicable to everyimmunosuppressive medication Transplant biopsies fre-quently are necessary to determine the cause of renaldysfunction and the interpretation must be performed bypathologists with resources and experience in handlingand reading the transplant biopsy specimen
bull Daily until graft function is stable (2D) c
82 We suggest measuring urine protein excretion (2C)at leastbull Once in the first month to determine a baseline
(2D)bull Every 3 months during the first year (2D)bull Annually thereafter (2D)
83 We recommend measuring serum creatinine (1B) atleastbull Daily for 7 days or until hospital discharge
whichever occurs sooner (2C)bull 2-3 times per week for weeks 2-4 (2C)bull Weekly for months 2 and 3 (2C)bull Every 2 weeks for months 4-6 (2C)bull Monthly for months 7-12 (2C)bull Every 2-3 months thereafter (2C)
831 We suggest estimating GFR whenever se-rum creatinine is measured (2D) usingbull One of several formulas validated for
adults (2C) orbull The Schwartz formula for children and
adolescents (2C)
84 We suggest including a kidney allograft ultrasoundexamination as part of the assessment of kidneyallograft dysfunction (2C)
DOQIRationale andCommentary
RoutineScreeningTestsandTimeandFrequencyofMonitoring
Regular surveillance and vigilant monitoring ofidney allograft function are important in improv-ng short- and long-term outcomes Early detectionf kidney allograft dysfunction will allow timelyiagnosis and treatment that may improve patientnd graft survival Frequency and types of routinecreening tests after kidney transplant are shown inig 2Although there is no standard protocol for therequency and type of monitoring recommenda-ions are guided by the likelihood of problemspecific to the particular transplant population Inhe early posttransplant period when rejection andomplications are the most likely testing is per-ormed more frequently Thereafter the follow-upnterval will depend in part on the patientrsquos generalondition and the development of additional prob-ems The AST recommended routine posttrans-lant 2-3 visits per week during month 1 every 1-3eeks during month 2-3 every 4-8 weeks duringonths 4-12 and every 2-4 months after therst year These early visits often are providedy the transplant physician or surgeon of theransplant center After 3-6 months monitor-ng may be performed by the transplant physi-
ian or community nephrologist15 In a recent
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KDOQI Commentary 9
ARTICLE IN PRESS
urvey of posttransplant outpatient visits inedicare beneficiaries in the United States
requency of visits to transplant centers variedy center and region most visits were toephrologists16
At each clinic visit education regardingedication adherence diet and healthy life-
tyle should be given Screening for tobaccose should be implemented before dischargend annually Although the work group did notgree that screening all adults for Epstein-Barrirus (EBV) was of value (see commentarynder Chapter 13 for EBV) screening for allther elements listed in Fig 2 including screen-ng for proteinuria is reasonable In additiono these tests monitoring for HLA antibodiesgainst the donor (donor-specific antibodies)hich is not described in the KDIGO guide-
ine is becoming more common in some USenters The optimal timing and frequency ofuch screening has yet to be determined1718
SerumCreatinineandEstimatedGFR
Serum creatinine measurement remains theost commonly used index of renal allograft
unction It is reliable for detecting acute changesn kidney function Furthermore serum creati-ine level at year 1 after transplant is a riskactor for subsequent outcomes19 and mayelp in the management of the frequency ofisits However it is less reliable for detecting
Figure 2 Routine screen-ng after kidney transplantomplete blood cell count in-ludes white blood cells hemo-lobin and platelets Screenor diabetes is by fasting bloodlucose level glucose toler-nce test or hemoglobin A1c
evel Lipid profile includes fast-ng cholesterol low-density li-oprotein cholesterol high-ensity lipoprotein cholesterolnd triglyceride levels Screensor BK polyoma virus (BKV)nd Epstein-Barr virus (EBV)se plasma nucleic acid test-
ng (NAT) EBV screen is foratients with no antibody toBV at transplant Adapted
rom the KDIGO transplantuideline3 with permission ofDIGO
ong-term changes in kidney function in the
idney transplant recipient Formulas to esti-ate GFR using serum creatinine values have
een tested in KTRs but no formula consis-ently has been shown to be superior to an-ther As with CKD considerable renal patho-ogic states can be present without dramatichanges in serum creatinine levels
In 2005 the definition of CKD was amendedo include all KTRs regardless of markers ofidney damage or GFR2021 Although the workroup agreed that CKD staging in KTRs isseful it must be noted that there is consider-ble difference in the rate of progression inhese 2 groups Progression is much slower inTRs in whom kidney half-life is longer at
very level of CKD Renal ultrasound is thereferred imaging study in KTRs (KDIGOuggestion 84)22
DIGORecommendations inChapter 9 Kidneyllograft Biopsy
91 We recommend kidney allograft biopsy whenthere is a persistent unexplained increase inserum creatinine (1C)
92 We suggest kidney allograft biopsy when serumcreatinine has not returned to baseline after treat-ment of acute rejection (2D)
93 We suggest kidney allograft biopsy every 7-10 daysduring delayed function (2C)
94 We suggest kidney allograft biopsy if expectedkidney function is not achieved within the first 1-2months after transplantation (2D)
95 We suggest kidney allograft biopsy when there is
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bull New onset of proteinuria (2C)bull Unexplained proteinuria 30 g per gram creati-
nine or 30 g per 24 hours (2C)
DOQIRationale andCommentary
Biopsy
Renal allograft biopsy is the gold standard foriagnosing the cause of a change in renal allo-raft function It is useful in all clinical situationsescribed in KDIGO suggestions 91-94 Poten-ial causes of allograft dysfunction include vol-me depletion compromised renal blood flowrinary outflow obstruction parenchymal causesuch as acute rejection (cellular andor humoral)hronic allograft nephropathy recurrent or deovo disease or BK nephropathy Patients show-ng a 20-25 increase in creatinine level aboveaseline values warrant consideration for biopsyther indications for pursuing renal allograftiopsy would be a less-than-expected responseo treatment of acute rejection The expectedesponse would be dependent on the severity ofissue injury noted on the diagnostic biopsy speci-
en Delayed graft function lasting longer than-7 days warrants biopsy with repeated biopsieserformed every 7-10 days until graft functionecovers New-onset proteinuria protein 20g creatinine or 20 g24 h also merits aidney biopsy De novo and recurrent glomerulariseases are common causes of new-onset pro-einuria Patients with de novo or recurrent glo-erular diseases should be followed up closely
y transplant nephrologists or community neph-ologists with close communication with theransplant center because treatment of some recur-ent kidney diseases may prevent or delay thenset of graft failure2324
SafetyandAccuracy
The safety of kidney transplant biopsies haseen documented and the overall risk of compli-ations is low Most biopsies are performed inhe transplant center by transplant nephrologistsommunity nephrologists also may perform bi-psies of the kidney in KTRs more than a yearosttransplant It is prudent to obtain a diagnosticltrasound before biopsy to rule out unexpectedlterations in blood flow or urinary tract obstruc-ion It is imperative that a pathologist familiar
ith the transplant process interprets the pathol-
gy in consultation with the referring nephrolo-ist using appropriate stains and other studies
MolecularMarkers
In addition to conventional histopathologicxamination several US transplant centers aresing molecular markers as well as genomic orroteomic methods to enhance our understand-ng of the mechanism of immunologic and non-mmunologic pathway of injury As an exampleolymerase chain reaction (PCR) has been usedo detect messenger RNA for IL-2 and otheriomarkers in biopsy samples Using this ap-roach IL-2 upregulated during rejection coulde detected 2 days before rejection was apparentsing histologic or clinical criteria Such PCRpproaches have been used to detect other generoducts upregulated during acute rejection suchs granzyme B perforin transforming growthactor IL-10 and IL-1525-27 These newerethods are performed almost exclusively in
ransplant centers and may become a standardethod of transplant biopsy analysis in the fu-
ure
DIGORecommendations inChapter 10ecurrentDisease
101 We suggest screening KTRs with primary kidneydisease caused by FSGS for proteinuria (2C) atleastbull Daily for 1 week (2D)bull Weekly for 4 weeks (2D)bull Every 3 months for the first year (2D) Every
year thereafter (2D)
102 We suggest screening KTRs with potentially treat-able recurrence of primary kidney disease fromIgA nephropathy MPGN anti-GBM disease orANCA-associated vasculitis for microhematuria(2C) at leastbull Once in the first month to determine a baseline
(2D)bull Every 3 months during the first year (2D)
Annually thereafter (2D)
103 During episodes of graft dysfunction in patientswith primary HUS we suggest screening forthrombotic microangiopathy (eg with plateletcount peripheral smear for blood cell morphologyplasma haptoglobin and serum lactate dehydroge-nase) (2D)
104 When screening suggests possible treatable recur-rent disease we suggest obtaining an allograftbiopsy (2C)
105 Treatment of recurrent kidney disease1051 We suggest plasma exchange if a biopsy
shows minimal change disease or FSGS
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KDOQI Commentary 11
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in those with primary FSGS as theirprimary kidney disease (2D)
1052 We suggest high-dose corticosteroids andcyclophosphamide in patients with recur-rent ANCA-associated vasculitis or anti-GBM disease (2D)
1053 We suggest using an ACE-I [ACE inhibi-tor] or an ARB for patients with recurrentglomerulonephritis and proteinuria (2C)
1054 For KTRs with primary hyperoxaluriawe suggest appropriate measures to pre-vent oxalate deposition until plasma andurine oxalate levels are normal (2C)includingbull Pyridoxine (2C)bull High calcium and low oxalate diet
(2C)bull Increased oral fluid intake to enhance
urinary dilution of oxalate (2C)bull Potassium or sodium citrate to alkalin-
ize the urine (2C)bull Orthophosphate (2C)bull Magnesium oxide (2C)bull Intensive hemodialysis to remove ox-
alate (2C)
DOQIRationale andCommentary
Recurrent disease accounts for a substantialmount of graft loss after renal transplant It isifficult to assess the percentage of grafts lost toecurrent disease because many patients presentith end-stage renal disease without benefit of aiagnostic native renal biopsy The likelihood ofecurrent disease after transplant is dependent onhe disease with certain diseases at particularlyigh risk of recurrence28
Recurrent Focal SegmentalGlomerulosclerosis
We agree with recommendation 101 regard-ng frequent and regular screening for protein-ria in patients with primary focal segmentallomerulosclerosis (FSGS) as the cause of end-tage renal disease If the patient is still produc-ng urine at the time of transplant a preoperativerine protein-creatinine ratio can be a very help-ul baseline measure of proteinuria Early detec-ion of FSGS recurrence which can present withormal light microscopy but foot-process efface-ent on electron microscopy29 provides the best
pportunity for intervention and amelioration ofisease
IgANephropathy
Recurrence rates of immunoglobulin A (IgA)
ephropathy are variable We agree with recom- b
endation 102 for screening routinely for micro-ematuria Recurrent disease is confirmed with aenal allograft biopsy Histologic recurrence ofisease is much more common than is clinicalisease recurrence There is no proven therapyor treatment of recurrent disease30
MembranoproliferativeGlomerulonephritis
Recurrence of membranoproliferative glomer-lonephritis (MPGN) is common as high as 80ith MPGN type II (dense-deposit disease) Theost common cause of MPGN type I is hepatitisndashassociated immune complex formation Wegree with the proposed regularly scheduledcreening for microhematuria and proteinuria inecommendation 102 Patients with known hepa-itis Cndashassociated MPGN pretransplant also maye screened for cryoglobulins which are associ-ted with MPGN31
HemolyticUremic Syndrome
Hemolytic uremic syndrome (HUS) typicallys divided into diarrheal associated (D) andonndashdiarrheal associated (D) D disease oc-urs mostly in children and rarely recurs post-ransplant However D HUS is more commonn adults and can recur In HUS associated with aomplement abnormality such as factor H defi-iency or factor I mutation recurrence rates cane as high as 80 Screening for evidence ofecurrence allows for an earlier diagnosis whichill require biopsy in most cases and provides
n opportunity for earlier intervention There iso comment in the guideline regarding recur-ence of thrombotic thrombocytopenic purpuraut early detection of recurrence provides anpportunity for treatment with plasmapheresisnd intravenous immune globulin (IVIG)
BiopsyandTreatment
As stated kidney biopsy and interpretation bypathologist with expertise in transplant speci-en readings is critical in the diagnosis of dis-
ase recurrence Treatment for most recurrentisease in renal transplantation is based on aombination of case reports case cohorts andetrospective reviews Recurrent diseases post-ransplant are not common enough that random-zed controlled trials can be implemented there-ore most recommendations for treatment are
ased on a consensus of opinion Despite this we
at
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gree in general with the recommendations de-ailed in 105
DIGORecommendations inChapter 11reventingDetecting andTreatingonadherence
111 Consider providing all KTRs and family memberswith education prevention and treatment mea-sures to minimize nonadherence to immunosup-pressive medications (Not Graded)
112 Consider providing KTRs at increased risk fornonadherence with increased levels of screeningfor nonadherence (Not Graded)
DOQIRationale andCommentary
Noncompliance or nonadherence to diet andedication is a common problem in KTRs Nonad-
erence to medication is associated with a high riskf acute rejection and allograft loss We agree thatarly efforts should be made to identify KTRs atncreased risk of nonadherence and that these pa-ients should be monitored closely Prevention iden-ification and treatment of nonadherence are inte-ral to the monitoring of kidney allograft functionnd long-term care of KTRs Certain subgroup ofTRs younger patients African Americans and
hose with financial hardships have an enhancedisk of nonadherence3233
In addition to identifying patients at risk it ismportant to have a system for addressing patientonadherence This requires coordinated efforts ofocial workers transplant coordinators financialounselors pharmacists primary nephrologists andhe patientrsquos family34 A combination of educa-ional behavioral and social support interventionsrovides the best results Because there is no per-ect measure of adherence consideration should beiven to multiple approaches for adherence moni-oring Similar team approaches also are importantn other areas requiring adherence such as dietxercise tobacco alcohol and drug use
DIGORecommendations inChapter 12accination
121 We recommend giving all KTRs approvedinactivated vaccines according to recommendedschedules for the general population except forHBV vaccination (1D)1211 We suggest HBV vaccination (ideally
prior to transplantation) and HBsAb titers6-12 weeks after completing the vaccina-
tion series (2D) h
12111 We suggest annual HBsAb[antibody to hepatitis B sur-face antigen] titers (2D)
12112 We suggest revaccination ifthe antibody titer falls below10 mIUmL (2D)
122 We suggest avoiding live vaccines in KTRs (2C)123 We suggest avoiding vaccinations except influ-
enza vaccination in the first 6 months followingkidney transplantation (2C)1231 We suggest resuming immunizations once
patients are receiving minimal mainte-nance doses of immunosuppressive medi-cations (2C)
1232 We recommend giving all KTRs whoare at least 1-month post-transplantinfluenza vaccination prior to the onsetof the annual influenza season regard-less of status of immunosuppression(1C)
124 We suggest giving the following vaccines to KTRswho due to age direct exposure residence ortravel to endemic areas or other epidemiologicalrisk factors are at increased risk for the specificdiseasesbull rabies (2D)bull tick-borne meningoencephalitis (2D)bull Japanese B encephalitismdashinactivated (2D)bull Meningococcus (2D)bull Pneumococcus (2D)bull Salmonella typhimdashinactivated (2D)1241 Consult an infectious disease specialist a
travel clinic or public health official forguidance on whether specific cases war-rant these vaccinations (Not Graded)
DOQIRationale andCommentary
KTRs are at particular risk of viral infectionsecause of the preferential suppression of T lympho-ytes by both induction and maintenance immuno-uppression The risk and consequence of develop-ng a viral infection warrant use of selected vaccineshe suggestions regarding which vaccines are safend which are contraindicated are based on whetherhe vaccine contains live or killed virus Live virusaccines are contraindicated in immunosuppressedTRs The KDIGO recommendations for vaccina-
ions agree with updated guidelines recently pub-ished by the AST35 Specific comments on theDIGO suggestions regarding vaccinations are
isted in the following sections
Hepatitis B
The work group did not concur with KDIGOuggestion 1211 Neither revaccination against
epatitis after transplant nor following up hepa-
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KDOQI Commentary 13
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itis B antibody titers annually is a commonractice in the United States Hepatitis B is nots prevalent in the United States as in otherarts of the world and evidence supportingcreening in all patients posttransplant is lack-ng However screening for seroconversion inatients at risk (receiving a hepatitis B corentibodyndashpositive kidney) is appropriate Theseatients may benefit from lamivudine or ente-avir therapy36
LiveVaccineandTimingofVaccine
There is no particular reason for a 6-monthag between transplant and vaccination Theheory is that vaccines are less likely to beffective in the period when immunosuppres-ion is high In the United States most individu-ls are on their baseline maintenance immuno-uppression therapy by 3 months posttransplantecisions regarding the timing of vaccines areade based on immunosuppression exposure
nd risk of infection Recipients also shouldvoid intimate contact with individuals whoave received live vaccines37 This includesvoiding close contact with children who haveeceived oral polio vaccine for 3 weeks anday include close contact with adults receiv-
ng the attenuated varicella vaccine to preventoster Immunosuppressed individuals are ad-ised to avoid contact for 7 days with individu-ls who have received live virus nasal spraysor influenza We concur with the recommenda-ion for flu vaccine but common practice inhe United States is to wait 3-6 months afterransplant before it is administered
DIGORecommendations inChapter 13 Viraliseases
131 BK POLYOMA VIRUS1311 We suggest screening all KTRs for BKV
with quantitative plasma NAT (2C) atleastbull monthly for the first 3-6 months after
transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull whenever there is an unexplained rise
in serum creatinine (2D)bull and after treatment for acute rejection
(2D)1312 We suggest reducing immunosuppressive
medications when BKV plasma NAT is
persistently greater than 10 000 cop-iesmL (107 copiesL) (2D)
132 CYTOMEGALOVIRUS1321 CMV prophylaxis We recommend that
KTRs (except when donor and recipi-ent both have negative CMV serolo-gies) receive chemoprophylaxis forCMV infection with oral ganciclovir orvalganciclovir for at least 3 monthsafter transplantation (1B) and for 6weeks after treatment with a T-cellndashdepleting antibody (1C)
1322 In patients with CMV disease we suggestweekly monitoring of CMV by NAT orpp65 antigenemia (2D)
1323 CMV treatment13231 We recommend that all pa-
tients with serious (includ-ing most patients with tissueinvasive) CMV disease betreated with intravenousganciclovir (1D)
13232 We recommend that CMVdisease in adult KTRs that isnot serious (eg episodes thatare associated with mildclinical symptoms) be treatedwith either intravenous gan-ciclovir or oral valganciclo-vir (1D)
13233 We recommend that allCMV disease in pediatricKTRs be treated with intra-venous ganciclovir (1D)
13234 We suggest continuing therapyuntil CMV is no longer detect-able by plasma NAT or pp65antigenemia (2D)
1324 We suggest reducing immunosuppressivemedication in life-threatening CMV dis-ease and CMV disease that persists in theface of treatment until CMV disease hasresolved (2D)13241 We suggest monitoring graft
function closely during CMVdisease (2D)
133 EPSTEIN-BARR VIRUS AND POST-TRANS-PLANT LYMPHOPROLIFERATIVE DISEASE1331 We suggest monitoring high-risk (donor
EBV seropositiverecipient seronegative)KTRs for EBV by NAT (2C)bull once in the first week after transplanta-
tion (2D)bull then at least monthly for the first 3-6
months after transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull and additionally after treatment for
acute rejection (2D)
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1332 We suggest that EBV-seronegative pa-tients with an increasing EBV load haveimmunosuppressive medication reduced(2D)
1333 We recommend that patients with EBVdisease including PTLD have a reduc-tion or cessation of immunosuppres-sive medication (1C)
134 HERPES SIMPLEX VIRUS 1 2 AND VARI-CELLA ZOSTER VIRUS1341 We recommend that KTRs who de-
velop a superficial HSV 1 2 infectionbe treated (1B) with an appropriateoral antiviral agent (eg acyclovir vala-cyclovir or famciclovir) until all le-sions have resolved (1D)
1342 We recommend that KTRs with sys-temic HSV 1 2 infection be treated(1B) with intravenous acyclovir and areduction in immunosuppressive medi-cation (1D)13421 We recommend that intrave-
nous acyclovir continue un-til the patient has a clinicalresponse (1B) then switch toan appropriate oral antiviralagent (eg acyclovir valacy-clovir or famciclovir) to com-plete a total treatment durationof 14-21 days (2D)
1343 We suggest using a prophylactic antiviralagent for KTRs experiencing frequentrecurrences of HSV 12 infection (2D)
1344 We recommend that primary VZV infec-tion (chicken pox) in KTRs be treated(1C) with either intravenous or oral acy-clovir or valacyclovir and a temporaryreduction in amount of immunosuppres-sive medication (2D)
135 HEPATITIS C VIRUS1351 We suggest that HCV-infected KTRs be
treated only when the benefits of treat-ment clearly outweigh the risk of allo-graft rejection due to interferon-basedtherapy (eg fibrosing cholestatic hepati-tis life-threatening vasculitis) (2D)[Based on KDIGO Hepatitis C Recom-mendation 215]
1352 We suggest monotherapy with standardinterferon for HCV-infected KTRs inwhom the benefits of antiviral treatmentclearly outweigh the risks (2D) [Basedon KDIGO Hepatitis C Recommenda-tions 224 and 442]
1353 We suggest that all conventional currentinduction and maintenance immunosup-pressive regimens can be used in HCVinfected patients (2D) [Based on KDIGO
Hepatitis C Recommendation 43]
1354 Measure ALT in HCV-infected patientsmonthly for the first 6 months and every3-6 months thereafter Perform imagingannually to look for cirrhosis and hepato-cellular carcinoma (Not Graded) [Basedon KDIGO Hepatitis C Recommendation441] (See Recommendation 193)
1355 Test HCV-infected patients at least every3-6 months for proteinuria (Not Graded)[Based on KDIGO Hepatitis C Recom-mendation 444]13551 For patients who develop new
onset proteinuria (either urineproteincreatinine ratio 1 or24-hour urine protein 1 g ontwo or more occasions) per-form an allograft biopsy withimmunofluorescence and elec-tron microscopy (Not Graded)[Based on KDIGO Hepatitis CRecommendation 444]
1356 We suggest that patients with HCV asso-ciated glomerulopathy not receive inter-feron (2D) [Based on KDIGO HepatitisC Recommendation 445]
136 HEPATITIS B VIRUS1361 We suggest that any currently available
induction and maintenance immunosup-pressive medication can be used in HBV-infected KTRs (2D)
1362 We suggest that interferon treatmentshould generally be avoided in HBVinfected KTRs (2C)
1363 We suggest that all HBsAg-positive KTRsreceive prophylaxis with tenofovir ente-cavir or lamivudine (2B)13631 Tenofovir or entecavir are pref-
erable to lamivudine to mini-mize development of potentialdrug resistance unless medica-tion cost requires that lami-vudinebe used (Not Graded)
13632 During therapy with antivi-rals measure HBV DNA andALT levels every 3 months tomonitor efficacy and to detectdrug resistance (Not Graded)
1364 We suggest treatment with adefovir ortenofovir for KTRs with lamivudine resis-tance (5 log10 copiesmL rebound ofHBV-DNA) (2D)
1365 Screen HBsAg-positive patients with cir-rhosis for hepatocellular carcinoma every12 months with liver ultrasound andalpha feto-protein (Not Graded) (SeeRecommendation 193)
1366 We suggest that patients who are negativefor HBsAg and have HBsAb titer 10mIUmL receive booster vaccination to
raise the titer to 100 mIUmL (2D)
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KDOQI Commentary 15
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137 HUMAN IMMUNODEFICIENCY VIRUS1371 If not already done screen for HIV
infection (Not Graded)1372 To determine antiretroviral therapy refer
HIV-infected KTRs to an HIV specialistwho should pay special attention to drugndashdrug interactions and appropriate dosingof medications (Not Graded)
DOQIRationale andCommentary
Viral infections are particularly problematic inransplant recipients because of the preferentialnhibition of T-lymphocyte function by both induc-ion and maintenance immunosuppression Use ofnduction immunosuppression with lymphocyte-epleting agents (thymoglobulin or alemtuzumab)s associated with a greater risk of viral infectionosttransplant In general the greater the cumula-ive exposure to immunosuppression the greaterhe risk of infectious complications The presenta-ion of viral infections can be asymptomatic vaguend nonspecific or life-threatening acute illnessany viral infections seen in KTRs are rarely seen
n immunocompetent patients and therefore do notnter into the differential diagnosis for physiciansnfamiliar with transplant recipients Close commu-ication with the transplant center is crucial inaring for the transplant population Early detectionnd institution of therapy provide the best chanceor viral eradication
BKVirus
Although the work group agreed with KDIGOuggestions for BK virus screening posttransplante did not think it was practical to require screen-
ng exclusively with quantitative plasma nucleiccid testing (NAT) because many US centers usenitial urinary screening and then test plasma onlyf urine screening results are positive Howeverhere is no disagreement that some type of screen-ng for BK virus is critical to avoid BK nephropa-hy for which there is no specific treatment when its established Complicating screening for BK vi-us is the variability in results between laboratoriesnd uncertainty about the level of viremia thathould trigger a response to decrease in immunosup-ression In the presence of viremia and increase inerum creatinine level a renal allograft biopsy isndicated to confirm the presence of BK nephropa-
hy Because BK viremia and viruria certainly can b
e detected beyond the first year it is not clear howong screening should be continued posttransplantlthough most centers screen for the first year onlyngoing clinical trials are exploring effective treat-ent for BK nephropathy3839 Decisions about
ecreases in immunosuppression currently theainstay of BK viremia management always
hould be made in consultation with the transplantenter
Cytomegalovirus
KDIGO recommendation 1321 regarding cyto-egalovirus (CMV) prophylaxis is reasonable and
pplicable to the US population Universal prophy-axis for CMV now is recommended over initiatingre-emptive treatment after CMV develops40 Aajor concern for US patients is the cost of CMV
rophylaxis with oral valgancyclovir Leukopeniaan be observed in patients using mycophenolatereparations when prophylaxis with valgancyclo-ir is used Screening for CMV is best performedsing NAT methods (1322) CMV antigenemiassays are still in use in many facilities but are nots sensitive as PCR assays41 There is no utility inhecking for serologic response to CMV with IgGr IgM titers posttransplant because the immuneesponse is not predictable Patients with CMVisease should be cared for by clinicians familiarith treating this disease It is recommended that
reatment be continued until viral load is undetect-ble followed by prophylactic doses of valgancy-lovir for an additional 3 months35
Epstein-BarrVirus
Current practice regarding EBV screening variesmong centers in the United States and many doot routinely screen for EBV posttransplant evenn recipient-negative donor-positive cases In con-rast to KDIGO recommendation 1311 routineBV screening is not recommended in AST infec-
ious disease guidelines35 In many centers EBVcreening is reserved for children who are muchore commonly EBV negative pretransplant than
dults EBV-induced posttransplant lymphoprolif-rative disorder (PTLD) affects many more pediat-ic than adult KTRs If screening is someday to beoutinely implemented in US centers details regard-ng the best method of screening and levels ofiremia above which a clinical intervention should
e triggered need to be better defined
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HerpesandVaricella
Systemic herpesvirus infections can be lifehreatening in transplant recipients and should bereated aggressively with intravenous antiviralgents as described in the KDIGO recommenda-ions Less aggressive cutaneous infection can bereated with oral antiviral agents as outlined inhe KDIGO guidelines
Varicella exposure is particularly concerning inransplant recipients The work group disputes theecommended dosing of acyclovir for varicellaxposure Acyclovir at a dose of 10 mgkg or about00 mg 4 times daily of oral acyclovir would betandard dosing We agree with the use of varicellammune globulin and emphasize the need to avoidhe varicella vaccine because it is a live virushould a transplant recipient develop a systemicaricella infection hospitalization and high-dosentravenous acyclovir therapy are warranted
Hepatitis C
Hepatitis C management posttransplant is ahallenge The KDIGO guidelines cited hereere based on the recently published KDIGOuideline for hepatitis C in CKD4 Hepatitis Cypically is not treated posttransplant because ofhe risk (50) of rejection precipitated bynterferon therapy particularly in US KTRs inhom hepatitis C commonly is genotype 1 which
s more resistant to treatment with interferon42
owever should hepatitis Cndashrelated glomerulo-ephritis develop the risk-benefit ratio may fa-or treatment in selected patients Such decisionslways should be made in consultation withepatology and infectious disease experts andhe transplant center Monitoring liver enzymeevels specifically alanine aminotransferaseALT) may reflect a change in hepatitis activityut monitoring hepatitis C viral load is not recom-ended because it does not seem to correlateith outcome Annual monitoring for hepatocel-
ular carcinoma using -fetoprotein and imagings encouraged but not often practiced
Hepatitis B
KDIGO recommendations for hepatitis B areeasonable and currently are followed in mostS centers except for recommendation 1366
see previous recommendation under vaccina-ions) KTRs with hepatitis C or hepatitis B also
hould be followed up by a hepatologist
Human ImmunodeficiencyVirus
Human immunodeficiency virus (HIV)-posi-ive individuals are now acceptable for transplantf CD4 count is 200 cellsL and viral loadVL) is undetectable3543 Transplant should beerformed at centers with expertise in managingIV-positive individuals and care should be co-rdinated carefully with HIV specialists Somentiretroviral agents in particular the proteasenhibitors have potentially serious drug interac-ions with immunosuppressive agents35
DIGORecommendations inChapter 14Othernfections
141 URINARY TRACT INFECTION1411 We suggest that all KTRs receive UTI
prophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 monthsafter transplantation (2B)
1412 For allograft pyelonephritis we suggestinitial hospitalization and treatment withintravenous antibiotics (2C)
142 PNEUMOCYSTIS JIROVECII PNEUMONIA1421 We recommend that all KTRs receive
PCP prophylaxis with daily tri-methoprimndashsulfamethoxazole for 3-6months after transplantation (1B)
1422 We suggest that all KTRs receive PCPprophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 weeksduring and after treatment for acute rejec-tion (2C)
1423 We recommend that KTRs with PCPdiagnosed by bronchial alveolar lavageandor lung biopsy be treated withhigh-dose intravenous trimethoprimndashsulfamethoxazole corticosteroids anda reduction in immunosuppressivemedication (1C)
1424 We recommend treatment with cortico-steroids for KTRs with moderate tosevere PCP (as defined by PaO2 lt70mm Hg in room air or an alveolargradient of gt35 mm Hg) (1C)
143 TUBERCULOSIS1431 We suggest that TB prophylaxis and
treatment regimens be the same in KTRsas would be used in the local generalpopulation who require therapy (2D)
1432 We recommend monitoring CNI andmTORi [mTOR inhibitor] blood levels inpatients receiving rifampin (1C)14321 Consider substituting rifabu-
tin for rifampin to minimize
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KDOQI Commentary 17
ARTICLE IN PRESS
interactions with CNIs andmTORi (Not Graded)
144 CANDIDA PROPHYLAXIS1441 We suggest oral and esophageal Candida
prophylaxis with oral clotrimazole loz-enges nystatin or fluconazole for 1-3months after transplantation and for 1month after treatment with an antilympho-cyte antibody (2C)
DOQIRationale andCommentary
UrinaryTract Infection
Urinary tract infections (UTIs) after kidneyransplant are very common and account for aarge percentage of readmissions posttransplantTIs are common because of multiple factors
ncluding the disrupted anatomy of the urinaryract with a ureteroneocystotomy incompleteladder emptying because of diabetes or pros-atic hypertrophy and impaired immune re-ponses Prophylaxis of UTIs usually is under-aken with trimethoprim-sulfamethoxazole for 6onths posttransplant although infections often
ccur despite therapy because of the develop-ent of drug resistance Although native kidney
yelonephritis does not always require hospital-zation it is recommended that all KTRs withhis diagnosis be hospitalized because the graftysfunction that usually accompanies transplantyelonephritis requires aggressive investigationnd treatment Individuals with recurrent UTIsarrant evaluation with urologic assessment Pa-
ients with recurrent UTIs may benefit fromong-term suppressive therapy
Pneumocystic Pneumonia
We agree that Pneumocystis jirovecii pneumoniaPCP) prophylaxis is important for the first 3-6onths posttransplant (1421)After the first month
very-other-day dosing of trimethoprim-sulfame-hoxazole or atovaquone is believed to be adequaterophylaxis In cases in which neither of thesegents can be used an individual may be treatedrophylactically with inhaled pentamidine OurDOQI work group emphasized that patients whoevelop PCP should be transferred to the transplantenter promptly for management and adjustmentsn immunosuppression
Tuberculosis
Monitoring for latent tuberculosis has posed a
hallenge in the immunosuppressed population be-
ause of the unreliable nature of skin testing Newerechniques involving interferon release assays aremerging as the new gold standard for detection ofatent tuberculosis4445
CandidaProphylaxis
Oral candidiasis must be screened for usingral mucosa examination on follow-up visitsn KTRs This is especially true in the earlyosttransplant period when immunosuppres-ive medication dosage is the highest Wegree with these recommendations and empha-ize that if fluconazole is used there is aotential for serious drug interactions becausef cytochrome P-450 3A4 inhibition
SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
Improvement in short-term outcomes has not trans-lated into significant improvements in long-term out-comes in KTRs The lack of significant improvement inlong-term survival may be related to post-transplantcomplications Frequent posttransplant monitoring mayimprove long-term outcomes by decreasing chronic graftfailure or death with a functioning graft Our work groupconcurred with the recommendation and schedules ofroutine screening in monitoring kidney allograft functionafter kidney transplant with a low threshold for perform-ing kidney biopsy in cases of graft dysfunction or protein-uria Expert tissue processing and interpretation of trans-plant biopsy specimens by pathologists with transplantexperience are critical Regular surveillance of the pa-tientrsquos kidney function at the transplant center or in thenephrologistrsquos office offers an opportunity to enhancepatient adherence to medication diet and healthy life-style Although CKD in KTRs progresses more slowlythan CKD in other patients the work group agreed thatthe KDIGO guidelines on CKD should be followed inKTRs
Opportunistic infections are common in KTRs al-though advances in diagnosis and treatment have led toimproved survival in KTRs with infection It is nowstandard of care to use vaccinations in KTRs as long asthe vaccine does not contain live or attenuated virus Italso is routine to screen for or use prophylaxis to preventseveral posttransplant viral infections With few excep-tions (related to EBV and BK virus screening andhepatitis B vaccination posttransplant) we concurredwith KDIGO guidelines for vaccination screening and
treatment of infection posttransplant
KD
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ARTICLE IN PRESS
COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULAR
DISEASE
DIGORecommendations inChapter 15iabetesMellitus
151 Screening for New-Onset Diabetes after Transplan-tation1511 We recommend screening all nondia-
betic KTRs with fasting plasma glu-cose oral glucose tolerance testingandor HbA1c (1C) at leastbull weekly for 4 weeks (2D)bull every 3 months for 1 year (2D)bull and annually thereafter (2D)
1512 We suggest screening for NODAT withfasting glucose oral glucose tolerancetesting andor after starting or substan-tially increasing the dose of CNIsmTORi or corticosteroids (2D)
152 Managing NODAT or Diabetes Present at Trans-plantation1521 If NODAT develops consider modifying
the immunosuppressive drug regimen toreverse or ameliorate diabetes afterweighing the risk of rejection and otherpotential adverse effects (Not Graded)
1522 Consider targeting HbA1c 70-75and avoid targeting HbA1c 60 espe-cially if hypoglycemic reactions are com-mon (Not Graded)
1523 We suggest that in patients with diabetesaspirin (65-100 mgd) use for the primaryprevention of CVD be based on patientpreferences and values balancing the riskfor ischemic events to that of bleeding(2D)
DOQIRationale andCommentary
Diabetic Screening
We agree with screening for new-onset diabetesfter transplantation (NODAT) as outlined by theDIGO work group Definitions used are similar
o those of the American Diabetes AssociationADA) The greater frequency of testing initially isustified by the high risk of NODAT in the earlyosttransplant period however ongoing screenings required because the risk of the development ofODAT continues to increase over time4647 We
lso point out that prediabetic states (impairedasting glucose level and impaired glucose toler-nce) occur even more commonly than overt diabe-es48 and may be associated with metabolic syn-rome as well as with increased cardiovascular
ortality49-51 Potential implications of these predia-
etic states emphasize the importance of perform-ng blood tests under fasting conditions For pa-ients with fasting hyperglycemia an oral glucoseolerance test or hemoglobinA1c (HbA1c) test shoulde performed Although more cumbersome to per-orm data suggest that an oral glucose toleranceest is a more sensitive indicator of NODAT inyperglycemic KTRs52 This may allow earlieretection of overt diabetes and more prompt institu-ion of treatment
DiabetesManagement
Data supporting a substantial benefit in themelioration or reversal of NODAT using immu-osuppression modification in KTRs are veryimited There was consensus in our work grouphat considering the paucity of data for reversingODAT by changing immunosuppression and
he potential risk of an adverse outcome withuch a maneuver KDIGO suggestion 1521 couldot be supported Certainly if such a step waseing considered it should be done in conjunc-ion with the transplant center Targeting an HbA1c
evel of 7-75 and avoiding levels 6 isased on data showing increased cardiovascularvents with the lower HbA1c target5354
DIGORecommendations inChapter 16ypertensionDyslipidemias TobaccoUse andbesity
161 Hypertension1611 We recommend measuring blood pres-
sure at each clinic visit (1C)1612 We suggest maintaining blood pressure at
130 mm Hg systolic and 80 mm Hgdiastolic if 18 years of age and 90th
percentile for sex age and height if 18years old (2C)
1613 To treat hypertension (Not Graded)bull Use any class of antihypertensive
agentbull Monitor closely for adverse effects
and drug-drug interactions and whenurine protein excretion 1 gd for18 years old and 600 mgm224 hfor 18 years old consider an ACE-Ior an ARB as first-line therapy
162 Dyslipidemias (These recommendations are basedon KDOQI Dyslipidemia Guidelines and are thusnot graded)1621 Measure a complete lipid profile in all
adult (18 years old) and adolescent
(puberty to 18 years old) KTRs [Based on
K
2saaottgswdCctarahtAGccKie
KDOQI Commentary 19
ARTICLE IN PRESS
KDOQI Dyslipidemia Recommendation1]bull 2-3 months after transplantationbull 2-3 months after a change in treatment
or other conditions known to causedyslipidemias
bull at least annually thereafter1622 Evaluate KTRs with dyslipidemias for
secondary causes [Based on KDOQI Dys-lipidemia Recommendation 3]16221 For KTRs with fasting triglyc-
erides 500 mgdL (565mmolL) that cannot be cor-rected by removing an under-lying cause treat withbull Adults therapeutic lifestyle
changes and a triglyceride-lowering agent [Based onKDOQI Recommendation41]
bull Adolescents therapeutic life-style changes [Based onKDOQI Recommendation51]
16222 For KTRs with elevatedLDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)treat to reduce LDL-C to100 mgdL (259mmolL) [Based on KDOQIGuideline 42]
bull Adolescents If LDL-C130 mgdL (336 mmolL) treat to reduce LDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 52]
16223 For KTRs with normalLDL-C elevated triglyceridesand elevated non-HDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)fasting triglycerides 200mgdL (226 mmolL)and non-HDL-C 130mgdL (336 mmolL)treat to reduce non-HDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 43]
bull Adolescents If LDL-C130 mgdL (336 mmolL) fasting triglycerides200 mgdL (226 mmolL) and non-HDL-C 160mgdL (414 mmolL)treat to reduce non-HDL-C
to 160 mgdL (414 i
mmolL) [Based on KDOQIGuideline 53]
163 Tobacco Use1631 Screen and counsel all KTRs including
adolescents and children for tobacco useand record the results in the medicalrecord (Not Graded)bull Screen during initial transplant hospi-
talizationbull Screen at least annually thereafter
1632 Offer treatment to all patients who usetobacco (Not Graded)
164 Obesity1641 Assess obesity at each visit (Not Graded)
bull Measure height and weight at eachvisit in adults and children
bull Calculate BMI at each visitbull Measure waist circumference when
weight and physical appearance sug-gest obesity but BMI is 35 kgm2
1642 Offer a weight-reduction program to allobese KTRs (Not Graded)
DOQIRationale andCommentary
Hypertension
The KDIGO work group adapted the KDOQI004 recommendations for target blood pres-ure in KTRs55 Self measurement is useful inssessing response to therapy and enhancesdherence56 In general we agree that the classf antihypertensive agent does not matter inhe treatment of blood pressure elevation inhis population and that attention should beiven to potential side effects of antihyperten-ive agents as well as possible interactionsith the immunosuppressive regimen (eg non-ihydropyridine calcium channel blockers andNIs) In the absence of adequate randomizedontrolled trials it is not known whether angio-ensin-converting enzyme (ACE) inhibitors andngiotensin receptor blockers (ARBs) prolongecipient or allograft survival Some but notll retrospective studies suggest a benefitowever all these studies are limited by selec-ion bias5758 Although ACE inhibitors andRBs commonly lead to some decrease inFR treatment with these drugs should be
ontinued unless serum creatinine level in-reases by 25 to 30 in keeping withDOQI recommendations55 In KTRs receiv-
ng ACE inhibitors or ARBs it is important toducate patients to maintain adequate fluid
ntake during illness to prevent a prerenal
inwa
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Bia et al20
ARTICLE IN PRESS
nsult to the allograft Similarly awareness isecessary when using diuretics in conjunctionith therapies that block the renin-angiotensin-
ldosterone-system59
Dyslipidemia
The KDIGO work group based their recom-endations for evaluation and treatment of
yperlipidemia on the KDOQI dyslipidemiauidelines for KTRs60 We agree with theseecommendations CNIs potentiate the toxicityf statins by slowing their metabolism throughhe cytochrome P-450 system This interactionccurs more commonly with cyclosporine61
han with tacrolimus Dyslipidemia especiallyypertriglyceridemia frequently complicatesTOR-inhibitor use and lipid-lowering therapy
s required in most patients using these agents
TobaccoUse
Not surprisingly tobacco use at the time ofransplant is associated with decreased patientnd graft survival as well as increased risk ofosttransplant cardiovascular disease (CVD)lthough the KDIGO work group recom-ends initial screening and intervention dur-
ng the hospitalization for transplant we be-ieve there may be benefit gained by startingounseling in the pretransplant period duringhe evaluation phase Unfortunately this doesot occur often because of time and personnelonstraints in transplant centers Ideally allransplant centers should have smoking-cessa-ion programs available to patients either in-ouse or through referral Ideally systemshould be created to continue to screen andonitor for smoking cessation at yearly inter-
als after transplant because there is a highate of relapse with this addiction As outlinedn KDIGO Table 253 although all pharmaco-ogic therapies for smoking cessation can besed in KTRs the starting dose of vareniclinehould be decreased in patients with GFR 30Lmin
Obesity
Obesity is an epidemic in the United Statesnd the proportion of obese kidney transplantandidates continues to grow In additioneight gain after transplant is very commonly
bserved Obesity in KTRs is associated with w
ncreased risks of wound complications de-ayed graft function acute rejection and NO-AT resulting in inferior patient and graftutcomes Attention to this potential complica-ion and counseling should be initiated duringhe pretransplant evaluation phase Informa-ion regarding pharmacologic therapies foreight loss in KTRs is not available and we
gree with the KDIGO work group that thera-eutic lifestyle measures should be encour-ged Data regarding steroid therapy with-rawal and weight gain are controversial Aecent double-blind randomized controlled trialxamining early steroid therapy withdrawalid not show a difference in weight gain at 5ears posttransplant compared with the cohortemaining on standard maintenance corticoste-oid therapy62
DIGORecommendations inChapter 17ardiovascularManagement
171 Consider managing CVD at least as intensively inKTRs as in the general population with appropri-ate diagnostic tests and treatments (Not Graded)
172 We suggest using aspirin (65-100 mgd) in allpatients with atherosclerotic CVD unless there arecontraindications (2B)
DOQIRationale andCommentary
Although outcomes are favorable comparedith remaining on the waiting list the risk of
ardiovascular mortality in KTRs is several-foldigher than observed in the general population63
specially in younger age groups and patientsith decreasing allograft function64 CVD is aajor cause of graft loss after the first post-
ransplant year In this context we strongly agreehat CVD should be managed in KTRs at least asntensively as in the general population Ideallyecreasing CVD risk in KTRs requires a multifac-ted and multidisciplinary approach Based onurrent practice models in the United States theransplant and nephrology community has notet been able to achieve these desirable goals65
his clearly deserves more attention becauseontrol of CVD has the potential to contributeore to long-term kidney graft survival than the
iscovery of newer drugs that decrease the ratef allograft rejection Our KDOQI working groupgreed with the use of low-dose aspirin in KTRs
ith evidence of atherosclerosis
Ko
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KDOQI Commentary 21
ARTICLE IN PRESS
SUMMARY OF COMMENTARY ONSECTION III CVD
COMMENTARY ON SECTION IV OF KDIGO
TRANSPLANT GUIDELINE MALIGNANCY
DIGORecommendations inChapter 18 Cancerf the Skin andLip
181 We recommend that KTRs especially thosewho have fair skin live in high sun-exposureclimates have occupations requiring sun expo-sure have had significant sun exposure as achild or have a history of skin cancer be toldthat their risk of skin and lip cancer is veryhigh (1C)
182 We recommend that KTRs minimize life-longsun exposure and use appropriate ultravioletlight blocking agents (1D)
183 We suggest that adult KTRs perform skin andlip self-examinations and report new lesions toa health-care provider (2D)
184 For adult KTRs we suggest that a qualified healthprofessional with experience in diagnosing skincancer perform annual skin and lip examinationon KTRs except possibly for KTRs with dark skinpigmentation (2D)
185 We suggest that patients with a history of skin orlip cancer or premalignant lesions be referred to andfollowed by a qualified health professional withexperience in diagnosing and treating skin cancer
With the decrease in acute rejection during the pastdecade in association with improved immunosuppres-sion regimens patient death now rivals chronic graftdysfunction as one of the leading causes of long-termgraft loss Because CVD is the most common cause ofpatient death in KTRs a concerted effort at minimizingrisk factors for heart disease likely will have as great oreven greater impact on optimizing patient and graftoutcomes than the discovery of new antirejection thera-pies CVD risk reduction strategies should include regularscreening for new-onset diabetes (using ADA-based defini-tions) in the posttransplant period in previously nondiabeticpatients good glycemic regulation for diabetic patients accord-ing to current ADA guidelines and lipid management andblood pressure control according to KDOQI recommenda-tions In addition promotion of a healthy lifestyle throughweight control exercise and smoking cessation should be acentral part of posttransplant counseling and care Whenimmunosuppression modification is being considered to miti-gate cardiovascular risk we recommend that this be inconjunction with the transplant center In summary we gener-ally concurred with the suggestions of the work group in thissection but based on current practice standards in the UnitedStateschallengesremainwith implementationof thisguideline
(2D) s
186 We suggest that patients with a history of skincancer be offered treatment with oral acitretin ifthere are no contraindications (2B)
DOQIRationale andCommentary
CounselingandSunscreen
We concur with recommendations 181 and82 because skin cancer is a major source oforbidity and sometimes mortality in KTRsarning patients at risk of the high danger of
kin cancer a 1C recommendation is reinforcedy a recent prospective case-control study ofrgan transplant recipients that showed that regu-ar use of broad-spectrum sunscreens that pro-ide UVA and UVB protection may prevent theevelopment of actinic keratosis invasive squa-ous cell carcinoma and to a lesser extent
asal cell carcinoma66 Most cancer-causing ra-iation is thought to come from the UVB spec-rum and newer broad-spectrum sunscreens pro-ide protection against UVA and UVB radiationounseling about sunscreen and the need for sunvoidance needs to be incorporated into routineffice visits although it may not always beuccessful In a recent study of KTRs in which1 of patients had been informed about theeed for sun protection only 46 used morehan a tube of sunscreen per year67
Dermatology Involvement
There is increased evidence to suggest thatpecialty dermatology clinics for organ trans-lant recipients improve outcome measures in-luding compliance with photoprotection andncreased awareness of skin cancer68 The re-ources required for these specialty clinics makemplementation difficult for community nephrol-gy groups that do not have direct access to aransplant center Transplant patients should bencouraged to have annual visits with their trans-lant center and if dermatology specialty clinicsre available attempt to coordinate a skin cancervaluation annually
UseofRetinoid-likeCompounds
There is a limited scientific basis for KDIGOuggestion recommendation 186 Although reti-oids now are used routinely in KTRs with aigh skin cancer burden our KDOQI work groupelieves that more data are needed before this
uggestion should be accepted as a guideline In
ldfivs
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ARTICLE IN PRESS
ow-immunologic-risk groups and particularlyifficult cases some data suggest that switchingrom CNI to sirolimus therapy may decrease thencidence of skin cancer69 however the riskersus benefit of this maneuver has not been welltudied
DIGORecommendations inChapter 19on-SkinMalignancies
191 Develop an individualized screening plan for eachKTR that takes into account the patientrsquos pastmedical and family history tobacco use compet-ing risks for death and the performance of thescreening methodology (Not Graded)
192 Screen for the following cancers as per localguidelines for the general population (Not Graded)Women cervical breast and colon cancer Menprostate and colon cancer
193 Obtain hepatic ultrasound and alpha feto-proteinevery 12 months in patients with compensatedcirrhosis (Not Graded) [See Recommendations1354 (HCV) and 1365 (HBV)]
DOQIRationale andCommentary
Screening
It is recognized that KTRs have a higher inci-ence of malignancy particularly those associatedith specific viral infections Although cancer
creening may have benefits in this higher riskopulation it should be reinforced that some meth-ds of screening have significant risks which shoulde considered on an individualized basis particu-arly in patients who have projected survival lesshan 5 years
Screening forCancer inPatientsWithHepatitis
Many patients who have underlying cirrhosisn the United States will be followed up by arofessional specializing in liver disease whoay provide additional insight into this cancer
creening recommendation Based on a recentuestionnaire of US gastroenterologists only 50creen patients for hepatocellular carcinoma70
herefore implementation of this guideline byS clinicians is unlikely to be widespread
DIGORecommendations inChapter 20anagingCancerwithReductionof
mmunosuppressiveMedication
201 We suggest consideration be given to reducingimmunosuppressive medications for KTRs with can-
cer (2C)
2011 Important factors for consideration in-clude (Not Graded)bull The stage of cancer at diagnosisbull Whether the cancer is likely to be
exacerbated by immunosuppressionbull The therapies available for the can-
cerbull Whether immunosuppressive medica-
tions interfere with ability to admin-ister the standard chemotherapy
202 For patients with Kaposi sarcoma we suggestusing mTORi along with a reduction in overallimmunosuppression (2C)
DOQIRationale andCommentary
Table 1 (Table 29 in the KDIGO report3 andxcerpted from Grulich et al71) lists cancershat are increased most in immunosuppressedTRs based on standardized incidence ratios
SIRs) which compare the incidence toatched populations Cancers with the highestIRs may be those most likely to respond to aecrease in immunosuppression Except foraposi sarcoma limited evidence is available
or a decrease in immunosuppression in theseettings A strategy to change immunosuppres-ion therapy must occur in consultation withhe transplant center Switching to sirolimusherapy and decreasing immunosuppression inatients who develop Kaposi sarcoma is basedn sound scientific rationale7273
SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
The incidence of cancer posttransplant is 2-20times higher than that in the general population andKDIGO guidelines have been written to outline stepsfor prevention and screening With few exceptions weagree with the recommendations as outlined Skincancer is common in US transplant patients andscreening and prevention are critical However imple-mentation of guidelines for doing so including theKDIGO guidelines is a challenge because of patientpreferences against the routine use of sunscreen aswell as time constraints during office visits Althoughmany posttransplant cancers are viral mediated andrelated to immunosuppression it is less clear how toalter immunosuppression after malignancy has oc-curred We agree that although age-specific screeningfor malignancy should be incorporated into care con-sideration must be given to the risk of screening inpatients with limited life spans (5 years) because of
comorbid conditions
KT
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
ommonPopu
i sarco-Hodgmelanise sm
sophaemia
estima standa10 c
ut esti
0 case
alized t
to guide treatment specifically before the
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
K
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CUcneucetcitdt
ttlhA(o
KH
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Ka
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
REFERENCES1 McCullough KP Keith DS Meyer KH et al Kidney
nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
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ml
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c2
p2
sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
ation Transpl Rev 200923191-19815 Abbud-Filho M Adams PL Alberuacute J et al A report
f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
cA
nrc
t2
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trN
hUt
Iwa
rl5
mi8
oe1
DA
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hm2
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Bia et al30
ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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KDOQI Commentary 9
ARTICLE IN PRESS
urvey of posttransplant outpatient visits inedicare beneficiaries in the United States
requency of visits to transplant centers variedy center and region most visits were toephrologists16
At each clinic visit education regardingedication adherence diet and healthy life-
tyle should be given Screening for tobaccose should be implemented before dischargend annually Although the work group did notgree that screening all adults for Epstein-Barrirus (EBV) was of value (see commentarynder Chapter 13 for EBV) screening for allther elements listed in Fig 2 including screen-ng for proteinuria is reasonable In additiono these tests monitoring for HLA antibodiesgainst the donor (donor-specific antibodies)hich is not described in the KDIGO guide-
ine is becoming more common in some USenters The optimal timing and frequency ofuch screening has yet to be determined1718
SerumCreatinineandEstimatedGFR
Serum creatinine measurement remains theost commonly used index of renal allograft
unction It is reliable for detecting acute changesn kidney function Furthermore serum creati-ine level at year 1 after transplant is a riskactor for subsequent outcomes19 and mayelp in the management of the frequency ofisits However it is less reliable for detecting
Figure 2 Routine screen-ng after kidney transplantomplete blood cell count in-ludes white blood cells hemo-lobin and platelets Screenor diabetes is by fasting bloodlucose level glucose toler-nce test or hemoglobin A1c
evel Lipid profile includes fast-ng cholesterol low-density li-oprotein cholesterol high-ensity lipoprotein cholesterolnd triglyceride levels Screensor BK polyoma virus (BKV)nd Epstein-Barr virus (EBV)se plasma nucleic acid test-
ng (NAT) EBV screen is foratients with no antibody toBV at transplant Adapted
rom the KDIGO transplantuideline3 with permission ofDIGO
ong-term changes in kidney function in the
idney transplant recipient Formulas to esti-ate GFR using serum creatinine values have
een tested in KTRs but no formula consis-ently has been shown to be superior to an-ther As with CKD considerable renal patho-ogic states can be present without dramatichanges in serum creatinine levels
In 2005 the definition of CKD was amendedo include all KTRs regardless of markers ofidney damage or GFR2021 Although the workroup agreed that CKD staging in KTRs isseful it must be noted that there is consider-ble difference in the rate of progression inhese 2 groups Progression is much slower inTRs in whom kidney half-life is longer at
very level of CKD Renal ultrasound is thereferred imaging study in KTRs (KDIGOuggestion 84)22
DIGORecommendations inChapter 9 Kidneyllograft Biopsy
91 We recommend kidney allograft biopsy whenthere is a persistent unexplained increase inserum creatinine (1C)
92 We suggest kidney allograft biopsy when serumcreatinine has not returned to baseline after treat-ment of acute rejection (2D)
93 We suggest kidney allograft biopsy every 7-10 daysduring delayed function (2C)
94 We suggest kidney allograft biopsy if expectedkidney function is not achieved within the first 1-2months after transplantation (2D)
95 We suggest kidney allograft biopsy when there is
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bull New onset of proteinuria (2C)bull Unexplained proteinuria 30 g per gram creati-
nine or 30 g per 24 hours (2C)
DOQIRationale andCommentary
Biopsy
Renal allograft biopsy is the gold standard foriagnosing the cause of a change in renal allo-raft function It is useful in all clinical situationsescribed in KDIGO suggestions 91-94 Poten-ial causes of allograft dysfunction include vol-me depletion compromised renal blood flowrinary outflow obstruction parenchymal causesuch as acute rejection (cellular andor humoral)hronic allograft nephropathy recurrent or deovo disease or BK nephropathy Patients show-ng a 20-25 increase in creatinine level aboveaseline values warrant consideration for biopsyther indications for pursuing renal allograftiopsy would be a less-than-expected responseo treatment of acute rejection The expectedesponse would be dependent on the severity ofissue injury noted on the diagnostic biopsy speci-
en Delayed graft function lasting longer than-7 days warrants biopsy with repeated biopsieserformed every 7-10 days until graft functionecovers New-onset proteinuria protein 20g creatinine or 20 g24 h also merits aidney biopsy De novo and recurrent glomerulariseases are common causes of new-onset pro-einuria Patients with de novo or recurrent glo-erular diseases should be followed up closely
y transplant nephrologists or community neph-ologists with close communication with theransplant center because treatment of some recur-ent kidney diseases may prevent or delay thenset of graft failure2324
SafetyandAccuracy
The safety of kidney transplant biopsies haseen documented and the overall risk of compli-ations is low Most biopsies are performed inhe transplant center by transplant nephrologistsommunity nephrologists also may perform bi-psies of the kidney in KTRs more than a yearosttransplant It is prudent to obtain a diagnosticltrasound before biopsy to rule out unexpectedlterations in blood flow or urinary tract obstruc-ion It is imperative that a pathologist familiar
ith the transplant process interprets the pathol-
gy in consultation with the referring nephrolo-ist using appropriate stains and other studies
MolecularMarkers
In addition to conventional histopathologicxamination several US transplant centers aresing molecular markers as well as genomic orroteomic methods to enhance our understand-ng of the mechanism of immunologic and non-mmunologic pathway of injury As an exampleolymerase chain reaction (PCR) has been usedo detect messenger RNA for IL-2 and otheriomarkers in biopsy samples Using this ap-roach IL-2 upregulated during rejection coulde detected 2 days before rejection was apparentsing histologic or clinical criteria Such PCRpproaches have been used to detect other generoducts upregulated during acute rejection suchs granzyme B perforin transforming growthactor IL-10 and IL-1525-27 These newerethods are performed almost exclusively in
ransplant centers and may become a standardethod of transplant biopsy analysis in the fu-
ure
DIGORecommendations inChapter 10ecurrentDisease
101 We suggest screening KTRs with primary kidneydisease caused by FSGS for proteinuria (2C) atleastbull Daily for 1 week (2D)bull Weekly for 4 weeks (2D)bull Every 3 months for the first year (2D) Every
year thereafter (2D)
102 We suggest screening KTRs with potentially treat-able recurrence of primary kidney disease fromIgA nephropathy MPGN anti-GBM disease orANCA-associated vasculitis for microhematuria(2C) at leastbull Once in the first month to determine a baseline
(2D)bull Every 3 months during the first year (2D)
Annually thereafter (2D)
103 During episodes of graft dysfunction in patientswith primary HUS we suggest screening forthrombotic microangiopathy (eg with plateletcount peripheral smear for blood cell morphologyplasma haptoglobin and serum lactate dehydroge-nase) (2D)
104 When screening suggests possible treatable recur-rent disease we suggest obtaining an allograftbiopsy (2C)
105 Treatment of recurrent kidney disease1051 We suggest plasma exchange if a biopsy
shows minimal change disease or FSGS
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KDOQI Commentary 11
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in those with primary FSGS as theirprimary kidney disease (2D)
1052 We suggest high-dose corticosteroids andcyclophosphamide in patients with recur-rent ANCA-associated vasculitis or anti-GBM disease (2D)
1053 We suggest using an ACE-I [ACE inhibi-tor] or an ARB for patients with recurrentglomerulonephritis and proteinuria (2C)
1054 For KTRs with primary hyperoxaluriawe suggest appropriate measures to pre-vent oxalate deposition until plasma andurine oxalate levels are normal (2C)includingbull Pyridoxine (2C)bull High calcium and low oxalate diet
(2C)bull Increased oral fluid intake to enhance
urinary dilution of oxalate (2C)bull Potassium or sodium citrate to alkalin-
ize the urine (2C)bull Orthophosphate (2C)bull Magnesium oxide (2C)bull Intensive hemodialysis to remove ox-
alate (2C)
DOQIRationale andCommentary
Recurrent disease accounts for a substantialmount of graft loss after renal transplant It isifficult to assess the percentage of grafts lost toecurrent disease because many patients presentith end-stage renal disease without benefit of aiagnostic native renal biopsy The likelihood ofecurrent disease after transplant is dependent onhe disease with certain diseases at particularlyigh risk of recurrence28
Recurrent Focal SegmentalGlomerulosclerosis
We agree with recommendation 101 regard-ng frequent and regular screening for protein-ria in patients with primary focal segmentallomerulosclerosis (FSGS) as the cause of end-tage renal disease If the patient is still produc-ng urine at the time of transplant a preoperativerine protein-creatinine ratio can be a very help-ul baseline measure of proteinuria Early detec-ion of FSGS recurrence which can present withormal light microscopy but foot-process efface-ent on electron microscopy29 provides the best
pportunity for intervention and amelioration ofisease
IgANephropathy
Recurrence rates of immunoglobulin A (IgA)
ephropathy are variable We agree with recom- b
endation 102 for screening routinely for micro-ematuria Recurrent disease is confirmed with aenal allograft biopsy Histologic recurrence ofisease is much more common than is clinicalisease recurrence There is no proven therapyor treatment of recurrent disease30
MembranoproliferativeGlomerulonephritis
Recurrence of membranoproliferative glomer-lonephritis (MPGN) is common as high as 80ith MPGN type II (dense-deposit disease) Theost common cause of MPGN type I is hepatitisndashassociated immune complex formation Wegree with the proposed regularly scheduledcreening for microhematuria and proteinuria inecommendation 102 Patients with known hepa-itis Cndashassociated MPGN pretransplant also maye screened for cryoglobulins which are associ-ted with MPGN31
HemolyticUremic Syndrome
Hemolytic uremic syndrome (HUS) typicallys divided into diarrheal associated (D) andonndashdiarrheal associated (D) D disease oc-urs mostly in children and rarely recurs post-ransplant However D HUS is more commonn adults and can recur In HUS associated with aomplement abnormality such as factor H defi-iency or factor I mutation recurrence rates cane as high as 80 Screening for evidence ofecurrence allows for an earlier diagnosis whichill require biopsy in most cases and provides
n opportunity for earlier intervention There iso comment in the guideline regarding recur-ence of thrombotic thrombocytopenic purpuraut early detection of recurrence provides anpportunity for treatment with plasmapheresisnd intravenous immune globulin (IVIG)
BiopsyandTreatment
As stated kidney biopsy and interpretation bypathologist with expertise in transplant speci-en readings is critical in the diagnosis of dis-
ase recurrence Treatment for most recurrentisease in renal transplantation is based on aombination of case reports case cohorts andetrospective reviews Recurrent diseases post-ransplant are not common enough that random-zed controlled trials can be implemented there-ore most recommendations for treatment are
ased on a consensus of opinion Despite this we
at
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gree in general with the recommendations de-ailed in 105
DIGORecommendations inChapter 11reventingDetecting andTreatingonadherence
111 Consider providing all KTRs and family memberswith education prevention and treatment mea-sures to minimize nonadherence to immunosup-pressive medications (Not Graded)
112 Consider providing KTRs at increased risk fornonadherence with increased levels of screeningfor nonadherence (Not Graded)
DOQIRationale andCommentary
Noncompliance or nonadherence to diet andedication is a common problem in KTRs Nonad-
erence to medication is associated with a high riskf acute rejection and allograft loss We agree thatarly efforts should be made to identify KTRs atncreased risk of nonadherence and that these pa-ients should be monitored closely Prevention iden-ification and treatment of nonadherence are inte-ral to the monitoring of kidney allograft functionnd long-term care of KTRs Certain subgroup ofTRs younger patients African Americans and
hose with financial hardships have an enhancedisk of nonadherence3233
In addition to identifying patients at risk it ismportant to have a system for addressing patientonadherence This requires coordinated efforts ofocial workers transplant coordinators financialounselors pharmacists primary nephrologists andhe patientrsquos family34 A combination of educa-ional behavioral and social support interventionsrovides the best results Because there is no per-ect measure of adherence consideration should beiven to multiple approaches for adherence moni-oring Similar team approaches also are importantn other areas requiring adherence such as dietxercise tobacco alcohol and drug use
DIGORecommendations inChapter 12accination
121 We recommend giving all KTRs approvedinactivated vaccines according to recommendedschedules for the general population except forHBV vaccination (1D)1211 We suggest HBV vaccination (ideally
prior to transplantation) and HBsAb titers6-12 weeks after completing the vaccina-
tion series (2D) h
12111 We suggest annual HBsAb[antibody to hepatitis B sur-face antigen] titers (2D)
12112 We suggest revaccination ifthe antibody titer falls below10 mIUmL (2D)
122 We suggest avoiding live vaccines in KTRs (2C)123 We suggest avoiding vaccinations except influ-
enza vaccination in the first 6 months followingkidney transplantation (2C)1231 We suggest resuming immunizations once
patients are receiving minimal mainte-nance doses of immunosuppressive medi-cations (2C)
1232 We recommend giving all KTRs whoare at least 1-month post-transplantinfluenza vaccination prior to the onsetof the annual influenza season regard-less of status of immunosuppression(1C)
124 We suggest giving the following vaccines to KTRswho due to age direct exposure residence ortravel to endemic areas or other epidemiologicalrisk factors are at increased risk for the specificdiseasesbull rabies (2D)bull tick-borne meningoencephalitis (2D)bull Japanese B encephalitismdashinactivated (2D)bull Meningococcus (2D)bull Pneumococcus (2D)bull Salmonella typhimdashinactivated (2D)1241 Consult an infectious disease specialist a
travel clinic or public health official forguidance on whether specific cases war-rant these vaccinations (Not Graded)
DOQIRationale andCommentary
KTRs are at particular risk of viral infectionsecause of the preferential suppression of T lympho-ytes by both induction and maintenance immuno-uppression The risk and consequence of develop-ng a viral infection warrant use of selected vaccineshe suggestions regarding which vaccines are safend which are contraindicated are based on whetherhe vaccine contains live or killed virus Live virusaccines are contraindicated in immunosuppressedTRs The KDIGO recommendations for vaccina-
ions agree with updated guidelines recently pub-ished by the AST35 Specific comments on theDIGO suggestions regarding vaccinations are
isted in the following sections
Hepatitis B
The work group did not concur with KDIGOuggestion 1211 Neither revaccination against
epatitis after transplant nor following up hepa-
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KDOQI Commentary 13
ARTICLE IN PRESS
itis B antibody titers annually is a commonractice in the United States Hepatitis B is nots prevalent in the United States as in otherarts of the world and evidence supportingcreening in all patients posttransplant is lack-ng However screening for seroconversion inatients at risk (receiving a hepatitis B corentibodyndashpositive kidney) is appropriate Theseatients may benefit from lamivudine or ente-avir therapy36
LiveVaccineandTimingofVaccine
There is no particular reason for a 6-monthag between transplant and vaccination Theheory is that vaccines are less likely to beffective in the period when immunosuppres-ion is high In the United States most individu-ls are on their baseline maintenance immuno-uppression therapy by 3 months posttransplantecisions regarding the timing of vaccines areade based on immunosuppression exposure
nd risk of infection Recipients also shouldvoid intimate contact with individuals whoave received live vaccines37 This includesvoiding close contact with children who haveeceived oral polio vaccine for 3 weeks anday include close contact with adults receiv-
ng the attenuated varicella vaccine to preventoster Immunosuppressed individuals are ad-ised to avoid contact for 7 days with individu-ls who have received live virus nasal spraysor influenza We concur with the recommenda-ion for flu vaccine but common practice inhe United States is to wait 3-6 months afterransplant before it is administered
DIGORecommendations inChapter 13 Viraliseases
131 BK POLYOMA VIRUS1311 We suggest screening all KTRs for BKV
with quantitative plasma NAT (2C) atleastbull monthly for the first 3-6 months after
transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull whenever there is an unexplained rise
in serum creatinine (2D)bull and after treatment for acute rejection
(2D)1312 We suggest reducing immunosuppressive
medications when BKV plasma NAT is
persistently greater than 10 000 cop-iesmL (107 copiesL) (2D)
132 CYTOMEGALOVIRUS1321 CMV prophylaxis We recommend that
KTRs (except when donor and recipi-ent both have negative CMV serolo-gies) receive chemoprophylaxis forCMV infection with oral ganciclovir orvalganciclovir for at least 3 monthsafter transplantation (1B) and for 6weeks after treatment with a T-cellndashdepleting antibody (1C)
1322 In patients with CMV disease we suggestweekly monitoring of CMV by NAT orpp65 antigenemia (2D)
1323 CMV treatment13231 We recommend that all pa-
tients with serious (includ-ing most patients with tissueinvasive) CMV disease betreated with intravenousganciclovir (1D)
13232 We recommend that CMVdisease in adult KTRs that isnot serious (eg episodes thatare associated with mildclinical symptoms) be treatedwith either intravenous gan-ciclovir or oral valganciclo-vir (1D)
13233 We recommend that allCMV disease in pediatricKTRs be treated with intra-venous ganciclovir (1D)
13234 We suggest continuing therapyuntil CMV is no longer detect-able by plasma NAT or pp65antigenemia (2D)
1324 We suggest reducing immunosuppressivemedication in life-threatening CMV dis-ease and CMV disease that persists in theface of treatment until CMV disease hasresolved (2D)13241 We suggest monitoring graft
function closely during CMVdisease (2D)
133 EPSTEIN-BARR VIRUS AND POST-TRANS-PLANT LYMPHOPROLIFERATIVE DISEASE1331 We suggest monitoring high-risk (donor
EBV seropositiverecipient seronegative)KTRs for EBV by NAT (2C)bull once in the first week after transplanta-
tion (2D)bull then at least monthly for the first 3-6
months after transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull and additionally after treatment for
acute rejection (2D)
Bia et al14
ARTICLE IN PRESS
1332 We suggest that EBV-seronegative pa-tients with an increasing EBV load haveimmunosuppressive medication reduced(2D)
1333 We recommend that patients with EBVdisease including PTLD have a reduc-tion or cessation of immunosuppres-sive medication (1C)
134 HERPES SIMPLEX VIRUS 1 2 AND VARI-CELLA ZOSTER VIRUS1341 We recommend that KTRs who de-
velop a superficial HSV 1 2 infectionbe treated (1B) with an appropriateoral antiviral agent (eg acyclovir vala-cyclovir or famciclovir) until all le-sions have resolved (1D)
1342 We recommend that KTRs with sys-temic HSV 1 2 infection be treated(1B) with intravenous acyclovir and areduction in immunosuppressive medi-cation (1D)13421 We recommend that intrave-
nous acyclovir continue un-til the patient has a clinicalresponse (1B) then switch toan appropriate oral antiviralagent (eg acyclovir valacy-clovir or famciclovir) to com-plete a total treatment durationof 14-21 days (2D)
1343 We suggest using a prophylactic antiviralagent for KTRs experiencing frequentrecurrences of HSV 12 infection (2D)
1344 We recommend that primary VZV infec-tion (chicken pox) in KTRs be treated(1C) with either intravenous or oral acy-clovir or valacyclovir and a temporaryreduction in amount of immunosuppres-sive medication (2D)
135 HEPATITIS C VIRUS1351 We suggest that HCV-infected KTRs be
treated only when the benefits of treat-ment clearly outweigh the risk of allo-graft rejection due to interferon-basedtherapy (eg fibrosing cholestatic hepati-tis life-threatening vasculitis) (2D)[Based on KDIGO Hepatitis C Recom-mendation 215]
1352 We suggest monotherapy with standardinterferon for HCV-infected KTRs inwhom the benefits of antiviral treatmentclearly outweigh the risks (2D) [Basedon KDIGO Hepatitis C Recommenda-tions 224 and 442]
1353 We suggest that all conventional currentinduction and maintenance immunosup-pressive regimens can be used in HCVinfected patients (2D) [Based on KDIGO
Hepatitis C Recommendation 43]
1354 Measure ALT in HCV-infected patientsmonthly for the first 6 months and every3-6 months thereafter Perform imagingannually to look for cirrhosis and hepato-cellular carcinoma (Not Graded) [Basedon KDIGO Hepatitis C Recommendation441] (See Recommendation 193)
1355 Test HCV-infected patients at least every3-6 months for proteinuria (Not Graded)[Based on KDIGO Hepatitis C Recom-mendation 444]13551 For patients who develop new
onset proteinuria (either urineproteincreatinine ratio 1 or24-hour urine protein 1 g ontwo or more occasions) per-form an allograft biopsy withimmunofluorescence and elec-tron microscopy (Not Graded)[Based on KDIGO Hepatitis CRecommendation 444]
1356 We suggest that patients with HCV asso-ciated glomerulopathy not receive inter-feron (2D) [Based on KDIGO HepatitisC Recommendation 445]
136 HEPATITIS B VIRUS1361 We suggest that any currently available
induction and maintenance immunosup-pressive medication can be used in HBV-infected KTRs (2D)
1362 We suggest that interferon treatmentshould generally be avoided in HBVinfected KTRs (2C)
1363 We suggest that all HBsAg-positive KTRsreceive prophylaxis with tenofovir ente-cavir or lamivudine (2B)13631 Tenofovir or entecavir are pref-
erable to lamivudine to mini-mize development of potentialdrug resistance unless medica-tion cost requires that lami-vudinebe used (Not Graded)
13632 During therapy with antivi-rals measure HBV DNA andALT levels every 3 months tomonitor efficacy and to detectdrug resistance (Not Graded)
1364 We suggest treatment with adefovir ortenofovir for KTRs with lamivudine resis-tance (5 log10 copiesmL rebound ofHBV-DNA) (2D)
1365 Screen HBsAg-positive patients with cir-rhosis for hepatocellular carcinoma every12 months with liver ultrasound andalpha feto-protein (Not Graded) (SeeRecommendation 193)
1366 We suggest that patients who are negativefor HBsAg and have HBsAb titer 10mIUmL receive booster vaccination to
raise the titer to 100 mIUmL (2D)
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KDOQI Commentary 15
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137 HUMAN IMMUNODEFICIENCY VIRUS1371 If not already done screen for HIV
infection (Not Graded)1372 To determine antiretroviral therapy refer
HIV-infected KTRs to an HIV specialistwho should pay special attention to drugndashdrug interactions and appropriate dosingof medications (Not Graded)
DOQIRationale andCommentary
Viral infections are particularly problematic inransplant recipients because of the preferentialnhibition of T-lymphocyte function by both induc-ion and maintenance immunosuppression Use ofnduction immunosuppression with lymphocyte-epleting agents (thymoglobulin or alemtuzumab)s associated with a greater risk of viral infectionosttransplant In general the greater the cumula-ive exposure to immunosuppression the greaterhe risk of infectious complications The presenta-ion of viral infections can be asymptomatic vaguend nonspecific or life-threatening acute illnessany viral infections seen in KTRs are rarely seen
n immunocompetent patients and therefore do notnter into the differential diagnosis for physiciansnfamiliar with transplant recipients Close commu-ication with the transplant center is crucial inaring for the transplant population Early detectionnd institution of therapy provide the best chanceor viral eradication
BKVirus
Although the work group agreed with KDIGOuggestions for BK virus screening posttransplante did not think it was practical to require screen-
ng exclusively with quantitative plasma nucleiccid testing (NAT) because many US centers usenitial urinary screening and then test plasma onlyf urine screening results are positive Howeverhere is no disagreement that some type of screen-ng for BK virus is critical to avoid BK nephropa-hy for which there is no specific treatment when its established Complicating screening for BK vi-us is the variability in results between laboratoriesnd uncertainty about the level of viremia thathould trigger a response to decrease in immunosup-ression In the presence of viremia and increase inerum creatinine level a renal allograft biopsy isndicated to confirm the presence of BK nephropa-
hy Because BK viremia and viruria certainly can b
e detected beyond the first year it is not clear howong screening should be continued posttransplantlthough most centers screen for the first year onlyngoing clinical trials are exploring effective treat-ent for BK nephropathy3839 Decisions about
ecreases in immunosuppression currently theainstay of BK viremia management always
hould be made in consultation with the transplantenter
Cytomegalovirus
KDIGO recommendation 1321 regarding cyto-egalovirus (CMV) prophylaxis is reasonable and
pplicable to the US population Universal prophy-axis for CMV now is recommended over initiatingre-emptive treatment after CMV develops40 Aajor concern for US patients is the cost of CMV
rophylaxis with oral valgancyclovir Leukopeniaan be observed in patients using mycophenolatereparations when prophylaxis with valgancyclo-ir is used Screening for CMV is best performedsing NAT methods (1322) CMV antigenemiassays are still in use in many facilities but are nots sensitive as PCR assays41 There is no utility inhecking for serologic response to CMV with IgGr IgM titers posttransplant because the immuneesponse is not predictable Patients with CMVisease should be cared for by clinicians familiarith treating this disease It is recommended that
reatment be continued until viral load is undetect-ble followed by prophylactic doses of valgancy-lovir for an additional 3 months35
Epstein-BarrVirus
Current practice regarding EBV screening variesmong centers in the United States and many doot routinely screen for EBV posttransplant evenn recipient-negative donor-positive cases In con-rast to KDIGO recommendation 1311 routineBV screening is not recommended in AST infec-
ious disease guidelines35 In many centers EBVcreening is reserved for children who are muchore commonly EBV negative pretransplant than
dults EBV-induced posttransplant lymphoprolif-rative disorder (PTLD) affects many more pediat-ic than adult KTRs If screening is someday to beoutinely implemented in US centers details regard-ng the best method of screening and levels ofiremia above which a clinical intervention should
e triggered need to be better defined
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HerpesandVaricella
Systemic herpesvirus infections can be lifehreatening in transplant recipients and should bereated aggressively with intravenous antiviralgents as described in the KDIGO recommenda-ions Less aggressive cutaneous infection can bereated with oral antiviral agents as outlined inhe KDIGO guidelines
Varicella exposure is particularly concerning inransplant recipients The work group disputes theecommended dosing of acyclovir for varicellaxposure Acyclovir at a dose of 10 mgkg or about00 mg 4 times daily of oral acyclovir would betandard dosing We agree with the use of varicellammune globulin and emphasize the need to avoidhe varicella vaccine because it is a live virushould a transplant recipient develop a systemicaricella infection hospitalization and high-dosentravenous acyclovir therapy are warranted
Hepatitis C
Hepatitis C management posttransplant is ahallenge The KDIGO guidelines cited hereere based on the recently published KDIGOuideline for hepatitis C in CKD4 Hepatitis Cypically is not treated posttransplant because ofhe risk (50) of rejection precipitated bynterferon therapy particularly in US KTRs inhom hepatitis C commonly is genotype 1 which
s more resistant to treatment with interferon42
owever should hepatitis Cndashrelated glomerulo-ephritis develop the risk-benefit ratio may fa-or treatment in selected patients Such decisionslways should be made in consultation withepatology and infectious disease experts andhe transplant center Monitoring liver enzymeevels specifically alanine aminotransferaseALT) may reflect a change in hepatitis activityut monitoring hepatitis C viral load is not recom-ended because it does not seem to correlateith outcome Annual monitoring for hepatocel-
ular carcinoma using -fetoprotein and imagings encouraged but not often practiced
Hepatitis B
KDIGO recommendations for hepatitis B areeasonable and currently are followed in mostS centers except for recommendation 1366
see previous recommendation under vaccina-ions) KTRs with hepatitis C or hepatitis B also
hould be followed up by a hepatologist
Human ImmunodeficiencyVirus
Human immunodeficiency virus (HIV)-posi-ive individuals are now acceptable for transplantf CD4 count is 200 cellsL and viral loadVL) is undetectable3543 Transplant should beerformed at centers with expertise in managingIV-positive individuals and care should be co-rdinated carefully with HIV specialists Somentiretroviral agents in particular the proteasenhibitors have potentially serious drug interac-ions with immunosuppressive agents35
DIGORecommendations inChapter 14Othernfections
141 URINARY TRACT INFECTION1411 We suggest that all KTRs receive UTI
prophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 monthsafter transplantation (2B)
1412 For allograft pyelonephritis we suggestinitial hospitalization and treatment withintravenous antibiotics (2C)
142 PNEUMOCYSTIS JIROVECII PNEUMONIA1421 We recommend that all KTRs receive
PCP prophylaxis with daily tri-methoprimndashsulfamethoxazole for 3-6months after transplantation (1B)
1422 We suggest that all KTRs receive PCPprophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 weeksduring and after treatment for acute rejec-tion (2C)
1423 We recommend that KTRs with PCPdiagnosed by bronchial alveolar lavageandor lung biopsy be treated withhigh-dose intravenous trimethoprimndashsulfamethoxazole corticosteroids anda reduction in immunosuppressivemedication (1C)
1424 We recommend treatment with cortico-steroids for KTRs with moderate tosevere PCP (as defined by PaO2 lt70mm Hg in room air or an alveolargradient of gt35 mm Hg) (1C)
143 TUBERCULOSIS1431 We suggest that TB prophylaxis and
treatment regimens be the same in KTRsas would be used in the local generalpopulation who require therapy (2D)
1432 We recommend monitoring CNI andmTORi [mTOR inhibitor] blood levels inpatients receiving rifampin (1C)14321 Consider substituting rifabu-
tin for rifampin to minimize
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KDOQI Commentary 17
ARTICLE IN PRESS
interactions with CNIs andmTORi (Not Graded)
144 CANDIDA PROPHYLAXIS1441 We suggest oral and esophageal Candida
prophylaxis with oral clotrimazole loz-enges nystatin or fluconazole for 1-3months after transplantation and for 1month after treatment with an antilympho-cyte antibody (2C)
DOQIRationale andCommentary
UrinaryTract Infection
Urinary tract infections (UTIs) after kidneyransplant are very common and account for aarge percentage of readmissions posttransplantTIs are common because of multiple factors
ncluding the disrupted anatomy of the urinaryract with a ureteroneocystotomy incompleteladder emptying because of diabetes or pros-atic hypertrophy and impaired immune re-ponses Prophylaxis of UTIs usually is under-aken with trimethoprim-sulfamethoxazole for 6onths posttransplant although infections often
ccur despite therapy because of the develop-ent of drug resistance Although native kidney
yelonephritis does not always require hospital-zation it is recommended that all KTRs withhis diagnosis be hospitalized because the graftysfunction that usually accompanies transplantyelonephritis requires aggressive investigationnd treatment Individuals with recurrent UTIsarrant evaluation with urologic assessment Pa-
ients with recurrent UTIs may benefit fromong-term suppressive therapy
Pneumocystic Pneumonia
We agree that Pneumocystis jirovecii pneumoniaPCP) prophylaxis is important for the first 3-6onths posttransplant (1421)After the first month
very-other-day dosing of trimethoprim-sulfame-hoxazole or atovaquone is believed to be adequaterophylaxis In cases in which neither of thesegents can be used an individual may be treatedrophylactically with inhaled pentamidine OurDOQI work group emphasized that patients whoevelop PCP should be transferred to the transplantenter promptly for management and adjustmentsn immunosuppression
Tuberculosis
Monitoring for latent tuberculosis has posed a
hallenge in the immunosuppressed population be-
ause of the unreliable nature of skin testing Newerechniques involving interferon release assays aremerging as the new gold standard for detection ofatent tuberculosis4445
CandidaProphylaxis
Oral candidiasis must be screened for usingral mucosa examination on follow-up visitsn KTRs This is especially true in the earlyosttransplant period when immunosuppres-ive medication dosage is the highest Wegree with these recommendations and empha-ize that if fluconazole is used there is aotential for serious drug interactions becausef cytochrome P-450 3A4 inhibition
SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
Improvement in short-term outcomes has not trans-lated into significant improvements in long-term out-comes in KTRs The lack of significant improvement inlong-term survival may be related to post-transplantcomplications Frequent posttransplant monitoring mayimprove long-term outcomes by decreasing chronic graftfailure or death with a functioning graft Our work groupconcurred with the recommendation and schedules ofroutine screening in monitoring kidney allograft functionafter kidney transplant with a low threshold for perform-ing kidney biopsy in cases of graft dysfunction or protein-uria Expert tissue processing and interpretation of trans-plant biopsy specimens by pathologists with transplantexperience are critical Regular surveillance of the pa-tientrsquos kidney function at the transplant center or in thenephrologistrsquos office offers an opportunity to enhancepatient adherence to medication diet and healthy life-style Although CKD in KTRs progresses more slowlythan CKD in other patients the work group agreed thatthe KDIGO guidelines on CKD should be followed inKTRs
Opportunistic infections are common in KTRs al-though advances in diagnosis and treatment have led toimproved survival in KTRs with infection It is nowstandard of care to use vaccinations in KTRs as long asthe vaccine does not contain live or attenuated virus Italso is routine to screen for or use prophylaxis to preventseveral posttransplant viral infections With few excep-tions (related to EBV and BK virus screening andhepatitis B vaccination posttransplant) we concurredwith KDIGO guidelines for vaccination screening and
treatment of infection posttransplant
KD
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ARTICLE IN PRESS
COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULAR
DISEASE
DIGORecommendations inChapter 15iabetesMellitus
151 Screening for New-Onset Diabetes after Transplan-tation1511 We recommend screening all nondia-
betic KTRs with fasting plasma glu-cose oral glucose tolerance testingandor HbA1c (1C) at leastbull weekly for 4 weeks (2D)bull every 3 months for 1 year (2D)bull and annually thereafter (2D)
1512 We suggest screening for NODAT withfasting glucose oral glucose tolerancetesting andor after starting or substan-tially increasing the dose of CNIsmTORi or corticosteroids (2D)
152 Managing NODAT or Diabetes Present at Trans-plantation1521 If NODAT develops consider modifying
the immunosuppressive drug regimen toreverse or ameliorate diabetes afterweighing the risk of rejection and otherpotential adverse effects (Not Graded)
1522 Consider targeting HbA1c 70-75and avoid targeting HbA1c 60 espe-cially if hypoglycemic reactions are com-mon (Not Graded)
1523 We suggest that in patients with diabetesaspirin (65-100 mgd) use for the primaryprevention of CVD be based on patientpreferences and values balancing the riskfor ischemic events to that of bleeding(2D)
DOQIRationale andCommentary
Diabetic Screening
We agree with screening for new-onset diabetesfter transplantation (NODAT) as outlined by theDIGO work group Definitions used are similar
o those of the American Diabetes AssociationADA) The greater frequency of testing initially isustified by the high risk of NODAT in the earlyosttransplant period however ongoing screenings required because the risk of the development ofODAT continues to increase over time4647 We
lso point out that prediabetic states (impairedasting glucose level and impaired glucose toler-nce) occur even more commonly than overt diabe-es48 and may be associated with metabolic syn-rome as well as with increased cardiovascular
ortality49-51 Potential implications of these predia-
etic states emphasize the importance of perform-ng blood tests under fasting conditions For pa-ients with fasting hyperglycemia an oral glucoseolerance test or hemoglobinA1c (HbA1c) test shoulde performed Although more cumbersome to per-orm data suggest that an oral glucose toleranceest is a more sensitive indicator of NODAT inyperglycemic KTRs52 This may allow earlieretection of overt diabetes and more prompt institu-ion of treatment
DiabetesManagement
Data supporting a substantial benefit in themelioration or reversal of NODAT using immu-osuppression modification in KTRs are veryimited There was consensus in our work grouphat considering the paucity of data for reversingODAT by changing immunosuppression and
he potential risk of an adverse outcome withuch a maneuver KDIGO suggestion 1521 couldot be supported Certainly if such a step waseing considered it should be done in conjunc-ion with the transplant center Targeting an HbA1c
evel of 7-75 and avoiding levels 6 isased on data showing increased cardiovascularvents with the lower HbA1c target5354
DIGORecommendations inChapter 16ypertensionDyslipidemias TobaccoUse andbesity
161 Hypertension1611 We recommend measuring blood pres-
sure at each clinic visit (1C)1612 We suggest maintaining blood pressure at
130 mm Hg systolic and 80 mm Hgdiastolic if 18 years of age and 90th
percentile for sex age and height if 18years old (2C)
1613 To treat hypertension (Not Graded)bull Use any class of antihypertensive
agentbull Monitor closely for adverse effects
and drug-drug interactions and whenurine protein excretion 1 gd for18 years old and 600 mgm224 hfor 18 years old consider an ACE-Ior an ARB as first-line therapy
162 Dyslipidemias (These recommendations are basedon KDOQI Dyslipidemia Guidelines and are thusnot graded)1621 Measure a complete lipid profile in all
adult (18 years old) and adolescent
(puberty to 18 years old) KTRs [Based on
K
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KDOQI Commentary 19
ARTICLE IN PRESS
KDOQI Dyslipidemia Recommendation1]bull 2-3 months after transplantationbull 2-3 months after a change in treatment
or other conditions known to causedyslipidemias
bull at least annually thereafter1622 Evaluate KTRs with dyslipidemias for
secondary causes [Based on KDOQI Dys-lipidemia Recommendation 3]16221 For KTRs with fasting triglyc-
erides 500 mgdL (565mmolL) that cannot be cor-rected by removing an under-lying cause treat withbull Adults therapeutic lifestyle
changes and a triglyceride-lowering agent [Based onKDOQI Recommendation41]
bull Adolescents therapeutic life-style changes [Based onKDOQI Recommendation51]
16222 For KTRs with elevatedLDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)treat to reduce LDL-C to100 mgdL (259mmolL) [Based on KDOQIGuideline 42]
bull Adolescents If LDL-C130 mgdL (336 mmolL) treat to reduce LDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 52]
16223 For KTRs with normalLDL-C elevated triglyceridesand elevated non-HDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)fasting triglycerides 200mgdL (226 mmolL)and non-HDL-C 130mgdL (336 mmolL)treat to reduce non-HDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 43]
bull Adolescents If LDL-C130 mgdL (336 mmolL) fasting triglycerides200 mgdL (226 mmolL) and non-HDL-C 160mgdL (414 mmolL)treat to reduce non-HDL-C
to 160 mgdL (414 i
mmolL) [Based on KDOQIGuideline 53]
163 Tobacco Use1631 Screen and counsel all KTRs including
adolescents and children for tobacco useand record the results in the medicalrecord (Not Graded)bull Screen during initial transplant hospi-
talizationbull Screen at least annually thereafter
1632 Offer treatment to all patients who usetobacco (Not Graded)
164 Obesity1641 Assess obesity at each visit (Not Graded)
bull Measure height and weight at eachvisit in adults and children
bull Calculate BMI at each visitbull Measure waist circumference when
weight and physical appearance sug-gest obesity but BMI is 35 kgm2
1642 Offer a weight-reduction program to allobese KTRs (Not Graded)
DOQIRationale andCommentary
Hypertension
The KDIGO work group adapted the KDOQI004 recommendations for target blood pres-ure in KTRs55 Self measurement is useful inssessing response to therapy and enhancesdherence56 In general we agree that the classf antihypertensive agent does not matter inhe treatment of blood pressure elevation inhis population and that attention should beiven to potential side effects of antihyperten-ive agents as well as possible interactionsith the immunosuppressive regimen (eg non-ihydropyridine calcium channel blockers andNIs) In the absence of adequate randomizedontrolled trials it is not known whether angio-ensin-converting enzyme (ACE) inhibitors andngiotensin receptor blockers (ARBs) prolongecipient or allograft survival Some but notll retrospective studies suggest a benefitowever all these studies are limited by selec-ion bias5758 Although ACE inhibitors andRBs commonly lead to some decrease inFR treatment with these drugs should be
ontinued unless serum creatinine level in-reases by 25 to 30 in keeping withDOQI recommendations55 In KTRs receiv-
ng ACE inhibitors or ARBs it is important toducate patients to maintain adequate fluid
ntake during illness to prevent a prerenal
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ARTICLE IN PRESS
nsult to the allograft Similarly awareness isecessary when using diuretics in conjunctionith therapies that block the renin-angiotensin-
ldosterone-system59
Dyslipidemia
The KDIGO work group based their recom-endations for evaluation and treatment of
yperlipidemia on the KDOQI dyslipidemiauidelines for KTRs60 We agree with theseecommendations CNIs potentiate the toxicityf statins by slowing their metabolism throughhe cytochrome P-450 system This interactionccurs more commonly with cyclosporine61
han with tacrolimus Dyslipidemia especiallyypertriglyceridemia frequently complicatesTOR-inhibitor use and lipid-lowering therapy
s required in most patients using these agents
TobaccoUse
Not surprisingly tobacco use at the time ofransplant is associated with decreased patientnd graft survival as well as increased risk ofosttransplant cardiovascular disease (CVD)lthough the KDIGO work group recom-ends initial screening and intervention dur-
ng the hospitalization for transplant we be-ieve there may be benefit gained by startingounseling in the pretransplant period duringhe evaluation phase Unfortunately this doesot occur often because of time and personnelonstraints in transplant centers Ideally allransplant centers should have smoking-cessa-ion programs available to patients either in-ouse or through referral Ideally systemshould be created to continue to screen andonitor for smoking cessation at yearly inter-
als after transplant because there is a highate of relapse with this addiction As outlinedn KDIGO Table 253 although all pharmaco-ogic therapies for smoking cessation can besed in KTRs the starting dose of vareniclinehould be decreased in patients with GFR 30Lmin
Obesity
Obesity is an epidemic in the United Statesnd the proportion of obese kidney transplantandidates continues to grow In additioneight gain after transplant is very commonly
bserved Obesity in KTRs is associated with w
ncreased risks of wound complications de-ayed graft function acute rejection and NO-AT resulting in inferior patient and graftutcomes Attention to this potential complica-ion and counseling should be initiated duringhe pretransplant evaluation phase Informa-ion regarding pharmacologic therapies foreight loss in KTRs is not available and we
gree with the KDIGO work group that thera-eutic lifestyle measures should be encour-ged Data regarding steroid therapy with-rawal and weight gain are controversial Aecent double-blind randomized controlled trialxamining early steroid therapy withdrawalid not show a difference in weight gain at 5ears posttransplant compared with the cohortemaining on standard maintenance corticoste-oid therapy62
DIGORecommendations inChapter 17ardiovascularManagement
171 Consider managing CVD at least as intensively inKTRs as in the general population with appropri-ate diagnostic tests and treatments (Not Graded)
172 We suggest using aspirin (65-100 mgd) in allpatients with atherosclerotic CVD unless there arecontraindications (2B)
DOQIRationale andCommentary
Although outcomes are favorable comparedith remaining on the waiting list the risk of
ardiovascular mortality in KTRs is several-foldigher than observed in the general population63
specially in younger age groups and patientsith decreasing allograft function64 CVD is aajor cause of graft loss after the first post-
ransplant year In this context we strongly agreehat CVD should be managed in KTRs at least asntensively as in the general population Ideallyecreasing CVD risk in KTRs requires a multifac-ted and multidisciplinary approach Based onurrent practice models in the United States theransplant and nephrology community has notet been able to achieve these desirable goals65
his clearly deserves more attention becauseontrol of CVD has the potential to contributeore to long-term kidney graft survival than the
iscovery of newer drugs that decrease the ratef allograft rejection Our KDOQI working groupgreed with the use of low-dose aspirin in KTRs
ith evidence of atherosclerosis
Ko
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KDOQI Commentary 21
ARTICLE IN PRESS
SUMMARY OF COMMENTARY ONSECTION III CVD
COMMENTARY ON SECTION IV OF KDIGO
TRANSPLANT GUIDELINE MALIGNANCY
DIGORecommendations inChapter 18 Cancerf the Skin andLip
181 We recommend that KTRs especially thosewho have fair skin live in high sun-exposureclimates have occupations requiring sun expo-sure have had significant sun exposure as achild or have a history of skin cancer be toldthat their risk of skin and lip cancer is veryhigh (1C)
182 We recommend that KTRs minimize life-longsun exposure and use appropriate ultravioletlight blocking agents (1D)
183 We suggest that adult KTRs perform skin andlip self-examinations and report new lesions toa health-care provider (2D)
184 For adult KTRs we suggest that a qualified healthprofessional with experience in diagnosing skincancer perform annual skin and lip examinationon KTRs except possibly for KTRs with dark skinpigmentation (2D)
185 We suggest that patients with a history of skin orlip cancer or premalignant lesions be referred to andfollowed by a qualified health professional withexperience in diagnosing and treating skin cancer
With the decrease in acute rejection during the pastdecade in association with improved immunosuppres-sion regimens patient death now rivals chronic graftdysfunction as one of the leading causes of long-termgraft loss Because CVD is the most common cause ofpatient death in KTRs a concerted effort at minimizingrisk factors for heart disease likely will have as great oreven greater impact on optimizing patient and graftoutcomes than the discovery of new antirejection thera-pies CVD risk reduction strategies should include regularscreening for new-onset diabetes (using ADA-based defini-tions) in the posttransplant period in previously nondiabeticpatients good glycemic regulation for diabetic patients accord-ing to current ADA guidelines and lipid management andblood pressure control according to KDOQI recommenda-tions In addition promotion of a healthy lifestyle throughweight control exercise and smoking cessation should be acentral part of posttransplant counseling and care Whenimmunosuppression modification is being considered to miti-gate cardiovascular risk we recommend that this be inconjunction with the transplant center In summary we gener-ally concurred with the suggestions of the work group in thissection but based on current practice standards in the UnitedStateschallengesremainwith implementationof thisguideline
(2D) s
186 We suggest that patients with a history of skincancer be offered treatment with oral acitretin ifthere are no contraindications (2B)
DOQIRationale andCommentary
CounselingandSunscreen
We concur with recommendations 181 and82 because skin cancer is a major source oforbidity and sometimes mortality in KTRsarning patients at risk of the high danger of
kin cancer a 1C recommendation is reinforcedy a recent prospective case-control study ofrgan transplant recipients that showed that regu-ar use of broad-spectrum sunscreens that pro-ide UVA and UVB protection may prevent theevelopment of actinic keratosis invasive squa-ous cell carcinoma and to a lesser extent
asal cell carcinoma66 Most cancer-causing ra-iation is thought to come from the UVB spec-rum and newer broad-spectrum sunscreens pro-ide protection against UVA and UVB radiationounseling about sunscreen and the need for sunvoidance needs to be incorporated into routineffice visits although it may not always beuccessful In a recent study of KTRs in which1 of patients had been informed about theeed for sun protection only 46 used morehan a tube of sunscreen per year67
Dermatology Involvement
There is increased evidence to suggest thatpecialty dermatology clinics for organ trans-lant recipients improve outcome measures in-luding compliance with photoprotection andncreased awareness of skin cancer68 The re-ources required for these specialty clinics makemplementation difficult for community nephrol-gy groups that do not have direct access to aransplant center Transplant patients should bencouraged to have annual visits with their trans-lant center and if dermatology specialty clinicsre available attempt to coordinate a skin cancervaluation annually
UseofRetinoid-likeCompounds
There is a limited scientific basis for KDIGOuggestion recommendation 186 Although reti-oids now are used routinely in KTRs with aigh skin cancer burden our KDOQI work groupelieves that more data are needed before this
uggestion should be accepted as a guideline In
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ARTICLE IN PRESS
ow-immunologic-risk groups and particularlyifficult cases some data suggest that switchingrom CNI to sirolimus therapy may decrease thencidence of skin cancer69 however the riskersus benefit of this maneuver has not been welltudied
DIGORecommendations inChapter 19on-SkinMalignancies
191 Develop an individualized screening plan for eachKTR that takes into account the patientrsquos pastmedical and family history tobacco use compet-ing risks for death and the performance of thescreening methodology (Not Graded)
192 Screen for the following cancers as per localguidelines for the general population (Not Graded)Women cervical breast and colon cancer Menprostate and colon cancer
193 Obtain hepatic ultrasound and alpha feto-proteinevery 12 months in patients with compensatedcirrhosis (Not Graded) [See Recommendations1354 (HCV) and 1365 (HBV)]
DOQIRationale andCommentary
Screening
It is recognized that KTRs have a higher inci-ence of malignancy particularly those associatedith specific viral infections Although cancer
creening may have benefits in this higher riskopulation it should be reinforced that some meth-ds of screening have significant risks which shoulde considered on an individualized basis particu-arly in patients who have projected survival lesshan 5 years
Screening forCancer inPatientsWithHepatitis
Many patients who have underlying cirrhosisn the United States will be followed up by arofessional specializing in liver disease whoay provide additional insight into this cancer
creening recommendation Based on a recentuestionnaire of US gastroenterologists only 50creen patients for hepatocellular carcinoma70
herefore implementation of this guideline byS clinicians is unlikely to be widespread
DIGORecommendations inChapter 20anagingCancerwithReductionof
mmunosuppressiveMedication
201 We suggest consideration be given to reducingimmunosuppressive medications for KTRs with can-
cer (2C)
2011 Important factors for consideration in-clude (Not Graded)bull The stage of cancer at diagnosisbull Whether the cancer is likely to be
exacerbated by immunosuppressionbull The therapies available for the can-
cerbull Whether immunosuppressive medica-
tions interfere with ability to admin-ister the standard chemotherapy
202 For patients with Kaposi sarcoma we suggestusing mTORi along with a reduction in overallimmunosuppression (2C)
DOQIRationale andCommentary
Table 1 (Table 29 in the KDIGO report3 andxcerpted from Grulich et al71) lists cancershat are increased most in immunosuppressedTRs based on standardized incidence ratios
SIRs) which compare the incidence toatched populations Cancers with the highestIRs may be those most likely to respond to aecrease in immunosuppression Except foraposi sarcoma limited evidence is available
or a decrease in immunosuppression in theseettings A strategy to change immunosuppres-ion therapy must occur in consultation withhe transplant center Switching to sirolimusherapy and decreasing immunosuppression inatients who develop Kaposi sarcoma is basedn sound scientific rationale7273
SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
The incidence of cancer posttransplant is 2-20times higher than that in the general population andKDIGO guidelines have been written to outline stepsfor prevention and screening With few exceptions weagree with the recommendations as outlined Skincancer is common in US transplant patients andscreening and prevention are critical However imple-mentation of guidelines for doing so including theKDIGO guidelines is a challenge because of patientpreferences against the routine use of sunscreen aswell as time constraints during office visits Althoughmany posttransplant cancers are viral mediated andrelated to immunosuppression it is less clear how toalter immunosuppression after malignancy has oc-curred We agree that although age-specific screeningfor malignancy should be incorporated into care con-sideration must be given to the risk of screening inpatients with limited life spans (5 years) because of
comorbid conditions
KT
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
ommonPopu
i sarco-Hodgmelanise sm
sophaemia
estima standa10 c
ut esti
0 case
alized t
to guide treatment specifically before the
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
K
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
REFERENCES1 McCullough KP Keith DS Meyer KH et al Kidney
nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
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ml
gt1
p2
ps2
c2
p2
sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
ation Transpl Rev 200923191-19815 Abbud-Filho M Adams PL Alberuacute J et al A report
f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
cA
nrc
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trN
hUt
Iwa
rl5
mi8
oe1
DA
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hm2
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Bia et al30
ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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Bia et al10
ARTICLE IN PRESS
bull New onset of proteinuria (2C)bull Unexplained proteinuria 30 g per gram creati-
nine or 30 g per 24 hours (2C)
DOQIRationale andCommentary
Biopsy
Renal allograft biopsy is the gold standard foriagnosing the cause of a change in renal allo-raft function It is useful in all clinical situationsescribed in KDIGO suggestions 91-94 Poten-ial causes of allograft dysfunction include vol-me depletion compromised renal blood flowrinary outflow obstruction parenchymal causesuch as acute rejection (cellular andor humoral)hronic allograft nephropathy recurrent or deovo disease or BK nephropathy Patients show-ng a 20-25 increase in creatinine level aboveaseline values warrant consideration for biopsyther indications for pursuing renal allograftiopsy would be a less-than-expected responseo treatment of acute rejection The expectedesponse would be dependent on the severity ofissue injury noted on the diagnostic biopsy speci-
en Delayed graft function lasting longer than-7 days warrants biopsy with repeated biopsieserformed every 7-10 days until graft functionecovers New-onset proteinuria protein 20g creatinine or 20 g24 h also merits aidney biopsy De novo and recurrent glomerulariseases are common causes of new-onset pro-einuria Patients with de novo or recurrent glo-erular diseases should be followed up closely
y transplant nephrologists or community neph-ologists with close communication with theransplant center because treatment of some recur-ent kidney diseases may prevent or delay thenset of graft failure2324
SafetyandAccuracy
The safety of kidney transplant biopsies haseen documented and the overall risk of compli-ations is low Most biopsies are performed inhe transplant center by transplant nephrologistsommunity nephrologists also may perform bi-psies of the kidney in KTRs more than a yearosttransplant It is prudent to obtain a diagnosticltrasound before biopsy to rule out unexpectedlterations in blood flow or urinary tract obstruc-ion It is imperative that a pathologist familiar
ith the transplant process interprets the pathol-
gy in consultation with the referring nephrolo-ist using appropriate stains and other studies
MolecularMarkers
In addition to conventional histopathologicxamination several US transplant centers aresing molecular markers as well as genomic orroteomic methods to enhance our understand-ng of the mechanism of immunologic and non-mmunologic pathway of injury As an exampleolymerase chain reaction (PCR) has been usedo detect messenger RNA for IL-2 and otheriomarkers in biopsy samples Using this ap-roach IL-2 upregulated during rejection coulde detected 2 days before rejection was apparentsing histologic or clinical criteria Such PCRpproaches have been used to detect other generoducts upregulated during acute rejection suchs granzyme B perforin transforming growthactor IL-10 and IL-1525-27 These newerethods are performed almost exclusively in
ransplant centers and may become a standardethod of transplant biopsy analysis in the fu-
ure
DIGORecommendations inChapter 10ecurrentDisease
101 We suggest screening KTRs with primary kidneydisease caused by FSGS for proteinuria (2C) atleastbull Daily for 1 week (2D)bull Weekly for 4 weeks (2D)bull Every 3 months for the first year (2D) Every
year thereafter (2D)
102 We suggest screening KTRs with potentially treat-able recurrence of primary kidney disease fromIgA nephropathy MPGN anti-GBM disease orANCA-associated vasculitis for microhematuria(2C) at leastbull Once in the first month to determine a baseline
(2D)bull Every 3 months during the first year (2D)
Annually thereafter (2D)
103 During episodes of graft dysfunction in patientswith primary HUS we suggest screening forthrombotic microangiopathy (eg with plateletcount peripheral smear for blood cell morphologyplasma haptoglobin and serum lactate dehydroge-nase) (2D)
104 When screening suggests possible treatable recur-rent disease we suggest obtaining an allograftbiopsy (2C)
105 Treatment of recurrent kidney disease1051 We suggest plasma exchange if a biopsy
shows minimal change disease or FSGS
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KDOQI Commentary 11
ARTICLE IN PRESS
in those with primary FSGS as theirprimary kidney disease (2D)
1052 We suggest high-dose corticosteroids andcyclophosphamide in patients with recur-rent ANCA-associated vasculitis or anti-GBM disease (2D)
1053 We suggest using an ACE-I [ACE inhibi-tor] or an ARB for patients with recurrentglomerulonephritis and proteinuria (2C)
1054 For KTRs with primary hyperoxaluriawe suggest appropriate measures to pre-vent oxalate deposition until plasma andurine oxalate levels are normal (2C)includingbull Pyridoxine (2C)bull High calcium and low oxalate diet
(2C)bull Increased oral fluid intake to enhance
urinary dilution of oxalate (2C)bull Potassium or sodium citrate to alkalin-
ize the urine (2C)bull Orthophosphate (2C)bull Magnesium oxide (2C)bull Intensive hemodialysis to remove ox-
alate (2C)
DOQIRationale andCommentary
Recurrent disease accounts for a substantialmount of graft loss after renal transplant It isifficult to assess the percentage of grafts lost toecurrent disease because many patients presentith end-stage renal disease without benefit of aiagnostic native renal biopsy The likelihood ofecurrent disease after transplant is dependent onhe disease with certain diseases at particularlyigh risk of recurrence28
Recurrent Focal SegmentalGlomerulosclerosis
We agree with recommendation 101 regard-ng frequent and regular screening for protein-ria in patients with primary focal segmentallomerulosclerosis (FSGS) as the cause of end-tage renal disease If the patient is still produc-ng urine at the time of transplant a preoperativerine protein-creatinine ratio can be a very help-ul baseline measure of proteinuria Early detec-ion of FSGS recurrence which can present withormal light microscopy but foot-process efface-ent on electron microscopy29 provides the best
pportunity for intervention and amelioration ofisease
IgANephropathy
Recurrence rates of immunoglobulin A (IgA)
ephropathy are variable We agree with recom- b
endation 102 for screening routinely for micro-ematuria Recurrent disease is confirmed with aenal allograft biopsy Histologic recurrence ofisease is much more common than is clinicalisease recurrence There is no proven therapyor treatment of recurrent disease30
MembranoproliferativeGlomerulonephritis
Recurrence of membranoproliferative glomer-lonephritis (MPGN) is common as high as 80ith MPGN type II (dense-deposit disease) Theost common cause of MPGN type I is hepatitisndashassociated immune complex formation Wegree with the proposed regularly scheduledcreening for microhematuria and proteinuria inecommendation 102 Patients with known hepa-itis Cndashassociated MPGN pretransplant also maye screened for cryoglobulins which are associ-ted with MPGN31
HemolyticUremic Syndrome
Hemolytic uremic syndrome (HUS) typicallys divided into diarrheal associated (D) andonndashdiarrheal associated (D) D disease oc-urs mostly in children and rarely recurs post-ransplant However D HUS is more commonn adults and can recur In HUS associated with aomplement abnormality such as factor H defi-iency or factor I mutation recurrence rates cane as high as 80 Screening for evidence ofecurrence allows for an earlier diagnosis whichill require biopsy in most cases and provides
n opportunity for earlier intervention There iso comment in the guideline regarding recur-ence of thrombotic thrombocytopenic purpuraut early detection of recurrence provides anpportunity for treatment with plasmapheresisnd intravenous immune globulin (IVIG)
BiopsyandTreatment
As stated kidney biopsy and interpretation bypathologist with expertise in transplant speci-en readings is critical in the diagnosis of dis-
ase recurrence Treatment for most recurrentisease in renal transplantation is based on aombination of case reports case cohorts andetrospective reviews Recurrent diseases post-ransplant are not common enough that random-zed controlled trials can be implemented there-ore most recommendations for treatment are
ased on a consensus of opinion Despite this we
at
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gree in general with the recommendations de-ailed in 105
DIGORecommendations inChapter 11reventingDetecting andTreatingonadherence
111 Consider providing all KTRs and family memberswith education prevention and treatment mea-sures to minimize nonadherence to immunosup-pressive medications (Not Graded)
112 Consider providing KTRs at increased risk fornonadherence with increased levels of screeningfor nonadherence (Not Graded)
DOQIRationale andCommentary
Noncompliance or nonadherence to diet andedication is a common problem in KTRs Nonad-
erence to medication is associated with a high riskf acute rejection and allograft loss We agree thatarly efforts should be made to identify KTRs atncreased risk of nonadherence and that these pa-ients should be monitored closely Prevention iden-ification and treatment of nonadherence are inte-ral to the monitoring of kidney allograft functionnd long-term care of KTRs Certain subgroup ofTRs younger patients African Americans and
hose with financial hardships have an enhancedisk of nonadherence3233
In addition to identifying patients at risk it ismportant to have a system for addressing patientonadherence This requires coordinated efforts ofocial workers transplant coordinators financialounselors pharmacists primary nephrologists andhe patientrsquos family34 A combination of educa-ional behavioral and social support interventionsrovides the best results Because there is no per-ect measure of adherence consideration should beiven to multiple approaches for adherence moni-oring Similar team approaches also are importantn other areas requiring adherence such as dietxercise tobacco alcohol and drug use
DIGORecommendations inChapter 12accination
121 We recommend giving all KTRs approvedinactivated vaccines according to recommendedschedules for the general population except forHBV vaccination (1D)1211 We suggest HBV vaccination (ideally
prior to transplantation) and HBsAb titers6-12 weeks after completing the vaccina-
tion series (2D) h
12111 We suggest annual HBsAb[antibody to hepatitis B sur-face antigen] titers (2D)
12112 We suggest revaccination ifthe antibody titer falls below10 mIUmL (2D)
122 We suggest avoiding live vaccines in KTRs (2C)123 We suggest avoiding vaccinations except influ-
enza vaccination in the first 6 months followingkidney transplantation (2C)1231 We suggest resuming immunizations once
patients are receiving minimal mainte-nance doses of immunosuppressive medi-cations (2C)
1232 We recommend giving all KTRs whoare at least 1-month post-transplantinfluenza vaccination prior to the onsetof the annual influenza season regard-less of status of immunosuppression(1C)
124 We suggest giving the following vaccines to KTRswho due to age direct exposure residence ortravel to endemic areas or other epidemiologicalrisk factors are at increased risk for the specificdiseasesbull rabies (2D)bull tick-borne meningoencephalitis (2D)bull Japanese B encephalitismdashinactivated (2D)bull Meningococcus (2D)bull Pneumococcus (2D)bull Salmonella typhimdashinactivated (2D)1241 Consult an infectious disease specialist a
travel clinic or public health official forguidance on whether specific cases war-rant these vaccinations (Not Graded)
DOQIRationale andCommentary
KTRs are at particular risk of viral infectionsecause of the preferential suppression of T lympho-ytes by both induction and maintenance immuno-uppression The risk and consequence of develop-ng a viral infection warrant use of selected vaccineshe suggestions regarding which vaccines are safend which are contraindicated are based on whetherhe vaccine contains live or killed virus Live virusaccines are contraindicated in immunosuppressedTRs The KDIGO recommendations for vaccina-
ions agree with updated guidelines recently pub-ished by the AST35 Specific comments on theDIGO suggestions regarding vaccinations are
isted in the following sections
Hepatitis B
The work group did not concur with KDIGOuggestion 1211 Neither revaccination against
epatitis after transplant nor following up hepa-
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KDOQI Commentary 13
ARTICLE IN PRESS
itis B antibody titers annually is a commonractice in the United States Hepatitis B is nots prevalent in the United States as in otherarts of the world and evidence supportingcreening in all patients posttransplant is lack-ng However screening for seroconversion inatients at risk (receiving a hepatitis B corentibodyndashpositive kidney) is appropriate Theseatients may benefit from lamivudine or ente-avir therapy36
LiveVaccineandTimingofVaccine
There is no particular reason for a 6-monthag between transplant and vaccination Theheory is that vaccines are less likely to beffective in the period when immunosuppres-ion is high In the United States most individu-ls are on their baseline maintenance immuno-uppression therapy by 3 months posttransplantecisions regarding the timing of vaccines areade based on immunosuppression exposure
nd risk of infection Recipients also shouldvoid intimate contact with individuals whoave received live vaccines37 This includesvoiding close contact with children who haveeceived oral polio vaccine for 3 weeks anday include close contact with adults receiv-
ng the attenuated varicella vaccine to preventoster Immunosuppressed individuals are ad-ised to avoid contact for 7 days with individu-ls who have received live virus nasal spraysor influenza We concur with the recommenda-ion for flu vaccine but common practice inhe United States is to wait 3-6 months afterransplant before it is administered
DIGORecommendations inChapter 13 Viraliseases
131 BK POLYOMA VIRUS1311 We suggest screening all KTRs for BKV
with quantitative plasma NAT (2C) atleastbull monthly for the first 3-6 months after
transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull whenever there is an unexplained rise
in serum creatinine (2D)bull and after treatment for acute rejection
(2D)1312 We suggest reducing immunosuppressive
medications when BKV plasma NAT is
persistently greater than 10 000 cop-iesmL (107 copiesL) (2D)
132 CYTOMEGALOVIRUS1321 CMV prophylaxis We recommend that
KTRs (except when donor and recipi-ent both have negative CMV serolo-gies) receive chemoprophylaxis forCMV infection with oral ganciclovir orvalganciclovir for at least 3 monthsafter transplantation (1B) and for 6weeks after treatment with a T-cellndashdepleting antibody (1C)
1322 In patients with CMV disease we suggestweekly monitoring of CMV by NAT orpp65 antigenemia (2D)
1323 CMV treatment13231 We recommend that all pa-
tients with serious (includ-ing most patients with tissueinvasive) CMV disease betreated with intravenousganciclovir (1D)
13232 We recommend that CMVdisease in adult KTRs that isnot serious (eg episodes thatare associated with mildclinical symptoms) be treatedwith either intravenous gan-ciclovir or oral valganciclo-vir (1D)
13233 We recommend that allCMV disease in pediatricKTRs be treated with intra-venous ganciclovir (1D)
13234 We suggest continuing therapyuntil CMV is no longer detect-able by plasma NAT or pp65antigenemia (2D)
1324 We suggest reducing immunosuppressivemedication in life-threatening CMV dis-ease and CMV disease that persists in theface of treatment until CMV disease hasresolved (2D)13241 We suggest monitoring graft
function closely during CMVdisease (2D)
133 EPSTEIN-BARR VIRUS AND POST-TRANS-PLANT LYMPHOPROLIFERATIVE DISEASE1331 We suggest monitoring high-risk (donor
EBV seropositiverecipient seronegative)KTRs for EBV by NAT (2C)bull once in the first week after transplanta-
tion (2D)bull then at least monthly for the first 3-6
months after transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull and additionally after treatment for
acute rejection (2D)
Bia et al14
ARTICLE IN PRESS
1332 We suggest that EBV-seronegative pa-tients with an increasing EBV load haveimmunosuppressive medication reduced(2D)
1333 We recommend that patients with EBVdisease including PTLD have a reduc-tion or cessation of immunosuppres-sive medication (1C)
134 HERPES SIMPLEX VIRUS 1 2 AND VARI-CELLA ZOSTER VIRUS1341 We recommend that KTRs who de-
velop a superficial HSV 1 2 infectionbe treated (1B) with an appropriateoral antiviral agent (eg acyclovir vala-cyclovir or famciclovir) until all le-sions have resolved (1D)
1342 We recommend that KTRs with sys-temic HSV 1 2 infection be treated(1B) with intravenous acyclovir and areduction in immunosuppressive medi-cation (1D)13421 We recommend that intrave-
nous acyclovir continue un-til the patient has a clinicalresponse (1B) then switch toan appropriate oral antiviralagent (eg acyclovir valacy-clovir or famciclovir) to com-plete a total treatment durationof 14-21 days (2D)
1343 We suggest using a prophylactic antiviralagent for KTRs experiencing frequentrecurrences of HSV 12 infection (2D)
1344 We recommend that primary VZV infec-tion (chicken pox) in KTRs be treated(1C) with either intravenous or oral acy-clovir or valacyclovir and a temporaryreduction in amount of immunosuppres-sive medication (2D)
135 HEPATITIS C VIRUS1351 We suggest that HCV-infected KTRs be
treated only when the benefits of treat-ment clearly outweigh the risk of allo-graft rejection due to interferon-basedtherapy (eg fibrosing cholestatic hepati-tis life-threatening vasculitis) (2D)[Based on KDIGO Hepatitis C Recom-mendation 215]
1352 We suggest monotherapy with standardinterferon for HCV-infected KTRs inwhom the benefits of antiviral treatmentclearly outweigh the risks (2D) [Basedon KDIGO Hepatitis C Recommenda-tions 224 and 442]
1353 We suggest that all conventional currentinduction and maintenance immunosup-pressive regimens can be used in HCVinfected patients (2D) [Based on KDIGO
Hepatitis C Recommendation 43]
1354 Measure ALT in HCV-infected patientsmonthly for the first 6 months and every3-6 months thereafter Perform imagingannually to look for cirrhosis and hepato-cellular carcinoma (Not Graded) [Basedon KDIGO Hepatitis C Recommendation441] (See Recommendation 193)
1355 Test HCV-infected patients at least every3-6 months for proteinuria (Not Graded)[Based on KDIGO Hepatitis C Recom-mendation 444]13551 For patients who develop new
onset proteinuria (either urineproteincreatinine ratio 1 or24-hour urine protein 1 g ontwo or more occasions) per-form an allograft biopsy withimmunofluorescence and elec-tron microscopy (Not Graded)[Based on KDIGO Hepatitis CRecommendation 444]
1356 We suggest that patients with HCV asso-ciated glomerulopathy not receive inter-feron (2D) [Based on KDIGO HepatitisC Recommendation 445]
136 HEPATITIS B VIRUS1361 We suggest that any currently available
induction and maintenance immunosup-pressive medication can be used in HBV-infected KTRs (2D)
1362 We suggest that interferon treatmentshould generally be avoided in HBVinfected KTRs (2C)
1363 We suggest that all HBsAg-positive KTRsreceive prophylaxis with tenofovir ente-cavir or lamivudine (2B)13631 Tenofovir or entecavir are pref-
erable to lamivudine to mini-mize development of potentialdrug resistance unless medica-tion cost requires that lami-vudinebe used (Not Graded)
13632 During therapy with antivi-rals measure HBV DNA andALT levels every 3 months tomonitor efficacy and to detectdrug resistance (Not Graded)
1364 We suggest treatment with adefovir ortenofovir for KTRs with lamivudine resis-tance (5 log10 copiesmL rebound ofHBV-DNA) (2D)
1365 Screen HBsAg-positive patients with cir-rhosis for hepatocellular carcinoma every12 months with liver ultrasound andalpha feto-protein (Not Graded) (SeeRecommendation 193)
1366 We suggest that patients who are negativefor HBsAg and have HBsAb titer 10mIUmL receive booster vaccination to
raise the titer to 100 mIUmL (2D)
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KDOQI Commentary 15
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137 HUMAN IMMUNODEFICIENCY VIRUS1371 If not already done screen for HIV
infection (Not Graded)1372 To determine antiretroviral therapy refer
HIV-infected KTRs to an HIV specialistwho should pay special attention to drugndashdrug interactions and appropriate dosingof medications (Not Graded)
DOQIRationale andCommentary
Viral infections are particularly problematic inransplant recipients because of the preferentialnhibition of T-lymphocyte function by both induc-ion and maintenance immunosuppression Use ofnduction immunosuppression with lymphocyte-epleting agents (thymoglobulin or alemtuzumab)s associated with a greater risk of viral infectionosttransplant In general the greater the cumula-ive exposure to immunosuppression the greaterhe risk of infectious complications The presenta-ion of viral infections can be asymptomatic vaguend nonspecific or life-threatening acute illnessany viral infections seen in KTRs are rarely seen
n immunocompetent patients and therefore do notnter into the differential diagnosis for physiciansnfamiliar with transplant recipients Close commu-ication with the transplant center is crucial inaring for the transplant population Early detectionnd institution of therapy provide the best chanceor viral eradication
BKVirus
Although the work group agreed with KDIGOuggestions for BK virus screening posttransplante did not think it was practical to require screen-
ng exclusively with quantitative plasma nucleiccid testing (NAT) because many US centers usenitial urinary screening and then test plasma onlyf urine screening results are positive Howeverhere is no disagreement that some type of screen-ng for BK virus is critical to avoid BK nephropa-hy for which there is no specific treatment when its established Complicating screening for BK vi-us is the variability in results between laboratoriesnd uncertainty about the level of viremia thathould trigger a response to decrease in immunosup-ression In the presence of viremia and increase inerum creatinine level a renal allograft biopsy isndicated to confirm the presence of BK nephropa-
hy Because BK viremia and viruria certainly can b
e detected beyond the first year it is not clear howong screening should be continued posttransplantlthough most centers screen for the first year onlyngoing clinical trials are exploring effective treat-ent for BK nephropathy3839 Decisions about
ecreases in immunosuppression currently theainstay of BK viremia management always
hould be made in consultation with the transplantenter
Cytomegalovirus
KDIGO recommendation 1321 regarding cyto-egalovirus (CMV) prophylaxis is reasonable and
pplicable to the US population Universal prophy-axis for CMV now is recommended over initiatingre-emptive treatment after CMV develops40 Aajor concern for US patients is the cost of CMV
rophylaxis with oral valgancyclovir Leukopeniaan be observed in patients using mycophenolatereparations when prophylaxis with valgancyclo-ir is used Screening for CMV is best performedsing NAT methods (1322) CMV antigenemiassays are still in use in many facilities but are nots sensitive as PCR assays41 There is no utility inhecking for serologic response to CMV with IgGr IgM titers posttransplant because the immuneesponse is not predictable Patients with CMVisease should be cared for by clinicians familiarith treating this disease It is recommended that
reatment be continued until viral load is undetect-ble followed by prophylactic doses of valgancy-lovir for an additional 3 months35
Epstein-BarrVirus
Current practice regarding EBV screening variesmong centers in the United States and many doot routinely screen for EBV posttransplant evenn recipient-negative donor-positive cases In con-rast to KDIGO recommendation 1311 routineBV screening is not recommended in AST infec-
ious disease guidelines35 In many centers EBVcreening is reserved for children who are muchore commonly EBV negative pretransplant than
dults EBV-induced posttransplant lymphoprolif-rative disorder (PTLD) affects many more pediat-ic than adult KTRs If screening is someday to beoutinely implemented in US centers details regard-ng the best method of screening and levels ofiremia above which a clinical intervention should
e triggered need to be better defined
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HerpesandVaricella
Systemic herpesvirus infections can be lifehreatening in transplant recipients and should bereated aggressively with intravenous antiviralgents as described in the KDIGO recommenda-ions Less aggressive cutaneous infection can bereated with oral antiviral agents as outlined inhe KDIGO guidelines
Varicella exposure is particularly concerning inransplant recipients The work group disputes theecommended dosing of acyclovir for varicellaxposure Acyclovir at a dose of 10 mgkg or about00 mg 4 times daily of oral acyclovir would betandard dosing We agree with the use of varicellammune globulin and emphasize the need to avoidhe varicella vaccine because it is a live virushould a transplant recipient develop a systemicaricella infection hospitalization and high-dosentravenous acyclovir therapy are warranted
Hepatitis C
Hepatitis C management posttransplant is ahallenge The KDIGO guidelines cited hereere based on the recently published KDIGOuideline for hepatitis C in CKD4 Hepatitis Cypically is not treated posttransplant because ofhe risk (50) of rejection precipitated bynterferon therapy particularly in US KTRs inhom hepatitis C commonly is genotype 1 which
s more resistant to treatment with interferon42
owever should hepatitis Cndashrelated glomerulo-ephritis develop the risk-benefit ratio may fa-or treatment in selected patients Such decisionslways should be made in consultation withepatology and infectious disease experts andhe transplant center Monitoring liver enzymeevels specifically alanine aminotransferaseALT) may reflect a change in hepatitis activityut monitoring hepatitis C viral load is not recom-ended because it does not seem to correlateith outcome Annual monitoring for hepatocel-
ular carcinoma using -fetoprotein and imagings encouraged but not often practiced
Hepatitis B
KDIGO recommendations for hepatitis B areeasonable and currently are followed in mostS centers except for recommendation 1366
see previous recommendation under vaccina-ions) KTRs with hepatitis C or hepatitis B also
hould be followed up by a hepatologist
Human ImmunodeficiencyVirus
Human immunodeficiency virus (HIV)-posi-ive individuals are now acceptable for transplantf CD4 count is 200 cellsL and viral loadVL) is undetectable3543 Transplant should beerformed at centers with expertise in managingIV-positive individuals and care should be co-rdinated carefully with HIV specialists Somentiretroviral agents in particular the proteasenhibitors have potentially serious drug interac-ions with immunosuppressive agents35
DIGORecommendations inChapter 14Othernfections
141 URINARY TRACT INFECTION1411 We suggest that all KTRs receive UTI
prophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 monthsafter transplantation (2B)
1412 For allograft pyelonephritis we suggestinitial hospitalization and treatment withintravenous antibiotics (2C)
142 PNEUMOCYSTIS JIROVECII PNEUMONIA1421 We recommend that all KTRs receive
PCP prophylaxis with daily tri-methoprimndashsulfamethoxazole for 3-6months after transplantation (1B)
1422 We suggest that all KTRs receive PCPprophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 weeksduring and after treatment for acute rejec-tion (2C)
1423 We recommend that KTRs with PCPdiagnosed by bronchial alveolar lavageandor lung biopsy be treated withhigh-dose intravenous trimethoprimndashsulfamethoxazole corticosteroids anda reduction in immunosuppressivemedication (1C)
1424 We recommend treatment with cortico-steroids for KTRs with moderate tosevere PCP (as defined by PaO2 lt70mm Hg in room air or an alveolargradient of gt35 mm Hg) (1C)
143 TUBERCULOSIS1431 We suggest that TB prophylaxis and
treatment regimens be the same in KTRsas would be used in the local generalpopulation who require therapy (2D)
1432 We recommend monitoring CNI andmTORi [mTOR inhibitor] blood levels inpatients receiving rifampin (1C)14321 Consider substituting rifabu-
tin for rifampin to minimize
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KDOQI Commentary 17
ARTICLE IN PRESS
interactions with CNIs andmTORi (Not Graded)
144 CANDIDA PROPHYLAXIS1441 We suggest oral and esophageal Candida
prophylaxis with oral clotrimazole loz-enges nystatin or fluconazole for 1-3months after transplantation and for 1month after treatment with an antilympho-cyte antibody (2C)
DOQIRationale andCommentary
UrinaryTract Infection
Urinary tract infections (UTIs) after kidneyransplant are very common and account for aarge percentage of readmissions posttransplantTIs are common because of multiple factors
ncluding the disrupted anatomy of the urinaryract with a ureteroneocystotomy incompleteladder emptying because of diabetes or pros-atic hypertrophy and impaired immune re-ponses Prophylaxis of UTIs usually is under-aken with trimethoprim-sulfamethoxazole for 6onths posttransplant although infections often
ccur despite therapy because of the develop-ent of drug resistance Although native kidney
yelonephritis does not always require hospital-zation it is recommended that all KTRs withhis diagnosis be hospitalized because the graftysfunction that usually accompanies transplantyelonephritis requires aggressive investigationnd treatment Individuals with recurrent UTIsarrant evaluation with urologic assessment Pa-
ients with recurrent UTIs may benefit fromong-term suppressive therapy
Pneumocystic Pneumonia
We agree that Pneumocystis jirovecii pneumoniaPCP) prophylaxis is important for the first 3-6onths posttransplant (1421)After the first month
very-other-day dosing of trimethoprim-sulfame-hoxazole or atovaquone is believed to be adequaterophylaxis In cases in which neither of thesegents can be used an individual may be treatedrophylactically with inhaled pentamidine OurDOQI work group emphasized that patients whoevelop PCP should be transferred to the transplantenter promptly for management and adjustmentsn immunosuppression
Tuberculosis
Monitoring for latent tuberculosis has posed a
hallenge in the immunosuppressed population be-
ause of the unreliable nature of skin testing Newerechniques involving interferon release assays aremerging as the new gold standard for detection ofatent tuberculosis4445
CandidaProphylaxis
Oral candidiasis must be screened for usingral mucosa examination on follow-up visitsn KTRs This is especially true in the earlyosttransplant period when immunosuppres-ive medication dosage is the highest Wegree with these recommendations and empha-ize that if fluconazole is used there is aotential for serious drug interactions becausef cytochrome P-450 3A4 inhibition
SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
Improvement in short-term outcomes has not trans-lated into significant improvements in long-term out-comes in KTRs The lack of significant improvement inlong-term survival may be related to post-transplantcomplications Frequent posttransplant monitoring mayimprove long-term outcomes by decreasing chronic graftfailure or death with a functioning graft Our work groupconcurred with the recommendation and schedules ofroutine screening in monitoring kidney allograft functionafter kidney transplant with a low threshold for perform-ing kidney biopsy in cases of graft dysfunction or protein-uria Expert tissue processing and interpretation of trans-plant biopsy specimens by pathologists with transplantexperience are critical Regular surveillance of the pa-tientrsquos kidney function at the transplant center or in thenephrologistrsquos office offers an opportunity to enhancepatient adherence to medication diet and healthy life-style Although CKD in KTRs progresses more slowlythan CKD in other patients the work group agreed thatthe KDIGO guidelines on CKD should be followed inKTRs
Opportunistic infections are common in KTRs al-though advances in diagnosis and treatment have led toimproved survival in KTRs with infection It is nowstandard of care to use vaccinations in KTRs as long asthe vaccine does not contain live or attenuated virus Italso is routine to screen for or use prophylaxis to preventseveral posttransplant viral infections With few excep-tions (related to EBV and BK virus screening andhepatitis B vaccination posttransplant) we concurredwith KDIGO guidelines for vaccination screening and
treatment of infection posttransplant
KD
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ARTICLE IN PRESS
COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULAR
DISEASE
DIGORecommendations inChapter 15iabetesMellitus
151 Screening for New-Onset Diabetes after Transplan-tation1511 We recommend screening all nondia-
betic KTRs with fasting plasma glu-cose oral glucose tolerance testingandor HbA1c (1C) at leastbull weekly for 4 weeks (2D)bull every 3 months for 1 year (2D)bull and annually thereafter (2D)
1512 We suggest screening for NODAT withfasting glucose oral glucose tolerancetesting andor after starting or substan-tially increasing the dose of CNIsmTORi or corticosteroids (2D)
152 Managing NODAT or Diabetes Present at Trans-plantation1521 If NODAT develops consider modifying
the immunosuppressive drug regimen toreverse or ameliorate diabetes afterweighing the risk of rejection and otherpotential adverse effects (Not Graded)
1522 Consider targeting HbA1c 70-75and avoid targeting HbA1c 60 espe-cially if hypoglycemic reactions are com-mon (Not Graded)
1523 We suggest that in patients with diabetesaspirin (65-100 mgd) use for the primaryprevention of CVD be based on patientpreferences and values balancing the riskfor ischemic events to that of bleeding(2D)
DOQIRationale andCommentary
Diabetic Screening
We agree with screening for new-onset diabetesfter transplantation (NODAT) as outlined by theDIGO work group Definitions used are similar
o those of the American Diabetes AssociationADA) The greater frequency of testing initially isustified by the high risk of NODAT in the earlyosttransplant period however ongoing screenings required because the risk of the development ofODAT continues to increase over time4647 We
lso point out that prediabetic states (impairedasting glucose level and impaired glucose toler-nce) occur even more commonly than overt diabe-es48 and may be associated with metabolic syn-rome as well as with increased cardiovascular
ortality49-51 Potential implications of these predia-
etic states emphasize the importance of perform-ng blood tests under fasting conditions For pa-ients with fasting hyperglycemia an oral glucoseolerance test or hemoglobinA1c (HbA1c) test shoulde performed Although more cumbersome to per-orm data suggest that an oral glucose toleranceest is a more sensitive indicator of NODAT inyperglycemic KTRs52 This may allow earlieretection of overt diabetes and more prompt institu-ion of treatment
DiabetesManagement
Data supporting a substantial benefit in themelioration or reversal of NODAT using immu-osuppression modification in KTRs are veryimited There was consensus in our work grouphat considering the paucity of data for reversingODAT by changing immunosuppression and
he potential risk of an adverse outcome withuch a maneuver KDIGO suggestion 1521 couldot be supported Certainly if such a step waseing considered it should be done in conjunc-ion with the transplant center Targeting an HbA1c
evel of 7-75 and avoiding levels 6 isased on data showing increased cardiovascularvents with the lower HbA1c target5354
DIGORecommendations inChapter 16ypertensionDyslipidemias TobaccoUse andbesity
161 Hypertension1611 We recommend measuring blood pres-
sure at each clinic visit (1C)1612 We suggest maintaining blood pressure at
130 mm Hg systolic and 80 mm Hgdiastolic if 18 years of age and 90th
percentile for sex age and height if 18years old (2C)
1613 To treat hypertension (Not Graded)bull Use any class of antihypertensive
agentbull Monitor closely for adverse effects
and drug-drug interactions and whenurine protein excretion 1 gd for18 years old and 600 mgm224 hfor 18 years old consider an ACE-Ior an ARB as first-line therapy
162 Dyslipidemias (These recommendations are basedon KDOQI Dyslipidemia Guidelines and are thusnot graded)1621 Measure a complete lipid profile in all
adult (18 years old) and adolescent
(puberty to 18 years old) KTRs [Based on
K
2saaottgswdCctarahtAGccKie
KDOQI Commentary 19
ARTICLE IN PRESS
KDOQI Dyslipidemia Recommendation1]bull 2-3 months after transplantationbull 2-3 months after a change in treatment
or other conditions known to causedyslipidemias
bull at least annually thereafter1622 Evaluate KTRs with dyslipidemias for
secondary causes [Based on KDOQI Dys-lipidemia Recommendation 3]16221 For KTRs with fasting triglyc-
erides 500 mgdL (565mmolL) that cannot be cor-rected by removing an under-lying cause treat withbull Adults therapeutic lifestyle
changes and a triglyceride-lowering agent [Based onKDOQI Recommendation41]
bull Adolescents therapeutic life-style changes [Based onKDOQI Recommendation51]
16222 For KTRs with elevatedLDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)treat to reduce LDL-C to100 mgdL (259mmolL) [Based on KDOQIGuideline 42]
bull Adolescents If LDL-C130 mgdL (336 mmolL) treat to reduce LDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 52]
16223 For KTRs with normalLDL-C elevated triglyceridesand elevated non-HDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)fasting triglycerides 200mgdL (226 mmolL)and non-HDL-C 130mgdL (336 mmolL)treat to reduce non-HDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 43]
bull Adolescents If LDL-C130 mgdL (336 mmolL) fasting triglycerides200 mgdL (226 mmolL) and non-HDL-C 160mgdL (414 mmolL)treat to reduce non-HDL-C
to 160 mgdL (414 i
mmolL) [Based on KDOQIGuideline 53]
163 Tobacco Use1631 Screen and counsel all KTRs including
adolescents and children for tobacco useand record the results in the medicalrecord (Not Graded)bull Screen during initial transplant hospi-
talizationbull Screen at least annually thereafter
1632 Offer treatment to all patients who usetobacco (Not Graded)
164 Obesity1641 Assess obesity at each visit (Not Graded)
bull Measure height and weight at eachvisit in adults and children
bull Calculate BMI at each visitbull Measure waist circumference when
weight and physical appearance sug-gest obesity but BMI is 35 kgm2
1642 Offer a weight-reduction program to allobese KTRs (Not Graded)
DOQIRationale andCommentary
Hypertension
The KDIGO work group adapted the KDOQI004 recommendations for target blood pres-ure in KTRs55 Self measurement is useful inssessing response to therapy and enhancesdherence56 In general we agree that the classf antihypertensive agent does not matter inhe treatment of blood pressure elevation inhis population and that attention should beiven to potential side effects of antihyperten-ive agents as well as possible interactionsith the immunosuppressive regimen (eg non-ihydropyridine calcium channel blockers andNIs) In the absence of adequate randomizedontrolled trials it is not known whether angio-ensin-converting enzyme (ACE) inhibitors andngiotensin receptor blockers (ARBs) prolongecipient or allograft survival Some but notll retrospective studies suggest a benefitowever all these studies are limited by selec-ion bias5758 Although ACE inhibitors andRBs commonly lead to some decrease inFR treatment with these drugs should be
ontinued unless serum creatinine level in-reases by 25 to 30 in keeping withDOQI recommendations55 In KTRs receiv-
ng ACE inhibitors or ARBs it is important toducate patients to maintain adequate fluid
ntake during illness to prevent a prerenal
inwa
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ARTICLE IN PRESS
nsult to the allograft Similarly awareness isecessary when using diuretics in conjunctionith therapies that block the renin-angiotensin-
ldosterone-system59
Dyslipidemia
The KDIGO work group based their recom-endations for evaluation and treatment of
yperlipidemia on the KDOQI dyslipidemiauidelines for KTRs60 We agree with theseecommendations CNIs potentiate the toxicityf statins by slowing their metabolism throughhe cytochrome P-450 system This interactionccurs more commonly with cyclosporine61
han with tacrolimus Dyslipidemia especiallyypertriglyceridemia frequently complicatesTOR-inhibitor use and lipid-lowering therapy
s required in most patients using these agents
TobaccoUse
Not surprisingly tobacco use at the time ofransplant is associated with decreased patientnd graft survival as well as increased risk ofosttransplant cardiovascular disease (CVD)lthough the KDIGO work group recom-ends initial screening and intervention dur-
ng the hospitalization for transplant we be-ieve there may be benefit gained by startingounseling in the pretransplant period duringhe evaluation phase Unfortunately this doesot occur often because of time and personnelonstraints in transplant centers Ideally allransplant centers should have smoking-cessa-ion programs available to patients either in-ouse or through referral Ideally systemshould be created to continue to screen andonitor for smoking cessation at yearly inter-
als after transplant because there is a highate of relapse with this addiction As outlinedn KDIGO Table 253 although all pharmaco-ogic therapies for smoking cessation can besed in KTRs the starting dose of vareniclinehould be decreased in patients with GFR 30Lmin
Obesity
Obesity is an epidemic in the United Statesnd the proportion of obese kidney transplantandidates continues to grow In additioneight gain after transplant is very commonly
bserved Obesity in KTRs is associated with w
ncreased risks of wound complications de-ayed graft function acute rejection and NO-AT resulting in inferior patient and graftutcomes Attention to this potential complica-ion and counseling should be initiated duringhe pretransplant evaluation phase Informa-ion regarding pharmacologic therapies foreight loss in KTRs is not available and we
gree with the KDIGO work group that thera-eutic lifestyle measures should be encour-ged Data regarding steroid therapy with-rawal and weight gain are controversial Aecent double-blind randomized controlled trialxamining early steroid therapy withdrawalid not show a difference in weight gain at 5ears posttransplant compared with the cohortemaining on standard maintenance corticoste-oid therapy62
DIGORecommendations inChapter 17ardiovascularManagement
171 Consider managing CVD at least as intensively inKTRs as in the general population with appropri-ate diagnostic tests and treatments (Not Graded)
172 We suggest using aspirin (65-100 mgd) in allpatients with atherosclerotic CVD unless there arecontraindications (2B)
DOQIRationale andCommentary
Although outcomes are favorable comparedith remaining on the waiting list the risk of
ardiovascular mortality in KTRs is several-foldigher than observed in the general population63
specially in younger age groups and patientsith decreasing allograft function64 CVD is aajor cause of graft loss after the first post-
ransplant year In this context we strongly agreehat CVD should be managed in KTRs at least asntensively as in the general population Ideallyecreasing CVD risk in KTRs requires a multifac-ted and multidisciplinary approach Based onurrent practice models in the United States theransplant and nephrology community has notet been able to achieve these desirable goals65
his clearly deserves more attention becauseontrol of CVD has the potential to contributeore to long-term kidney graft survival than the
iscovery of newer drugs that decrease the ratef allograft rejection Our KDOQI working groupgreed with the use of low-dose aspirin in KTRs
ith evidence of atherosclerosis
Ko
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KDOQI Commentary 21
ARTICLE IN PRESS
SUMMARY OF COMMENTARY ONSECTION III CVD
COMMENTARY ON SECTION IV OF KDIGO
TRANSPLANT GUIDELINE MALIGNANCY
DIGORecommendations inChapter 18 Cancerf the Skin andLip
181 We recommend that KTRs especially thosewho have fair skin live in high sun-exposureclimates have occupations requiring sun expo-sure have had significant sun exposure as achild or have a history of skin cancer be toldthat their risk of skin and lip cancer is veryhigh (1C)
182 We recommend that KTRs minimize life-longsun exposure and use appropriate ultravioletlight blocking agents (1D)
183 We suggest that adult KTRs perform skin andlip self-examinations and report new lesions toa health-care provider (2D)
184 For adult KTRs we suggest that a qualified healthprofessional with experience in diagnosing skincancer perform annual skin and lip examinationon KTRs except possibly for KTRs with dark skinpigmentation (2D)
185 We suggest that patients with a history of skin orlip cancer or premalignant lesions be referred to andfollowed by a qualified health professional withexperience in diagnosing and treating skin cancer
With the decrease in acute rejection during the pastdecade in association with improved immunosuppres-sion regimens patient death now rivals chronic graftdysfunction as one of the leading causes of long-termgraft loss Because CVD is the most common cause ofpatient death in KTRs a concerted effort at minimizingrisk factors for heart disease likely will have as great oreven greater impact on optimizing patient and graftoutcomes than the discovery of new antirejection thera-pies CVD risk reduction strategies should include regularscreening for new-onset diabetes (using ADA-based defini-tions) in the posttransplant period in previously nondiabeticpatients good glycemic regulation for diabetic patients accord-ing to current ADA guidelines and lipid management andblood pressure control according to KDOQI recommenda-tions In addition promotion of a healthy lifestyle throughweight control exercise and smoking cessation should be acentral part of posttransplant counseling and care Whenimmunosuppression modification is being considered to miti-gate cardiovascular risk we recommend that this be inconjunction with the transplant center In summary we gener-ally concurred with the suggestions of the work group in thissection but based on current practice standards in the UnitedStateschallengesremainwith implementationof thisguideline
(2D) s
186 We suggest that patients with a history of skincancer be offered treatment with oral acitretin ifthere are no contraindications (2B)
DOQIRationale andCommentary
CounselingandSunscreen
We concur with recommendations 181 and82 because skin cancer is a major source oforbidity and sometimes mortality in KTRsarning patients at risk of the high danger of
kin cancer a 1C recommendation is reinforcedy a recent prospective case-control study ofrgan transplant recipients that showed that regu-ar use of broad-spectrum sunscreens that pro-ide UVA and UVB protection may prevent theevelopment of actinic keratosis invasive squa-ous cell carcinoma and to a lesser extent
asal cell carcinoma66 Most cancer-causing ra-iation is thought to come from the UVB spec-rum and newer broad-spectrum sunscreens pro-ide protection against UVA and UVB radiationounseling about sunscreen and the need for sunvoidance needs to be incorporated into routineffice visits although it may not always beuccessful In a recent study of KTRs in which1 of patients had been informed about theeed for sun protection only 46 used morehan a tube of sunscreen per year67
Dermatology Involvement
There is increased evidence to suggest thatpecialty dermatology clinics for organ trans-lant recipients improve outcome measures in-luding compliance with photoprotection andncreased awareness of skin cancer68 The re-ources required for these specialty clinics makemplementation difficult for community nephrol-gy groups that do not have direct access to aransplant center Transplant patients should bencouraged to have annual visits with their trans-lant center and if dermatology specialty clinicsre available attempt to coordinate a skin cancervaluation annually
UseofRetinoid-likeCompounds
There is a limited scientific basis for KDIGOuggestion recommendation 186 Although reti-oids now are used routinely in KTRs with aigh skin cancer burden our KDOQI work groupelieves that more data are needed before this
uggestion should be accepted as a guideline In
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ARTICLE IN PRESS
ow-immunologic-risk groups and particularlyifficult cases some data suggest that switchingrom CNI to sirolimus therapy may decrease thencidence of skin cancer69 however the riskersus benefit of this maneuver has not been welltudied
DIGORecommendations inChapter 19on-SkinMalignancies
191 Develop an individualized screening plan for eachKTR that takes into account the patientrsquos pastmedical and family history tobacco use compet-ing risks for death and the performance of thescreening methodology (Not Graded)
192 Screen for the following cancers as per localguidelines for the general population (Not Graded)Women cervical breast and colon cancer Menprostate and colon cancer
193 Obtain hepatic ultrasound and alpha feto-proteinevery 12 months in patients with compensatedcirrhosis (Not Graded) [See Recommendations1354 (HCV) and 1365 (HBV)]
DOQIRationale andCommentary
Screening
It is recognized that KTRs have a higher inci-ence of malignancy particularly those associatedith specific viral infections Although cancer
creening may have benefits in this higher riskopulation it should be reinforced that some meth-ds of screening have significant risks which shoulde considered on an individualized basis particu-arly in patients who have projected survival lesshan 5 years
Screening forCancer inPatientsWithHepatitis
Many patients who have underlying cirrhosisn the United States will be followed up by arofessional specializing in liver disease whoay provide additional insight into this cancer
creening recommendation Based on a recentuestionnaire of US gastroenterologists only 50creen patients for hepatocellular carcinoma70
herefore implementation of this guideline byS clinicians is unlikely to be widespread
DIGORecommendations inChapter 20anagingCancerwithReductionof
mmunosuppressiveMedication
201 We suggest consideration be given to reducingimmunosuppressive medications for KTRs with can-
cer (2C)
2011 Important factors for consideration in-clude (Not Graded)bull The stage of cancer at diagnosisbull Whether the cancer is likely to be
exacerbated by immunosuppressionbull The therapies available for the can-
cerbull Whether immunosuppressive medica-
tions interfere with ability to admin-ister the standard chemotherapy
202 For patients with Kaposi sarcoma we suggestusing mTORi along with a reduction in overallimmunosuppression (2C)
DOQIRationale andCommentary
Table 1 (Table 29 in the KDIGO report3 andxcerpted from Grulich et al71) lists cancershat are increased most in immunosuppressedTRs based on standardized incidence ratios
SIRs) which compare the incidence toatched populations Cancers with the highestIRs may be those most likely to respond to aecrease in immunosuppression Except foraposi sarcoma limited evidence is available
or a decrease in immunosuppression in theseettings A strategy to change immunosuppres-ion therapy must occur in consultation withhe transplant center Switching to sirolimusherapy and decreasing immunosuppression inatients who develop Kaposi sarcoma is basedn sound scientific rationale7273
SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
The incidence of cancer posttransplant is 2-20times higher than that in the general population andKDIGO guidelines have been written to outline stepsfor prevention and screening With few exceptions weagree with the recommendations as outlined Skincancer is common in US transplant patients andscreening and prevention are critical However imple-mentation of guidelines for doing so including theKDIGO guidelines is a challenge because of patientpreferences against the routine use of sunscreen aswell as time constraints during office visits Althoughmany posttransplant cancers are viral mediated andrelated to immunosuppression it is less clear how toalter immunosuppression after malignancy has oc-curred We agree that although age-specific screeningfor malignancy should be incorporated into care con-sideration must be given to the risk of screening inpatients with limited life spans (5 years) because of
comorbid conditions
KT
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
ommonPopu
i sarco-Hodgmelanise sm
sophaemia
estima standa10 c
ut esti
0 case
alized t
to guide treatment specifically before the
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
K
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ttlhA(o
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
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nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
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ar
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ml
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c2
p2
sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
ation Transpl Rev 200923191-19815 Abbud-Filho M Adams PL Alberuacute J et al A report
f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
cA
nrc
t2
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trN
hUt
Iwa
rl5
mi8
oe1
DA
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hm2
EA
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Bia et al30
ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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KDOQI Commentary 11
ARTICLE IN PRESS
in those with primary FSGS as theirprimary kidney disease (2D)
1052 We suggest high-dose corticosteroids andcyclophosphamide in patients with recur-rent ANCA-associated vasculitis or anti-GBM disease (2D)
1053 We suggest using an ACE-I [ACE inhibi-tor] or an ARB for patients with recurrentglomerulonephritis and proteinuria (2C)
1054 For KTRs with primary hyperoxaluriawe suggest appropriate measures to pre-vent oxalate deposition until plasma andurine oxalate levels are normal (2C)includingbull Pyridoxine (2C)bull High calcium and low oxalate diet
(2C)bull Increased oral fluid intake to enhance
urinary dilution of oxalate (2C)bull Potassium or sodium citrate to alkalin-
ize the urine (2C)bull Orthophosphate (2C)bull Magnesium oxide (2C)bull Intensive hemodialysis to remove ox-
alate (2C)
DOQIRationale andCommentary
Recurrent disease accounts for a substantialmount of graft loss after renal transplant It isifficult to assess the percentage of grafts lost toecurrent disease because many patients presentith end-stage renal disease without benefit of aiagnostic native renal biopsy The likelihood ofecurrent disease after transplant is dependent onhe disease with certain diseases at particularlyigh risk of recurrence28
Recurrent Focal SegmentalGlomerulosclerosis
We agree with recommendation 101 regard-ng frequent and regular screening for protein-ria in patients with primary focal segmentallomerulosclerosis (FSGS) as the cause of end-tage renal disease If the patient is still produc-ng urine at the time of transplant a preoperativerine protein-creatinine ratio can be a very help-ul baseline measure of proteinuria Early detec-ion of FSGS recurrence which can present withormal light microscopy but foot-process efface-ent on electron microscopy29 provides the best
pportunity for intervention and amelioration ofisease
IgANephropathy
Recurrence rates of immunoglobulin A (IgA)
ephropathy are variable We agree with recom- b
endation 102 for screening routinely for micro-ematuria Recurrent disease is confirmed with aenal allograft biopsy Histologic recurrence ofisease is much more common than is clinicalisease recurrence There is no proven therapyor treatment of recurrent disease30
MembranoproliferativeGlomerulonephritis
Recurrence of membranoproliferative glomer-lonephritis (MPGN) is common as high as 80ith MPGN type II (dense-deposit disease) Theost common cause of MPGN type I is hepatitisndashassociated immune complex formation Wegree with the proposed regularly scheduledcreening for microhematuria and proteinuria inecommendation 102 Patients with known hepa-itis Cndashassociated MPGN pretransplant also maye screened for cryoglobulins which are associ-ted with MPGN31
HemolyticUremic Syndrome
Hemolytic uremic syndrome (HUS) typicallys divided into diarrheal associated (D) andonndashdiarrheal associated (D) D disease oc-urs mostly in children and rarely recurs post-ransplant However D HUS is more commonn adults and can recur In HUS associated with aomplement abnormality such as factor H defi-iency or factor I mutation recurrence rates cane as high as 80 Screening for evidence ofecurrence allows for an earlier diagnosis whichill require biopsy in most cases and provides
n opportunity for earlier intervention There iso comment in the guideline regarding recur-ence of thrombotic thrombocytopenic purpuraut early detection of recurrence provides anpportunity for treatment with plasmapheresisnd intravenous immune globulin (IVIG)
BiopsyandTreatment
As stated kidney biopsy and interpretation bypathologist with expertise in transplant speci-en readings is critical in the diagnosis of dis-
ase recurrence Treatment for most recurrentisease in renal transplantation is based on aombination of case reports case cohorts andetrospective reviews Recurrent diseases post-ransplant are not common enough that random-zed controlled trials can be implemented there-ore most recommendations for treatment are
ased on a consensus of opinion Despite this we
at
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ARTICLE IN PRESS
gree in general with the recommendations de-ailed in 105
DIGORecommendations inChapter 11reventingDetecting andTreatingonadherence
111 Consider providing all KTRs and family memberswith education prevention and treatment mea-sures to minimize nonadherence to immunosup-pressive medications (Not Graded)
112 Consider providing KTRs at increased risk fornonadherence with increased levels of screeningfor nonadherence (Not Graded)
DOQIRationale andCommentary
Noncompliance or nonadherence to diet andedication is a common problem in KTRs Nonad-
erence to medication is associated with a high riskf acute rejection and allograft loss We agree thatarly efforts should be made to identify KTRs atncreased risk of nonadherence and that these pa-ients should be monitored closely Prevention iden-ification and treatment of nonadherence are inte-ral to the monitoring of kidney allograft functionnd long-term care of KTRs Certain subgroup ofTRs younger patients African Americans and
hose with financial hardships have an enhancedisk of nonadherence3233
In addition to identifying patients at risk it ismportant to have a system for addressing patientonadherence This requires coordinated efforts ofocial workers transplant coordinators financialounselors pharmacists primary nephrologists andhe patientrsquos family34 A combination of educa-ional behavioral and social support interventionsrovides the best results Because there is no per-ect measure of adherence consideration should beiven to multiple approaches for adherence moni-oring Similar team approaches also are importantn other areas requiring adherence such as dietxercise tobacco alcohol and drug use
DIGORecommendations inChapter 12accination
121 We recommend giving all KTRs approvedinactivated vaccines according to recommendedschedules for the general population except forHBV vaccination (1D)1211 We suggest HBV vaccination (ideally
prior to transplantation) and HBsAb titers6-12 weeks after completing the vaccina-
tion series (2D) h
12111 We suggest annual HBsAb[antibody to hepatitis B sur-face antigen] titers (2D)
12112 We suggest revaccination ifthe antibody titer falls below10 mIUmL (2D)
122 We suggest avoiding live vaccines in KTRs (2C)123 We suggest avoiding vaccinations except influ-
enza vaccination in the first 6 months followingkidney transplantation (2C)1231 We suggest resuming immunizations once
patients are receiving minimal mainte-nance doses of immunosuppressive medi-cations (2C)
1232 We recommend giving all KTRs whoare at least 1-month post-transplantinfluenza vaccination prior to the onsetof the annual influenza season regard-less of status of immunosuppression(1C)
124 We suggest giving the following vaccines to KTRswho due to age direct exposure residence ortravel to endemic areas or other epidemiologicalrisk factors are at increased risk for the specificdiseasesbull rabies (2D)bull tick-borne meningoencephalitis (2D)bull Japanese B encephalitismdashinactivated (2D)bull Meningococcus (2D)bull Pneumococcus (2D)bull Salmonella typhimdashinactivated (2D)1241 Consult an infectious disease specialist a
travel clinic or public health official forguidance on whether specific cases war-rant these vaccinations (Not Graded)
DOQIRationale andCommentary
KTRs are at particular risk of viral infectionsecause of the preferential suppression of T lympho-ytes by both induction and maintenance immuno-uppression The risk and consequence of develop-ng a viral infection warrant use of selected vaccineshe suggestions regarding which vaccines are safend which are contraindicated are based on whetherhe vaccine contains live or killed virus Live virusaccines are contraindicated in immunosuppressedTRs The KDIGO recommendations for vaccina-
ions agree with updated guidelines recently pub-ished by the AST35 Specific comments on theDIGO suggestions regarding vaccinations are
isted in the following sections
Hepatitis B
The work group did not concur with KDIGOuggestion 1211 Neither revaccination against
epatitis after transplant nor following up hepa-
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KDOQI Commentary 13
ARTICLE IN PRESS
itis B antibody titers annually is a commonractice in the United States Hepatitis B is nots prevalent in the United States as in otherarts of the world and evidence supportingcreening in all patients posttransplant is lack-ng However screening for seroconversion inatients at risk (receiving a hepatitis B corentibodyndashpositive kidney) is appropriate Theseatients may benefit from lamivudine or ente-avir therapy36
LiveVaccineandTimingofVaccine
There is no particular reason for a 6-monthag between transplant and vaccination Theheory is that vaccines are less likely to beffective in the period when immunosuppres-ion is high In the United States most individu-ls are on their baseline maintenance immuno-uppression therapy by 3 months posttransplantecisions regarding the timing of vaccines areade based on immunosuppression exposure
nd risk of infection Recipients also shouldvoid intimate contact with individuals whoave received live vaccines37 This includesvoiding close contact with children who haveeceived oral polio vaccine for 3 weeks anday include close contact with adults receiv-
ng the attenuated varicella vaccine to preventoster Immunosuppressed individuals are ad-ised to avoid contact for 7 days with individu-ls who have received live virus nasal spraysor influenza We concur with the recommenda-ion for flu vaccine but common practice inhe United States is to wait 3-6 months afterransplant before it is administered
DIGORecommendations inChapter 13 Viraliseases
131 BK POLYOMA VIRUS1311 We suggest screening all KTRs for BKV
with quantitative plasma NAT (2C) atleastbull monthly for the first 3-6 months after
transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull whenever there is an unexplained rise
in serum creatinine (2D)bull and after treatment for acute rejection
(2D)1312 We suggest reducing immunosuppressive
medications when BKV plasma NAT is
persistently greater than 10 000 cop-iesmL (107 copiesL) (2D)
132 CYTOMEGALOVIRUS1321 CMV prophylaxis We recommend that
KTRs (except when donor and recipi-ent both have negative CMV serolo-gies) receive chemoprophylaxis forCMV infection with oral ganciclovir orvalganciclovir for at least 3 monthsafter transplantation (1B) and for 6weeks after treatment with a T-cellndashdepleting antibody (1C)
1322 In patients with CMV disease we suggestweekly monitoring of CMV by NAT orpp65 antigenemia (2D)
1323 CMV treatment13231 We recommend that all pa-
tients with serious (includ-ing most patients with tissueinvasive) CMV disease betreated with intravenousganciclovir (1D)
13232 We recommend that CMVdisease in adult KTRs that isnot serious (eg episodes thatare associated with mildclinical symptoms) be treatedwith either intravenous gan-ciclovir or oral valganciclo-vir (1D)
13233 We recommend that allCMV disease in pediatricKTRs be treated with intra-venous ganciclovir (1D)
13234 We suggest continuing therapyuntil CMV is no longer detect-able by plasma NAT or pp65antigenemia (2D)
1324 We suggest reducing immunosuppressivemedication in life-threatening CMV dis-ease and CMV disease that persists in theface of treatment until CMV disease hasresolved (2D)13241 We suggest monitoring graft
function closely during CMVdisease (2D)
133 EPSTEIN-BARR VIRUS AND POST-TRANS-PLANT LYMPHOPROLIFERATIVE DISEASE1331 We suggest monitoring high-risk (donor
EBV seropositiverecipient seronegative)KTRs for EBV by NAT (2C)bull once in the first week after transplanta-
tion (2D)bull then at least monthly for the first 3-6
months after transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull and additionally after treatment for
acute rejection (2D)
Bia et al14
ARTICLE IN PRESS
1332 We suggest that EBV-seronegative pa-tients with an increasing EBV load haveimmunosuppressive medication reduced(2D)
1333 We recommend that patients with EBVdisease including PTLD have a reduc-tion or cessation of immunosuppres-sive medication (1C)
134 HERPES SIMPLEX VIRUS 1 2 AND VARI-CELLA ZOSTER VIRUS1341 We recommend that KTRs who de-
velop a superficial HSV 1 2 infectionbe treated (1B) with an appropriateoral antiviral agent (eg acyclovir vala-cyclovir or famciclovir) until all le-sions have resolved (1D)
1342 We recommend that KTRs with sys-temic HSV 1 2 infection be treated(1B) with intravenous acyclovir and areduction in immunosuppressive medi-cation (1D)13421 We recommend that intrave-
nous acyclovir continue un-til the patient has a clinicalresponse (1B) then switch toan appropriate oral antiviralagent (eg acyclovir valacy-clovir or famciclovir) to com-plete a total treatment durationof 14-21 days (2D)
1343 We suggest using a prophylactic antiviralagent for KTRs experiencing frequentrecurrences of HSV 12 infection (2D)
1344 We recommend that primary VZV infec-tion (chicken pox) in KTRs be treated(1C) with either intravenous or oral acy-clovir or valacyclovir and a temporaryreduction in amount of immunosuppres-sive medication (2D)
135 HEPATITIS C VIRUS1351 We suggest that HCV-infected KTRs be
treated only when the benefits of treat-ment clearly outweigh the risk of allo-graft rejection due to interferon-basedtherapy (eg fibrosing cholestatic hepati-tis life-threatening vasculitis) (2D)[Based on KDIGO Hepatitis C Recom-mendation 215]
1352 We suggest monotherapy with standardinterferon for HCV-infected KTRs inwhom the benefits of antiviral treatmentclearly outweigh the risks (2D) [Basedon KDIGO Hepatitis C Recommenda-tions 224 and 442]
1353 We suggest that all conventional currentinduction and maintenance immunosup-pressive regimens can be used in HCVinfected patients (2D) [Based on KDIGO
Hepatitis C Recommendation 43]
1354 Measure ALT in HCV-infected patientsmonthly for the first 6 months and every3-6 months thereafter Perform imagingannually to look for cirrhosis and hepato-cellular carcinoma (Not Graded) [Basedon KDIGO Hepatitis C Recommendation441] (See Recommendation 193)
1355 Test HCV-infected patients at least every3-6 months for proteinuria (Not Graded)[Based on KDIGO Hepatitis C Recom-mendation 444]13551 For patients who develop new
onset proteinuria (either urineproteincreatinine ratio 1 or24-hour urine protein 1 g ontwo or more occasions) per-form an allograft biopsy withimmunofluorescence and elec-tron microscopy (Not Graded)[Based on KDIGO Hepatitis CRecommendation 444]
1356 We suggest that patients with HCV asso-ciated glomerulopathy not receive inter-feron (2D) [Based on KDIGO HepatitisC Recommendation 445]
136 HEPATITIS B VIRUS1361 We suggest that any currently available
induction and maintenance immunosup-pressive medication can be used in HBV-infected KTRs (2D)
1362 We suggest that interferon treatmentshould generally be avoided in HBVinfected KTRs (2C)
1363 We suggest that all HBsAg-positive KTRsreceive prophylaxis with tenofovir ente-cavir or lamivudine (2B)13631 Tenofovir or entecavir are pref-
erable to lamivudine to mini-mize development of potentialdrug resistance unless medica-tion cost requires that lami-vudinebe used (Not Graded)
13632 During therapy with antivi-rals measure HBV DNA andALT levels every 3 months tomonitor efficacy and to detectdrug resistance (Not Graded)
1364 We suggest treatment with adefovir ortenofovir for KTRs with lamivudine resis-tance (5 log10 copiesmL rebound ofHBV-DNA) (2D)
1365 Screen HBsAg-positive patients with cir-rhosis for hepatocellular carcinoma every12 months with liver ultrasound andalpha feto-protein (Not Graded) (SeeRecommendation 193)
1366 We suggest that patients who are negativefor HBsAg and have HBsAb titer 10mIUmL receive booster vaccination to
raise the titer to 100 mIUmL (2D)
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KDOQI Commentary 15
ARTICLE IN PRESS
137 HUMAN IMMUNODEFICIENCY VIRUS1371 If not already done screen for HIV
infection (Not Graded)1372 To determine antiretroviral therapy refer
HIV-infected KTRs to an HIV specialistwho should pay special attention to drugndashdrug interactions and appropriate dosingof medications (Not Graded)
DOQIRationale andCommentary
Viral infections are particularly problematic inransplant recipients because of the preferentialnhibition of T-lymphocyte function by both induc-ion and maintenance immunosuppression Use ofnduction immunosuppression with lymphocyte-epleting agents (thymoglobulin or alemtuzumab)s associated with a greater risk of viral infectionosttransplant In general the greater the cumula-ive exposure to immunosuppression the greaterhe risk of infectious complications The presenta-ion of viral infections can be asymptomatic vaguend nonspecific or life-threatening acute illnessany viral infections seen in KTRs are rarely seen
n immunocompetent patients and therefore do notnter into the differential diagnosis for physiciansnfamiliar with transplant recipients Close commu-ication with the transplant center is crucial inaring for the transplant population Early detectionnd institution of therapy provide the best chanceor viral eradication
BKVirus
Although the work group agreed with KDIGOuggestions for BK virus screening posttransplante did not think it was practical to require screen-
ng exclusively with quantitative plasma nucleiccid testing (NAT) because many US centers usenitial urinary screening and then test plasma onlyf urine screening results are positive Howeverhere is no disagreement that some type of screen-ng for BK virus is critical to avoid BK nephropa-hy for which there is no specific treatment when its established Complicating screening for BK vi-us is the variability in results between laboratoriesnd uncertainty about the level of viremia thathould trigger a response to decrease in immunosup-ression In the presence of viremia and increase inerum creatinine level a renal allograft biopsy isndicated to confirm the presence of BK nephropa-
hy Because BK viremia and viruria certainly can b
e detected beyond the first year it is not clear howong screening should be continued posttransplantlthough most centers screen for the first year onlyngoing clinical trials are exploring effective treat-ent for BK nephropathy3839 Decisions about
ecreases in immunosuppression currently theainstay of BK viremia management always
hould be made in consultation with the transplantenter
Cytomegalovirus
KDIGO recommendation 1321 regarding cyto-egalovirus (CMV) prophylaxis is reasonable and
pplicable to the US population Universal prophy-axis for CMV now is recommended over initiatingre-emptive treatment after CMV develops40 Aajor concern for US patients is the cost of CMV
rophylaxis with oral valgancyclovir Leukopeniaan be observed in patients using mycophenolatereparations when prophylaxis with valgancyclo-ir is used Screening for CMV is best performedsing NAT methods (1322) CMV antigenemiassays are still in use in many facilities but are nots sensitive as PCR assays41 There is no utility inhecking for serologic response to CMV with IgGr IgM titers posttransplant because the immuneesponse is not predictable Patients with CMVisease should be cared for by clinicians familiarith treating this disease It is recommended that
reatment be continued until viral load is undetect-ble followed by prophylactic doses of valgancy-lovir for an additional 3 months35
Epstein-BarrVirus
Current practice regarding EBV screening variesmong centers in the United States and many doot routinely screen for EBV posttransplant evenn recipient-negative donor-positive cases In con-rast to KDIGO recommendation 1311 routineBV screening is not recommended in AST infec-
ious disease guidelines35 In many centers EBVcreening is reserved for children who are muchore commonly EBV negative pretransplant than
dults EBV-induced posttransplant lymphoprolif-rative disorder (PTLD) affects many more pediat-ic than adult KTRs If screening is someday to beoutinely implemented in US centers details regard-ng the best method of screening and levels ofiremia above which a clinical intervention should
e triggered need to be better defined
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ARTICLE IN PRESS
HerpesandVaricella
Systemic herpesvirus infections can be lifehreatening in transplant recipients and should bereated aggressively with intravenous antiviralgents as described in the KDIGO recommenda-ions Less aggressive cutaneous infection can bereated with oral antiviral agents as outlined inhe KDIGO guidelines
Varicella exposure is particularly concerning inransplant recipients The work group disputes theecommended dosing of acyclovir for varicellaxposure Acyclovir at a dose of 10 mgkg or about00 mg 4 times daily of oral acyclovir would betandard dosing We agree with the use of varicellammune globulin and emphasize the need to avoidhe varicella vaccine because it is a live virushould a transplant recipient develop a systemicaricella infection hospitalization and high-dosentravenous acyclovir therapy are warranted
Hepatitis C
Hepatitis C management posttransplant is ahallenge The KDIGO guidelines cited hereere based on the recently published KDIGOuideline for hepatitis C in CKD4 Hepatitis Cypically is not treated posttransplant because ofhe risk (50) of rejection precipitated bynterferon therapy particularly in US KTRs inhom hepatitis C commonly is genotype 1 which
s more resistant to treatment with interferon42
owever should hepatitis Cndashrelated glomerulo-ephritis develop the risk-benefit ratio may fa-or treatment in selected patients Such decisionslways should be made in consultation withepatology and infectious disease experts andhe transplant center Monitoring liver enzymeevels specifically alanine aminotransferaseALT) may reflect a change in hepatitis activityut monitoring hepatitis C viral load is not recom-ended because it does not seem to correlateith outcome Annual monitoring for hepatocel-
ular carcinoma using -fetoprotein and imagings encouraged but not often practiced
Hepatitis B
KDIGO recommendations for hepatitis B areeasonable and currently are followed in mostS centers except for recommendation 1366
see previous recommendation under vaccina-ions) KTRs with hepatitis C or hepatitis B also
hould be followed up by a hepatologist
Human ImmunodeficiencyVirus
Human immunodeficiency virus (HIV)-posi-ive individuals are now acceptable for transplantf CD4 count is 200 cellsL and viral loadVL) is undetectable3543 Transplant should beerformed at centers with expertise in managingIV-positive individuals and care should be co-rdinated carefully with HIV specialists Somentiretroviral agents in particular the proteasenhibitors have potentially serious drug interac-ions with immunosuppressive agents35
DIGORecommendations inChapter 14Othernfections
141 URINARY TRACT INFECTION1411 We suggest that all KTRs receive UTI
prophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 monthsafter transplantation (2B)
1412 For allograft pyelonephritis we suggestinitial hospitalization and treatment withintravenous antibiotics (2C)
142 PNEUMOCYSTIS JIROVECII PNEUMONIA1421 We recommend that all KTRs receive
PCP prophylaxis with daily tri-methoprimndashsulfamethoxazole for 3-6months after transplantation (1B)
1422 We suggest that all KTRs receive PCPprophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 weeksduring and after treatment for acute rejec-tion (2C)
1423 We recommend that KTRs with PCPdiagnosed by bronchial alveolar lavageandor lung biopsy be treated withhigh-dose intravenous trimethoprimndashsulfamethoxazole corticosteroids anda reduction in immunosuppressivemedication (1C)
1424 We recommend treatment with cortico-steroids for KTRs with moderate tosevere PCP (as defined by PaO2 lt70mm Hg in room air or an alveolargradient of gt35 mm Hg) (1C)
143 TUBERCULOSIS1431 We suggest that TB prophylaxis and
treatment regimens be the same in KTRsas would be used in the local generalpopulation who require therapy (2D)
1432 We recommend monitoring CNI andmTORi [mTOR inhibitor] blood levels inpatients receiving rifampin (1C)14321 Consider substituting rifabu-
tin for rifampin to minimize
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KDOQI Commentary 17
ARTICLE IN PRESS
interactions with CNIs andmTORi (Not Graded)
144 CANDIDA PROPHYLAXIS1441 We suggest oral and esophageal Candida
prophylaxis with oral clotrimazole loz-enges nystatin or fluconazole for 1-3months after transplantation and for 1month after treatment with an antilympho-cyte antibody (2C)
DOQIRationale andCommentary
UrinaryTract Infection
Urinary tract infections (UTIs) after kidneyransplant are very common and account for aarge percentage of readmissions posttransplantTIs are common because of multiple factors
ncluding the disrupted anatomy of the urinaryract with a ureteroneocystotomy incompleteladder emptying because of diabetes or pros-atic hypertrophy and impaired immune re-ponses Prophylaxis of UTIs usually is under-aken with trimethoprim-sulfamethoxazole for 6onths posttransplant although infections often
ccur despite therapy because of the develop-ent of drug resistance Although native kidney
yelonephritis does not always require hospital-zation it is recommended that all KTRs withhis diagnosis be hospitalized because the graftysfunction that usually accompanies transplantyelonephritis requires aggressive investigationnd treatment Individuals with recurrent UTIsarrant evaluation with urologic assessment Pa-
ients with recurrent UTIs may benefit fromong-term suppressive therapy
Pneumocystic Pneumonia
We agree that Pneumocystis jirovecii pneumoniaPCP) prophylaxis is important for the first 3-6onths posttransplant (1421)After the first month
very-other-day dosing of trimethoprim-sulfame-hoxazole or atovaquone is believed to be adequaterophylaxis In cases in which neither of thesegents can be used an individual may be treatedrophylactically with inhaled pentamidine OurDOQI work group emphasized that patients whoevelop PCP should be transferred to the transplantenter promptly for management and adjustmentsn immunosuppression
Tuberculosis
Monitoring for latent tuberculosis has posed a
hallenge in the immunosuppressed population be-
ause of the unreliable nature of skin testing Newerechniques involving interferon release assays aremerging as the new gold standard for detection ofatent tuberculosis4445
CandidaProphylaxis
Oral candidiasis must be screened for usingral mucosa examination on follow-up visitsn KTRs This is especially true in the earlyosttransplant period when immunosuppres-ive medication dosage is the highest Wegree with these recommendations and empha-ize that if fluconazole is used there is aotential for serious drug interactions becausef cytochrome P-450 3A4 inhibition
SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
Improvement in short-term outcomes has not trans-lated into significant improvements in long-term out-comes in KTRs The lack of significant improvement inlong-term survival may be related to post-transplantcomplications Frequent posttransplant monitoring mayimprove long-term outcomes by decreasing chronic graftfailure or death with a functioning graft Our work groupconcurred with the recommendation and schedules ofroutine screening in monitoring kidney allograft functionafter kidney transplant with a low threshold for perform-ing kidney biopsy in cases of graft dysfunction or protein-uria Expert tissue processing and interpretation of trans-plant biopsy specimens by pathologists with transplantexperience are critical Regular surveillance of the pa-tientrsquos kidney function at the transplant center or in thenephrologistrsquos office offers an opportunity to enhancepatient adherence to medication diet and healthy life-style Although CKD in KTRs progresses more slowlythan CKD in other patients the work group agreed thatthe KDIGO guidelines on CKD should be followed inKTRs
Opportunistic infections are common in KTRs al-though advances in diagnosis and treatment have led toimproved survival in KTRs with infection It is nowstandard of care to use vaccinations in KTRs as long asthe vaccine does not contain live or attenuated virus Italso is routine to screen for or use prophylaxis to preventseveral posttransplant viral infections With few excep-tions (related to EBV and BK virus screening andhepatitis B vaccination posttransplant) we concurredwith KDIGO guidelines for vaccination screening and
treatment of infection posttransplant
KD
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Bia et al18
ARTICLE IN PRESS
COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULAR
DISEASE
DIGORecommendations inChapter 15iabetesMellitus
151 Screening for New-Onset Diabetes after Transplan-tation1511 We recommend screening all nondia-
betic KTRs with fasting plasma glu-cose oral glucose tolerance testingandor HbA1c (1C) at leastbull weekly for 4 weeks (2D)bull every 3 months for 1 year (2D)bull and annually thereafter (2D)
1512 We suggest screening for NODAT withfasting glucose oral glucose tolerancetesting andor after starting or substan-tially increasing the dose of CNIsmTORi or corticosteroids (2D)
152 Managing NODAT or Diabetes Present at Trans-plantation1521 If NODAT develops consider modifying
the immunosuppressive drug regimen toreverse or ameliorate diabetes afterweighing the risk of rejection and otherpotential adverse effects (Not Graded)
1522 Consider targeting HbA1c 70-75and avoid targeting HbA1c 60 espe-cially if hypoglycemic reactions are com-mon (Not Graded)
1523 We suggest that in patients with diabetesaspirin (65-100 mgd) use for the primaryprevention of CVD be based on patientpreferences and values balancing the riskfor ischemic events to that of bleeding(2D)
DOQIRationale andCommentary
Diabetic Screening
We agree with screening for new-onset diabetesfter transplantation (NODAT) as outlined by theDIGO work group Definitions used are similar
o those of the American Diabetes AssociationADA) The greater frequency of testing initially isustified by the high risk of NODAT in the earlyosttransplant period however ongoing screenings required because the risk of the development ofODAT continues to increase over time4647 We
lso point out that prediabetic states (impairedasting glucose level and impaired glucose toler-nce) occur even more commonly than overt diabe-es48 and may be associated with metabolic syn-rome as well as with increased cardiovascular
ortality49-51 Potential implications of these predia-
etic states emphasize the importance of perform-ng blood tests under fasting conditions For pa-ients with fasting hyperglycemia an oral glucoseolerance test or hemoglobinA1c (HbA1c) test shoulde performed Although more cumbersome to per-orm data suggest that an oral glucose toleranceest is a more sensitive indicator of NODAT inyperglycemic KTRs52 This may allow earlieretection of overt diabetes and more prompt institu-ion of treatment
DiabetesManagement
Data supporting a substantial benefit in themelioration or reversal of NODAT using immu-osuppression modification in KTRs are veryimited There was consensus in our work grouphat considering the paucity of data for reversingODAT by changing immunosuppression and
he potential risk of an adverse outcome withuch a maneuver KDIGO suggestion 1521 couldot be supported Certainly if such a step waseing considered it should be done in conjunc-ion with the transplant center Targeting an HbA1c
evel of 7-75 and avoiding levels 6 isased on data showing increased cardiovascularvents with the lower HbA1c target5354
DIGORecommendations inChapter 16ypertensionDyslipidemias TobaccoUse andbesity
161 Hypertension1611 We recommend measuring blood pres-
sure at each clinic visit (1C)1612 We suggest maintaining blood pressure at
130 mm Hg systolic and 80 mm Hgdiastolic if 18 years of age and 90th
percentile for sex age and height if 18years old (2C)
1613 To treat hypertension (Not Graded)bull Use any class of antihypertensive
agentbull Monitor closely for adverse effects
and drug-drug interactions and whenurine protein excretion 1 gd for18 years old and 600 mgm224 hfor 18 years old consider an ACE-Ior an ARB as first-line therapy
162 Dyslipidemias (These recommendations are basedon KDOQI Dyslipidemia Guidelines and are thusnot graded)1621 Measure a complete lipid profile in all
adult (18 years old) and adolescent
(puberty to 18 years old) KTRs [Based on
K
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KDOQI Commentary 19
ARTICLE IN PRESS
KDOQI Dyslipidemia Recommendation1]bull 2-3 months after transplantationbull 2-3 months after a change in treatment
or other conditions known to causedyslipidemias
bull at least annually thereafter1622 Evaluate KTRs with dyslipidemias for
secondary causes [Based on KDOQI Dys-lipidemia Recommendation 3]16221 For KTRs with fasting triglyc-
erides 500 mgdL (565mmolL) that cannot be cor-rected by removing an under-lying cause treat withbull Adults therapeutic lifestyle
changes and a triglyceride-lowering agent [Based onKDOQI Recommendation41]
bull Adolescents therapeutic life-style changes [Based onKDOQI Recommendation51]
16222 For KTRs with elevatedLDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)treat to reduce LDL-C to100 mgdL (259mmolL) [Based on KDOQIGuideline 42]
bull Adolescents If LDL-C130 mgdL (336 mmolL) treat to reduce LDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 52]
16223 For KTRs with normalLDL-C elevated triglyceridesand elevated non-HDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)fasting triglycerides 200mgdL (226 mmolL)and non-HDL-C 130mgdL (336 mmolL)treat to reduce non-HDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 43]
bull Adolescents If LDL-C130 mgdL (336 mmolL) fasting triglycerides200 mgdL (226 mmolL) and non-HDL-C 160mgdL (414 mmolL)treat to reduce non-HDL-C
to 160 mgdL (414 i
mmolL) [Based on KDOQIGuideline 53]
163 Tobacco Use1631 Screen and counsel all KTRs including
adolescents and children for tobacco useand record the results in the medicalrecord (Not Graded)bull Screen during initial transplant hospi-
talizationbull Screen at least annually thereafter
1632 Offer treatment to all patients who usetobacco (Not Graded)
164 Obesity1641 Assess obesity at each visit (Not Graded)
bull Measure height and weight at eachvisit in adults and children
bull Calculate BMI at each visitbull Measure waist circumference when
weight and physical appearance sug-gest obesity but BMI is 35 kgm2
1642 Offer a weight-reduction program to allobese KTRs (Not Graded)
DOQIRationale andCommentary
Hypertension
The KDIGO work group adapted the KDOQI004 recommendations for target blood pres-ure in KTRs55 Self measurement is useful inssessing response to therapy and enhancesdherence56 In general we agree that the classf antihypertensive agent does not matter inhe treatment of blood pressure elevation inhis population and that attention should beiven to potential side effects of antihyperten-ive agents as well as possible interactionsith the immunosuppressive regimen (eg non-ihydropyridine calcium channel blockers andNIs) In the absence of adequate randomizedontrolled trials it is not known whether angio-ensin-converting enzyme (ACE) inhibitors andngiotensin receptor blockers (ARBs) prolongecipient or allograft survival Some but notll retrospective studies suggest a benefitowever all these studies are limited by selec-ion bias5758 Although ACE inhibitors andRBs commonly lead to some decrease inFR treatment with these drugs should be
ontinued unless serum creatinine level in-reases by 25 to 30 in keeping withDOQI recommendations55 In KTRs receiv-
ng ACE inhibitors or ARBs it is important toducate patients to maintain adequate fluid
ntake during illness to prevent a prerenal
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ARTICLE IN PRESS
nsult to the allograft Similarly awareness isecessary when using diuretics in conjunctionith therapies that block the renin-angiotensin-
ldosterone-system59
Dyslipidemia
The KDIGO work group based their recom-endations for evaluation and treatment of
yperlipidemia on the KDOQI dyslipidemiauidelines for KTRs60 We agree with theseecommendations CNIs potentiate the toxicityf statins by slowing their metabolism throughhe cytochrome P-450 system This interactionccurs more commonly with cyclosporine61
han with tacrolimus Dyslipidemia especiallyypertriglyceridemia frequently complicatesTOR-inhibitor use and lipid-lowering therapy
s required in most patients using these agents
TobaccoUse
Not surprisingly tobacco use at the time ofransplant is associated with decreased patientnd graft survival as well as increased risk ofosttransplant cardiovascular disease (CVD)lthough the KDIGO work group recom-ends initial screening and intervention dur-
ng the hospitalization for transplant we be-ieve there may be benefit gained by startingounseling in the pretransplant period duringhe evaluation phase Unfortunately this doesot occur often because of time and personnelonstraints in transplant centers Ideally allransplant centers should have smoking-cessa-ion programs available to patients either in-ouse or through referral Ideally systemshould be created to continue to screen andonitor for smoking cessation at yearly inter-
als after transplant because there is a highate of relapse with this addiction As outlinedn KDIGO Table 253 although all pharmaco-ogic therapies for smoking cessation can besed in KTRs the starting dose of vareniclinehould be decreased in patients with GFR 30Lmin
Obesity
Obesity is an epidemic in the United Statesnd the proportion of obese kidney transplantandidates continues to grow In additioneight gain after transplant is very commonly
bserved Obesity in KTRs is associated with w
ncreased risks of wound complications de-ayed graft function acute rejection and NO-AT resulting in inferior patient and graftutcomes Attention to this potential complica-ion and counseling should be initiated duringhe pretransplant evaluation phase Informa-ion regarding pharmacologic therapies foreight loss in KTRs is not available and we
gree with the KDIGO work group that thera-eutic lifestyle measures should be encour-ged Data regarding steroid therapy with-rawal and weight gain are controversial Aecent double-blind randomized controlled trialxamining early steroid therapy withdrawalid not show a difference in weight gain at 5ears posttransplant compared with the cohortemaining on standard maintenance corticoste-oid therapy62
DIGORecommendations inChapter 17ardiovascularManagement
171 Consider managing CVD at least as intensively inKTRs as in the general population with appropri-ate diagnostic tests and treatments (Not Graded)
172 We suggest using aspirin (65-100 mgd) in allpatients with atherosclerotic CVD unless there arecontraindications (2B)
DOQIRationale andCommentary
Although outcomes are favorable comparedith remaining on the waiting list the risk of
ardiovascular mortality in KTRs is several-foldigher than observed in the general population63
specially in younger age groups and patientsith decreasing allograft function64 CVD is aajor cause of graft loss after the first post-
ransplant year In this context we strongly agreehat CVD should be managed in KTRs at least asntensively as in the general population Ideallyecreasing CVD risk in KTRs requires a multifac-ted and multidisciplinary approach Based onurrent practice models in the United States theransplant and nephrology community has notet been able to achieve these desirable goals65
his clearly deserves more attention becauseontrol of CVD has the potential to contributeore to long-term kidney graft survival than the
iscovery of newer drugs that decrease the ratef allograft rejection Our KDOQI working groupgreed with the use of low-dose aspirin in KTRs
ith evidence of atherosclerosis
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KDOQI Commentary 21
ARTICLE IN PRESS
SUMMARY OF COMMENTARY ONSECTION III CVD
COMMENTARY ON SECTION IV OF KDIGO
TRANSPLANT GUIDELINE MALIGNANCY
DIGORecommendations inChapter 18 Cancerf the Skin andLip
181 We recommend that KTRs especially thosewho have fair skin live in high sun-exposureclimates have occupations requiring sun expo-sure have had significant sun exposure as achild or have a history of skin cancer be toldthat their risk of skin and lip cancer is veryhigh (1C)
182 We recommend that KTRs minimize life-longsun exposure and use appropriate ultravioletlight blocking agents (1D)
183 We suggest that adult KTRs perform skin andlip self-examinations and report new lesions toa health-care provider (2D)
184 For adult KTRs we suggest that a qualified healthprofessional with experience in diagnosing skincancer perform annual skin and lip examinationon KTRs except possibly for KTRs with dark skinpigmentation (2D)
185 We suggest that patients with a history of skin orlip cancer or premalignant lesions be referred to andfollowed by a qualified health professional withexperience in diagnosing and treating skin cancer
With the decrease in acute rejection during the pastdecade in association with improved immunosuppres-sion regimens patient death now rivals chronic graftdysfunction as one of the leading causes of long-termgraft loss Because CVD is the most common cause ofpatient death in KTRs a concerted effort at minimizingrisk factors for heart disease likely will have as great oreven greater impact on optimizing patient and graftoutcomes than the discovery of new antirejection thera-pies CVD risk reduction strategies should include regularscreening for new-onset diabetes (using ADA-based defini-tions) in the posttransplant period in previously nondiabeticpatients good glycemic regulation for diabetic patients accord-ing to current ADA guidelines and lipid management andblood pressure control according to KDOQI recommenda-tions In addition promotion of a healthy lifestyle throughweight control exercise and smoking cessation should be acentral part of posttransplant counseling and care Whenimmunosuppression modification is being considered to miti-gate cardiovascular risk we recommend that this be inconjunction with the transplant center In summary we gener-ally concurred with the suggestions of the work group in thissection but based on current practice standards in the UnitedStateschallengesremainwith implementationof thisguideline
(2D) s
186 We suggest that patients with a history of skincancer be offered treatment with oral acitretin ifthere are no contraindications (2B)
DOQIRationale andCommentary
CounselingandSunscreen
We concur with recommendations 181 and82 because skin cancer is a major source oforbidity and sometimes mortality in KTRsarning patients at risk of the high danger of
kin cancer a 1C recommendation is reinforcedy a recent prospective case-control study ofrgan transplant recipients that showed that regu-ar use of broad-spectrum sunscreens that pro-ide UVA and UVB protection may prevent theevelopment of actinic keratosis invasive squa-ous cell carcinoma and to a lesser extent
asal cell carcinoma66 Most cancer-causing ra-iation is thought to come from the UVB spec-rum and newer broad-spectrum sunscreens pro-ide protection against UVA and UVB radiationounseling about sunscreen and the need for sunvoidance needs to be incorporated into routineffice visits although it may not always beuccessful In a recent study of KTRs in which1 of patients had been informed about theeed for sun protection only 46 used morehan a tube of sunscreen per year67
Dermatology Involvement
There is increased evidence to suggest thatpecialty dermatology clinics for organ trans-lant recipients improve outcome measures in-luding compliance with photoprotection andncreased awareness of skin cancer68 The re-ources required for these specialty clinics makemplementation difficult for community nephrol-gy groups that do not have direct access to aransplant center Transplant patients should bencouraged to have annual visits with their trans-lant center and if dermatology specialty clinicsre available attempt to coordinate a skin cancervaluation annually
UseofRetinoid-likeCompounds
There is a limited scientific basis for KDIGOuggestion recommendation 186 Although reti-oids now are used routinely in KTRs with aigh skin cancer burden our KDOQI work groupelieves that more data are needed before this
uggestion should be accepted as a guideline In
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ARTICLE IN PRESS
ow-immunologic-risk groups and particularlyifficult cases some data suggest that switchingrom CNI to sirolimus therapy may decrease thencidence of skin cancer69 however the riskersus benefit of this maneuver has not been welltudied
DIGORecommendations inChapter 19on-SkinMalignancies
191 Develop an individualized screening plan for eachKTR that takes into account the patientrsquos pastmedical and family history tobacco use compet-ing risks for death and the performance of thescreening methodology (Not Graded)
192 Screen for the following cancers as per localguidelines for the general population (Not Graded)Women cervical breast and colon cancer Menprostate and colon cancer
193 Obtain hepatic ultrasound and alpha feto-proteinevery 12 months in patients with compensatedcirrhosis (Not Graded) [See Recommendations1354 (HCV) and 1365 (HBV)]
DOQIRationale andCommentary
Screening
It is recognized that KTRs have a higher inci-ence of malignancy particularly those associatedith specific viral infections Although cancer
creening may have benefits in this higher riskopulation it should be reinforced that some meth-ds of screening have significant risks which shoulde considered on an individualized basis particu-arly in patients who have projected survival lesshan 5 years
Screening forCancer inPatientsWithHepatitis
Many patients who have underlying cirrhosisn the United States will be followed up by arofessional specializing in liver disease whoay provide additional insight into this cancer
creening recommendation Based on a recentuestionnaire of US gastroenterologists only 50creen patients for hepatocellular carcinoma70
herefore implementation of this guideline byS clinicians is unlikely to be widespread
DIGORecommendations inChapter 20anagingCancerwithReductionof
mmunosuppressiveMedication
201 We suggest consideration be given to reducingimmunosuppressive medications for KTRs with can-
cer (2C)
2011 Important factors for consideration in-clude (Not Graded)bull The stage of cancer at diagnosisbull Whether the cancer is likely to be
exacerbated by immunosuppressionbull The therapies available for the can-
cerbull Whether immunosuppressive medica-
tions interfere with ability to admin-ister the standard chemotherapy
202 For patients with Kaposi sarcoma we suggestusing mTORi along with a reduction in overallimmunosuppression (2C)
DOQIRationale andCommentary
Table 1 (Table 29 in the KDIGO report3 andxcerpted from Grulich et al71) lists cancershat are increased most in immunosuppressedTRs based on standardized incidence ratios
SIRs) which compare the incidence toatched populations Cancers with the highestIRs may be those most likely to respond to aecrease in immunosuppression Except foraposi sarcoma limited evidence is available
or a decrease in immunosuppression in theseettings A strategy to change immunosuppres-ion therapy must occur in consultation withhe transplant center Switching to sirolimusherapy and decreasing immunosuppression inatients who develop Kaposi sarcoma is basedn sound scientific rationale7273
SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
The incidence of cancer posttransplant is 2-20times higher than that in the general population andKDIGO guidelines have been written to outline stepsfor prevention and screening With few exceptions weagree with the recommendations as outlined Skincancer is common in US transplant patients andscreening and prevention are critical However imple-mentation of guidelines for doing so including theKDIGO guidelines is a challenge because of patientpreferences against the routine use of sunscreen aswell as time constraints during office visits Althoughmany posttransplant cancers are viral mediated andrelated to immunosuppression it is less clear how toalter immunosuppression after malignancy has oc-curred We agree that although age-specific screeningfor malignancy should be incorporated into care con-sideration must be given to the risk of screening inpatients with limited life spans (5 years) because of
comorbid conditions
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
ommonPopu
i sarco-Hodgmelanise sm
sophaemia
estima standa10 c
ut esti
0 case
alized t
to guide treatment specifically before the
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
REFERENCES1 McCullough KP Keith DS Meyer KH et al Kidney
nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
o2
Tf2
Tfh2
TfcM
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ar
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mi2
i2
uap
ba5
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cJ
sir
ml
gt1
p2
ps2
c2
p2
sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
ation Transpl Rev 200923191-19815 Abbud-Filho M Adams PL Alberuacute J et al A report
f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
A
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
cA
nrc
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trN
hUt
Iwa
rl5
mi8
oe1
DA
fsK
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sb2
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hm2
EA
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Bia et al30
ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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ARTICLE IN PRESS
gree in general with the recommendations de-ailed in 105
DIGORecommendations inChapter 11reventingDetecting andTreatingonadherence
111 Consider providing all KTRs and family memberswith education prevention and treatment mea-sures to minimize nonadherence to immunosup-pressive medications (Not Graded)
112 Consider providing KTRs at increased risk fornonadherence with increased levels of screeningfor nonadherence (Not Graded)
DOQIRationale andCommentary
Noncompliance or nonadherence to diet andedication is a common problem in KTRs Nonad-
erence to medication is associated with a high riskf acute rejection and allograft loss We agree thatarly efforts should be made to identify KTRs atncreased risk of nonadherence and that these pa-ients should be monitored closely Prevention iden-ification and treatment of nonadherence are inte-ral to the monitoring of kidney allograft functionnd long-term care of KTRs Certain subgroup ofTRs younger patients African Americans and
hose with financial hardships have an enhancedisk of nonadherence3233
In addition to identifying patients at risk it ismportant to have a system for addressing patientonadherence This requires coordinated efforts ofocial workers transplant coordinators financialounselors pharmacists primary nephrologists andhe patientrsquos family34 A combination of educa-ional behavioral and social support interventionsrovides the best results Because there is no per-ect measure of adherence consideration should beiven to multiple approaches for adherence moni-oring Similar team approaches also are importantn other areas requiring adherence such as dietxercise tobacco alcohol and drug use
DIGORecommendations inChapter 12accination
121 We recommend giving all KTRs approvedinactivated vaccines according to recommendedschedules for the general population except forHBV vaccination (1D)1211 We suggest HBV vaccination (ideally
prior to transplantation) and HBsAb titers6-12 weeks after completing the vaccina-
tion series (2D) h
12111 We suggest annual HBsAb[antibody to hepatitis B sur-face antigen] titers (2D)
12112 We suggest revaccination ifthe antibody titer falls below10 mIUmL (2D)
122 We suggest avoiding live vaccines in KTRs (2C)123 We suggest avoiding vaccinations except influ-
enza vaccination in the first 6 months followingkidney transplantation (2C)1231 We suggest resuming immunizations once
patients are receiving minimal mainte-nance doses of immunosuppressive medi-cations (2C)
1232 We recommend giving all KTRs whoare at least 1-month post-transplantinfluenza vaccination prior to the onsetof the annual influenza season regard-less of status of immunosuppression(1C)
124 We suggest giving the following vaccines to KTRswho due to age direct exposure residence ortravel to endemic areas or other epidemiologicalrisk factors are at increased risk for the specificdiseasesbull rabies (2D)bull tick-borne meningoencephalitis (2D)bull Japanese B encephalitismdashinactivated (2D)bull Meningococcus (2D)bull Pneumococcus (2D)bull Salmonella typhimdashinactivated (2D)1241 Consult an infectious disease specialist a
travel clinic or public health official forguidance on whether specific cases war-rant these vaccinations (Not Graded)
DOQIRationale andCommentary
KTRs are at particular risk of viral infectionsecause of the preferential suppression of T lympho-ytes by both induction and maintenance immuno-uppression The risk and consequence of develop-ng a viral infection warrant use of selected vaccineshe suggestions regarding which vaccines are safend which are contraindicated are based on whetherhe vaccine contains live or killed virus Live virusaccines are contraindicated in immunosuppressedTRs The KDIGO recommendations for vaccina-
ions agree with updated guidelines recently pub-ished by the AST35 Specific comments on theDIGO suggestions regarding vaccinations are
isted in the following sections
Hepatitis B
The work group did not concur with KDIGOuggestion 1211 Neither revaccination against
epatitis after transplant nor following up hepa-
tpapsipapc
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KD
KDOQI Commentary 13
ARTICLE IN PRESS
itis B antibody titers annually is a commonractice in the United States Hepatitis B is nots prevalent in the United States as in otherarts of the world and evidence supportingcreening in all patients posttransplant is lack-ng However screening for seroconversion inatients at risk (receiving a hepatitis B corentibodyndashpositive kidney) is appropriate Theseatients may benefit from lamivudine or ente-avir therapy36
LiveVaccineandTimingofVaccine
There is no particular reason for a 6-monthag between transplant and vaccination Theheory is that vaccines are less likely to beffective in the period when immunosuppres-ion is high In the United States most individu-ls are on their baseline maintenance immuno-uppression therapy by 3 months posttransplantecisions regarding the timing of vaccines areade based on immunosuppression exposure
nd risk of infection Recipients also shouldvoid intimate contact with individuals whoave received live vaccines37 This includesvoiding close contact with children who haveeceived oral polio vaccine for 3 weeks anday include close contact with adults receiv-
ng the attenuated varicella vaccine to preventoster Immunosuppressed individuals are ad-ised to avoid contact for 7 days with individu-ls who have received live virus nasal spraysor influenza We concur with the recommenda-ion for flu vaccine but common practice inhe United States is to wait 3-6 months afterransplant before it is administered
DIGORecommendations inChapter 13 Viraliseases
131 BK POLYOMA VIRUS1311 We suggest screening all KTRs for BKV
with quantitative plasma NAT (2C) atleastbull monthly for the first 3-6 months after
transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull whenever there is an unexplained rise
in serum creatinine (2D)bull and after treatment for acute rejection
(2D)1312 We suggest reducing immunosuppressive
medications when BKV plasma NAT is
persistently greater than 10 000 cop-iesmL (107 copiesL) (2D)
132 CYTOMEGALOVIRUS1321 CMV prophylaxis We recommend that
KTRs (except when donor and recipi-ent both have negative CMV serolo-gies) receive chemoprophylaxis forCMV infection with oral ganciclovir orvalganciclovir for at least 3 monthsafter transplantation (1B) and for 6weeks after treatment with a T-cellndashdepleting antibody (1C)
1322 In patients with CMV disease we suggestweekly monitoring of CMV by NAT orpp65 antigenemia (2D)
1323 CMV treatment13231 We recommend that all pa-
tients with serious (includ-ing most patients with tissueinvasive) CMV disease betreated with intravenousganciclovir (1D)
13232 We recommend that CMVdisease in adult KTRs that isnot serious (eg episodes thatare associated with mildclinical symptoms) be treatedwith either intravenous gan-ciclovir or oral valganciclo-vir (1D)
13233 We recommend that allCMV disease in pediatricKTRs be treated with intra-venous ganciclovir (1D)
13234 We suggest continuing therapyuntil CMV is no longer detect-able by plasma NAT or pp65antigenemia (2D)
1324 We suggest reducing immunosuppressivemedication in life-threatening CMV dis-ease and CMV disease that persists in theface of treatment until CMV disease hasresolved (2D)13241 We suggest monitoring graft
function closely during CMVdisease (2D)
133 EPSTEIN-BARR VIRUS AND POST-TRANS-PLANT LYMPHOPROLIFERATIVE DISEASE1331 We suggest monitoring high-risk (donor
EBV seropositiverecipient seronegative)KTRs for EBV by NAT (2C)bull once in the first week after transplanta-
tion (2D)bull then at least monthly for the first 3-6
months after transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull and additionally after treatment for
acute rejection (2D)
Bia et al14
ARTICLE IN PRESS
1332 We suggest that EBV-seronegative pa-tients with an increasing EBV load haveimmunosuppressive medication reduced(2D)
1333 We recommend that patients with EBVdisease including PTLD have a reduc-tion or cessation of immunosuppres-sive medication (1C)
134 HERPES SIMPLEX VIRUS 1 2 AND VARI-CELLA ZOSTER VIRUS1341 We recommend that KTRs who de-
velop a superficial HSV 1 2 infectionbe treated (1B) with an appropriateoral antiviral agent (eg acyclovir vala-cyclovir or famciclovir) until all le-sions have resolved (1D)
1342 We recommend that KTRs with sys-temic HSV 1 2 infection be treated(1B) with intravenous acyclovir and areduction in immunosuppressive medi-cation (1D)13421 We recommend that intrave-
nous acyclovir continue un-til the patient has a clinicalresponse (1B) then switch toan appropriate oral antiviralagent (eg acyclovir valacy-clovir or famciclovir) to com-plete a total treatment durationof 14-21 days (2D)
1343 We suggest using a prophylactic antiviralagent for KTRs experiencing frequentrecurrences of HSV 12 infection (2D)
1344 We recommend that primary VZV infec-tion (chicken pox) in KTRs be treated(1C) with either intravenous or oral acy-clovir or valacyclovir and a temporaryreduction in amount of immunosuppres-sive medication (2D)
135 HEPATITIS C VIRUS1351 We suggest that HCV-infected KTRs be
treated only when the benefits of treat-ment clearly outweigh the risk of allo-graft rejection due to interferon-basedtherapy (eg fibrosing cholestatic hepati-tis life-threatening vasculitis) (2D)[Based on KDIGO Hepatitis C Recom-mendation 215]
1352 We suggest monotherapy with standardinterferon for HCV-infected KTRs inwhom the benefits of antiviral treatmentclearly outweigh the risks (2D) [Basedon KDIGO Hepatitis C Recommenda-tions 224 and 442]
1353 We suggest that all conventional currentinduction and maintenance immunosup-pressive regimens can be used in HCVinfected patients (2D) [Based on KDIGO
Hepatitis C Recommendation 43]
1354 Measure ALT in HCV-infected patientsmonthly for the first 6 months and every3-6 months thereafter Perform imagingannually to look for cirrhosis and hepato-cellular carcinoma (Not Graded) [Basedon KDIGO Hepatitis C Recommendation441] (See Recommendation 193)
1355 Test HCV-infected patients at least every3-6 months for proteinuria (Not Graded)[Based on KDIGO Hepatitis C Recom-mendation 444]13551 For patients who develop new
onset proteinuria (either urineproteincreatinine ratio 1 or24-hour urine protein 1 g ontwo or more occasions) per-form an allograft biopsy withimmunofluorescence and elec-tron microscopy (Not Graded)[Based on KDIGO Hepatitis CRecommendation 444]
1356 We suggest that patients with HCV asso-ciated glomerulopathy not receive inter-feron (2D) [Based on KDIGO HepatitisC Recommendation 445]
136 HEPATITIS B VIRUS1361 We suggest that any currently available
induction and maintenance immunosup-pressive medication can be used in HBV-infected KTRs (2D)
1362 We suggest that interferon treatmentshould generally be avoided in HBVinfected KTRs (2C)
1363 We suggest that all HBsAg-positive KTRsreceive prophylaxis with tenofovir ente-cavir or lamivudine (2B)13631 Tenofovir or entecavir are pref-
erable to lamivudine to mini-mize development of potentialdrug resistance unless medica-tion cost requires that lami-vudinebe used (Not Graded)
13632 During therapy with antivi-rals measure HBV DNA andALT levels every 3 months tomonitor efficacy and to detectdrug resistance (Not Graded)
1364 We suggest treatment with adefovir ortenofovir for KTRs with lamivudine resis-tance (5 log10 copiesmL rebound ofHBV-DNA) (2D)
1365 Screen HBsAg-positive patients with cir-rhosis for hepatocellular carcinoma every12 months with liver ultrasound andalpha feto-protein (Not Graded) (SeeRecommendation 193)
1366 We suggest that patients who are negativefor HBsAg and have HBsAb titer 10mIUmL receive booster vaccination to
raise the titer to 100 mIUmL (2D)
K
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KDOQI Commentary 15
ARTICLE IN PRESS
137 HUMAN IMMUNODEFICIENCY VIRUS1371 If not already done screen for HIV
infection (Not Graded)1372 To determine antiretroviral therapy refer
HIV-infected KTRs to an HIV specialistwho should pay special attention to drugndashdrug interactions and appropriate dosingof medications (Not Graded)
DOQIRationale andCommentary
Viral infections are particularly problematic inransplant recipients because of the preferentialnhibition of T-lymphocyte function by both induc-ion and maintenance immunosuppression Use ofnduction immunosuppression with lymphocyte-epleting agents (thymoglobulin or alemtuzumab)s associated with a greater risk of viral infectionosttransplant In general the greater the cumula-ive exposure to immunosuppression the greaterhe risk of infectious complications The presenta-ion of viral infections can be asymptomatic vaguend nonspecific or life-threatening acute illnessany viral infections seen in KTRs are rarely seen
n immunocompetent patients and therefore do notnter into the differential diagnosis for physiciansnfamiliar with transplant recipients Close commu-ication with the transplant center is crucial inaring for the transplant population Early detectionnd institution of therapy provide the best chanceor viral eradication
BKVirus
Although the work group agreed with KDIGOuggestions for BK virus screening posttransplante did not think it was practical to require screen-
ng exclusively with quantitative plasma nucleiccid testing (NAT) because many US centers usenitial urinary screening and then test plasma onlyf urine screening results are positive Howeverhere is no disagreement that some type of screen-ng for BK virus is critical to avoid BK nephropa-hy for which there is no specific treatment when its established Complicating screening for BK vi-us is the variability in results between laboratoriesnd uncertainty about the level of viremia thathould trigger a response to decrease in immunosup-ression In the presence of viremia and increase inerum creatinine level a renal allograft biopsy isndicated to confirm the presence of BK nephropa-
hy Because BK viremia and viruria certainly can b
e detected beyond the first year it is not clear howong screening should be continued posttransplantlthough most centers screen for the first year onlyngoing clinical trials are exploring effective treat-ent for BK nephropathy3839 Decisions about
ecreases in immunosuppression currently theainstay of BK viremia management always
hould be made in consultation with the transplantenter
Cytomegalovirus
KDIGO recommendation 1321 regarding cyto-egalovirus (CMV) prophylaxis is reasonable and
pplicable to the US population Universal prophy-axis for CMV now is recommended over initiatingre-emptive treatment after CMV develops40 Aajor concern for US patients is the cost of CMV
rophylaxis with oral valgancyclovir Leukopeniaan be observed in patients using mycophenolatereparations when prophylaxis with valgancyclo-ir is used Screening for CMV is best performedsing NAT methods (1322) CMV antigenemiassays are still in use in many facilities but are nots sensitive as PCR assays41 There is no utility inhecking for serologic response to CMV with IgGr IgM titers posttransplant because the immuneesponse is not predictable Patients with CMVisease should be cared for by clinicians familiarith treating this disease It is recommended that
reatment be continued until viral load is undetect-ble followed by prophylactic doses of valgancy-lovir for an additional 3 months35
Epstein-BarrVirus
Current practice regarding EBV screening variesmong centers in the United States and many doot routinely screen for EBV posttransplant evenn recipient-negative donor-positive cases In con-rast to KDIGO recommendation 1311 routineBV screening is not recommended in AST infec-
ious disease guidelines35 In many centers EBVcreening is reserved for children who are muchore commonly EBV negative pretransplant than
dults EBV-induced posttransplant lymphoprolif-rative disorder (PTLD) affects many more pediat-ic than adult KTRs If screening is someday to beoutinely implemented in US centers details regard-ng the best method of screening and levels ofiremia above which a clinical intervention should
e triggered need to be better defined
ttattt
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ARTICLE IN PRESS
HerpesandVaricella
Systemic herpesvirus infections can be lifehreatening in transplant recipients and should bereated aggressively with intravenous antiviralgents as described in the KDIGO recommenda-ions Less aggressive cutaneous infection can bereated with oral antiviral agents as outlined inhe KDIGO guidelines
Varicella exposure is particularly concerning inransplant recipients The work group disputes theecommended dosing of acyclovir for varicellaxposure Acyclovir at a dose of 10 mgkg or about00 mg 4 times daily of oral acyclovir would betandard dosing We agree with the use of varicellammune globulin and emphasize the need to avoidhe varicella vaccine because it is a live virushould a transplant recipient develop a systemicaricella infection hospitalization and high-dosentravenous acyclovir therapy are warranted
Hepatitis C
Hepatitis C management posttransplant is ahallenge The KDIGO guidelines cited hereere based on the recently published KDIGOuideline for hepatitis C in CKD4 Hepatitis Cypically is not treated posttransplant because ofhe risk (50) of rejection precipitated bynterferon therapy particularly in US KTRs inhom hepatitis C commonly is genotype 1 which
s more resistant to treatment with interferon42
owever should hepatitis Cndashrelated glomerulo-ephritis develop the risk-benefit ratio may fa-or treatment in selected patients Such decisionslways should be made in consultation withepatology and infectious disease experts andhe transplant center Monitoring liver enzymeevels specifically alanine aminotransferaseALT) may reflect a change in hepatitis activityut monitoring hepatitis C viral load is not recom-ended because it does not seem to correlateith outcome Annual monitoring for hepatocel-
ular carcinoma using -fetoprotein and imagings encouraged but not often practiced
Hepatitis B
KDIGO recommendations for hepatitis B areeasonable and currently are followed in mostS centers except for recommendation 1366
see previous recommendation under vaccina-ions) KTRs with hepatitis C or hepatitis B also
hould be followed up by a hepatologist
Human ImmunodeficiencyVirus
Human immunodeficiency virus (HIV)-posi-ive individuals are now acceptable for transplantf CD4 count is 200 cellsL and viral loadVL) is undetectable3543 Transplant should beerformed at centers with expertise in managingIV-positive individuals and care should be co-rdinated carefully with HIV specialists Somentiretroviral agents in particular the proteasenhibitors have potentially serious drug interac-ions with immunosuppressive agents35
DIGORecommendations inChapter 14Othernfections
141 URINARY TRACT INFECTION1411 We suggest that all KTRs receive UTI
prophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 monthsafter transplantation (2B)
1412 For allograft pyelonephritis we suggestinitial hospitalization and treatment withintravenous antibiotics (2C)
142 PNEUMOCYSTIS JIROVECII PNEUMONIA1421 We recommend that all KTRs receive
PCP prophylaxis with daily tri-methoprimndashsulfamethoxazole for 3-6months after transplantation (1B)
1422 We suggest that all KTRs receive PCPprophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 weeksduring and after treatment for acute rejec-tion (2C)
1423 We recommend that KTRs with PCPdiagnosed by bronchial alveolar lavageandor lung biopsy be treated withhigh-dose intravenous trimethoprimndashsulfamethoxazole corticosteroids anda reduction in immunosuppressivemedication (1C)
1424 We recommend treatment with cortico-steroids for KTRs with moderate tosevere PCP (as defined by PaO2 lt70mm Hg in room air or an alveolargradient of gt35 mm Hg) (1C)
143 TUBERCULOSIS1431 We suggest that TB prophylaxis and
treatment regimens be the same in KTRsas would be used in the local generalpopulation who require therapy (2D)
1432 We recommend monitoring CNI andmTORi [mTOR inhibitor] blood levels inpatients receiving rifampin (1C)14321 Consider substituting rifabu-
tin for rifampin to minimize
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KDOQI Commentary 17
ARTICLE IN PRESS
interactions with CNIs andmTORi (Not Graded)
144 CANDIDA PROPHYLAXIS1441 We suggest oral and esophageal Candida
prophylaxis with oral clotrimazole loz-enges nystatin or fluconazole for 1-3months after transplantation and for 1month after treatment with an antilympho-cyte antibody (2C)
DOQIRationale andCommentary
UrinaryTract Infection
Urinary tract infections (UTIs) after kidneyransplant are very common and account for aarge percentage of readmissions posttransplantTIs are common because of multiple factors
ncluding the disrupted anatomy of the urinaryract with a ureteroneocystotomy incompleteladder emptying because of diabetes or pros-atic hypertrophy and impaired immune re-ponses Prophylaxis of UTIs usually is under-aken with trimethoprim-sulfamethoxazole for 6onths posttransplant although infections often
ccur despite therapy because of the develop-ent of drug resistance Although native kidney
yelonephritis does not always require hospital-zation it is recommended that all KTRs withhis diagnosis be hospitalized because the graftysfunction that usually accompanies transplantyelonephritis requires aggressive investigationnd treatment Individuals with recurrent UTIsarrant evaluation with urologic assessment Pa-
ients with recurrent UTIs may benefit fromong-term suppressive therapy
Pneumocystic Pneumonia
We agree that Pneumocystis jirovecii pneumoniaPCP) prophylaxis is important for the first 3-6onths posttransplant (1421)After the first month
very-other-day dosing of trimethoprim-sulfame-hoxazole or atovaquone is believed to be adequaterophylaxis In cases in which neither of thesegents can be used an individual may be treatedrophylactically with inhaled pentamidine OurDOQI work group emphasized that patients whoevelop PCP should be transferred to the transplantenter promptly for management and adjustmentsn immunosuppression
Tuberculosis
Monitoring for latent tuberculosis has posed a
hallenge in the immunosuppressed population be-
ause of the unreliable nature of skin testing Newerechniques involving interferon release assays aremerging as the new gold standard for detection ofatent tuberculosis4445
CandidaProphylaxis
Oral candidiasis must be screened for usingral mucosa examination on follow-up visitsn KTRs This is especially true in the earlyosttransplant period when immunosuppres-ive medication dosage is the highest Wegree with these recommendations and empha-ize that if fluconazole is used there is aotential for serious drug interactions becausef cytochrome P-450 3A4 inhibition
SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
Improvement in short-term outcomes has not trans-lated into significant improvements in long-term out-comes in KTRs The lack of significant improvement inlong-term survival may be related to post-transplantcomplications Frequent posttransplant monitoring mayimprove long-term outcomes by decreasing chronic graftfailure or death with a functioning graft Our work groupconcurred with the recommendation and schedules ofroutine screening in monitoring kidney allograft functionafter kidney transplant with a low threshold for perform-ing kidney biopsy in cases of graft dysfunction or protein-uria Expert tissue processing and interpretation of trans-plant biopsy specimens by pathologists with transplantexperience are critical Regular surveillance of the pa-tientrsquos kidney function at the transplant center or in thenephrologistrsquos office offers an opportunity to enhancepatient adherence to medication diet and healthy life-style Although CKD in KTRs progresses more slowlythan CKD in other patients the work group agreed thatthe KDIGO guidelines on CKD should be followed inKTRs
Opportunistic infections are common in KTRs al-though advances in diagnosis and treatment have led toimproved survival in KTRs with infection It is nowstandard of care to use vaccinations in KTRs as long asthe vaccine does not contain live or attenuated virus Italso is routine to screen for or use prophylaxis to preventseveral posttransplant viral infections With few excep-tions (related to EBV and BK virus screening andhepatitis B vaccination posttransplant) we concurredwith KDIGO guidelines for vaccination screening and
treatment of infection posttransplant
KD
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ARTICLE IN PRESS
COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULAR
DISEASE
DIGORecommendations inChapter 15iabetesMellitus
151 Screening for New-Onset Diabetes after Transplan-tation1511 We recommend screening all nondia-
betic KTRs with fasting plasma glu-cose oral glucose tolerance testingandor HbA1c (1C) at leastbull weekly for 4 weeks (2D)bull every 3 months for 1 year (2D)bull and annually thereafter (2D)
1512 We suggest screening for NODAT withfasting glucose oral glucose tolerancetesting andor after starting or substan-tially increasing the dose of CNIsmTORi or corticosteroids (2D)
152 Managing NODAT or Diabetes Present at Trans-plantation1521 If NODAT develops consider modifying
the immunosuppressive drug regimen toreverse or ameliorate diabetes afterweighing the risk of rejection and otherpotential adverse effects (Not Graded)
1522 Consider targeting HbA1c 70-75and avoid targeting HbA1c 60 espe-cially if hypoglycemic reactions are com-mon (Not Graded)
1523 We suggest that in patients with diabetesaspirin (65-100 mgd) use for the primaryprevention of CVD be based on patientpreferences and values balancing the riskfor ischemic events to that of bleeding(2D)
DOQIRationale andCommentary
Diabetic Screening
We agree with screening for new-onset diabetesfter transplantation (NODAT) as outlined by theDIGO work group Definitions used are similar
o those of the American Diabetes AssociationADA) The greater frequency of testing initially isustified by the high risk of NODAT in the earlyosttransplant period however ongoing screenings required because the risk of the development ofODAT continues to increase over time4647 We
lso point out that prediabetic states (impairedasting glucose level and impaired glucose toler-nce) occur even more commonly than overt diabe-es48 and may be associated with metabolic syn-rome as well as with increased cardiovascular
ortality49-51 Potential implications of these predia-
etic states emphasize the importance of perform-ng blood tests under fasting conditions For pa-ients with fasting hyperglycemia an oral glucoseolerance test or hemoglobinA1c (HbA1c) test shoulde performed Although more cumbersome to per-orm data suggest that an oral glucose toleranceest is a more sensitive indicator of NODAT inyperglycemic KTRs52 This may allow earlieretection of overt diabetes and more prompt institu-ion of treatment
DiabetesManagement
Data supporting a substantial benefit in themelioration or reversal of NODAT using immu-osuppression modification in KTRs are veryimited There was consensus in our work grouphat considering the paucity of data for reversingODAT by changing immunosuppression and
he potential risk of an adverse outcome withuch a maneuver KDIGO suggestion 1521 couldot be supported Certainly if such a step waseing considered it should be done in conjunc-ion with the transplant center Targeting an HbA1c
evel of 7-75 and avoiding levels 6 isased on data showing increased cardiovascularvents with the lower HbA1c target5354
DIGORecommendations inChapter 16ypertensionDyslipidemias TobaccoUse andbesity
161 Hypertension1611 We recommend measuring blood pres-
sure at each clinic visit (1C)1612 We suggest maintaining blood pressure at
130 mm Hg systolic and 80 mm Hgdiastolic if 18 years of age and 90th
percentile for sex age and height if 18years old (2C)
1613 To treat hypertension (Not Graded)bull Use any class of antihypertensive
agentbull Monitor closely for adverse effects
and drug-drug interactions and whenurine protein excretion 1 gd for18 years old and 600 mgm224 hfor 18 years old consider an ACE-Ior an ARB as first-line therapy
162 Dyslipidemias (These recommendations are basedon KDOQI Dyslipidemia Guidelines and are thusnot graded)1621 Measure a complete lipid profile in all
adult (18 years old) and adolescent
(puberty to 18 years old) KTRs [Based on
K
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KDOQI Commentary 19
ARTICLE IN PRESS
KDOQI Dyslipidemia Recommendation1]bull 2-3 months after transplantationbull 2-3 months after a change in treatment
or other conditions known to causedyslipidemias
bull at least annually thereafter1622 Evaluate KTRs with dyslipidemias for
secondary causes [Based on KDOQI Dys-lipidemia Recommendation 3]16221 For KTRs with fasting triglyc-
erides 500 mgdL (565mmolL) that cannot be cor-rected by removing an under-lying cause treat withbull Adults therapeutic lifestyle
changes and a triglyceride-lowering agent [Based onKDOQI Recommendation41]
bull Adolescents therapeutic life-style changes [Based onKDOQI Recommendation51]
16222 For KTRs with elevatedLDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)treat to reduce LDL-C to100 mgdL (259mmolL) [Based on KDOQIGuideline 42]
bull Adolescents If LDL-C130 mgdL (336 mmolL) treat to reduce LDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 52]
16223 For KTRs with normalLDL-C elevated triglyceridesand elevated non-HDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)fasting triglycerides 200mgdL (226 mmolL)and non-HDL-C 130mgdL (336 mmolL)treat to reduce non-HDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 43]
bull Adolescents If LDL-C130 mgdL (336 mmolL) fasting triglycerides200 mgdL (226 mmolL) and non-HDL-C 160mgdL (414 mmolL)treat to reduce non-HDL-C
to 160 mgdL (414 i
mmolL) [Based on KDOQIGuideline 53]
163 Tobacco Use1631 Screen and counsel all KTRs including
adolescents and children for tobacco useand record the results in the medicalrecord (Not Graded)bull Screen during initial transplant hospi-
talizationbull Screen at least annually thereafter
1632 Offer treatment to all patients who usetobacco (Not Graded)
164 Obesity1641 Assess obesity at each visit (Not Graded)
bull Measure height and weight at eachvisit in adults and children
bull Calculate BMI at each visitbull Measure waist circumference when
weight and physical appearance sug-gest obesity but BMI is 35 kgm2
1642 Offer a weight-reduction program to allobese KTRs (Not Graded)
DOQIRationale andCommentary
Hypertension
The KDIGO work group adapted the KDOQI004 recommendations for target blood pres-ure in KTRs55 Self measurement is useful inssessing response to therapy and enhancesdherence56 In general we agree that the classf antihypertensive agent does not matter inhe treatment of blood pressure elevation inhis population and that attention should beiven to potential side effects of antihyperten-ive agents as well as possible interactionsith the immunosuppressive regimen (eg non-ihydropyridine calcium channel blockers andNIs) In the absence of adequate randomizedontrolled trials it is not known whether angio-ensin-converting enzyme (ACE) inhibitors andngiotensin receptor blockers (ARBs) prolongecipient or allograft survival Some but notll retrospective studies suggest a benefitowever all these studies are limited by selec-ion bias5758 Although ACE inhibitors andRBs commonly lead to some decrease inFR treatment with these drugs should be
ontinued unless serum creatinine level in-reases by 25 to 30 in keeping withDOQI recommendations55 In KTRs receiv-
ng ACE inhibitors or ARBs it is important toducate patients to maintain adequate fluid
ntake during illness to prevent a prerenal
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ARTICLE IN PRESS
nsult to the allograft Similarly awareness isecessary when using diuretics in conjunctionith therapies that block the renin-angiotensin-
ldosterone-system59
Dyslipidemia
The KDIGO work group based their recom-endations for evaluation and treatment of
yperlipidemia on the KDOQI dyslipidemiauidelines for KTRs60 We agree with theseecommendations CNIs potentiate the toxicityf statins by slowing their metabolism throughhe cytochrome P-450 system This interactionccurs more commonly with cyclosporine61
han with tacrolimus Dyslipidemia especiallyypertriglyceridemia frequently complicatesTOR-inhibitor use and lipid-lowering therapy
s required in most patients using these agents
TobaccoUse
Not surprisingly tobacco use at the time ofransplant is associated with decreased patientnd graft survival as well as increased risk ofosttransplant cardiovascular disease (CVD)lthough the KDIGO work group recom-ends initial screening and intervention dur-
ng the hospitalization for transplant we be-ieve there may be benefit gained by startingounseling in the pretransplant period duringhe evaluation phase Unfortunately this doesot occur often because of time and personnelonstraints in transplant centers Ideally allransplant centers should have smoking-cessa-ion programs available to patients either in-ouse or through referral Ideally systemshould be created to continue to screen andonitor for smoking cessation at yearly inter-
als after transplant because there is a highate of relapse with this addiction As outlinedn KDIGO Table 253 although all pharmaco-ogic therapies for smoking cessation can besed in KTRs the starting dose of vareniclinehould be decreased in patients with GFR 30Lmin
Obesity
Obesity is an epidemic in the United Statesnd the proportion of obese kidney transplantandidates continues to grow In additioneight gain after transplant is very commonly
bserved Obesity in KTRs is associated with w
ncreased risks of wound complications de-ayed graft function acute rejection and NO-AT resulting in inferior patient and graftutcomes Attention to this potential complica-ion and counseling should be initiated duringhe pretransplant evaluation phase Informa-ion regarding pharmacologic therapies foreight loss in KTRs is not available and we
gree with the KDIGO work group that thera-eutic lifestyle measures should be encour-ged Data regarding steroid therapy with-rawal and weight gain are controversial Aecent double-blind randomized controlled trialxamining early steroid therapy withdrawalid not show a difference in weight gain at 5ears posttransplant compared with the cohortemaining on standard maintenance corticoste-oid therapy62
DIGORecommendations inChapter 17ardiovascularManagement
171 Consider managing CVD at least as intensively inKTRs as in the general population with appropri-ate diagnostic tests and treatments (Not Graded)
172 We suggest using aspirin (65-100 mgd) in allpatients with atherosclerotic CVD unless there arecontraindications (2B)
DOQIRationale andCommentary
Although outcomes are favorable comparedith remaining on the waiting list the risk of
ardiovascular mortality in KTRs is several-foldigher than observed in the general population63
specially in younger age groups and patientsith decreasing allograft function64 CVD is aajor cause of graft loss after the first post-
ransplant year In this context we strongly agreehat CVD should be managed in KTRs at least asntensively as in the general population Ideallyecreasing CVD risk in KTRs requires a multifac-ted and multidisciplinary approach Based onurrent practice models in the United States theransplant and nephrology community has notet been able to achieve these desirable goals65
his clearly deserves more attention becauseontrol of CVD has the potential to contributeore to long-term kidney graft survival than the
iscovery of newer drugs that decrease the ratef allograft rejection Our KDOQI working groupgreed with the use of low-dose aspirin in KTRs
ith evidence of atherosclerosis
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KDOQI Commentary 21
ARTICLE IN PRESS
SUMMARY OF COMMENTARY ONSECTION III CVD
COMMENTARY ON SECTION IV OF KDIGO
TRANSPLANT GUIDELINE MALIGNANCY
DIGORecommendations inChapter 18 Cancerf the Skin andLip
181 We recommend that KTRs especially thosewho have fair skin live in high sun-exposureclimates have occupations requiring sun expo-sure have had significant sun exposure as achild or have a history of skin cancer be toldthat their risk of skin and lip cancer is veryhigh (1C)
182 We recommend that KTRs minimize life-longsun exposure and use appropriate ultravioletlight blocking agents (1D)
183 We suggest that adult KTRs perform skin andlip self-examinations and report new lesions toa health-care provider (2D)
184 For adult KTRs we suggest that a qualified healthprofessional with experience in diagnosing skincancer perform annual skin and lip examinationon KTRs except possibly for KTRs with dark skinpigmentation (2D)
185 We suggest that patients with a history of skin orlip cancer or premalignant lesions be referred to andfollowed by a qualified health professional withexperience in diagnosing and treating skin cancer
With the decrease in acute rejection during the pastdecade in association with improved immunosuppres-sion regimens patient death now rivals chronic graftdysfunction as one of the leading causes of long-termgraft loss Because CVD is the most common cause ofpatient death in KTRs a concerted effort at minimizingrisk factors for heart disease likely will have as great oreven greater impact on optimizing patient and graftoutcomes than the discovery of new antirejection thera-pies CVD risk reduction strategies should include regularscreening for new-onset diabetes (using ADA-based defini-tions) in the posttransplant period in previously nondiabeticpatients good glycemic regulation for diabetic patients accord-ing to current ADA guidelines and lipid management andblood pressure control according to KDOQI recommenda-tions In addition promotion of a healthy lifestyle throughweight control exercise and smoking cessation should be acentral part of posttransplant counseling and care Whenimmunosuppression modification is being considered to miti-gate cardiovascular risk we recommend that this be inconjunction with the transplant center In summary we gener-ally concurred with the suggestions of the work group in thissection but based on current practice standards in the UnitedStateschallengesremainwith implementationof thisguideline
(2D) s
186 We suggest that patients with a history of skincancer be offered treatment with oral acitretin ifthere are no contraindications (2B)
DOQIRationale andCommentary
CounselingandSunscreen
We concur with recommendations 181 and82 because skin cancer is a major source oforbidity and sometimes mortality in KTRsarning patients at risk of the high danger of
kin cancer a 1C recommendation is reinforcedy a recent prospective case-control study ofrgan transplant recipients that showed that regu-ar use of broad-spectrum sunscreens that pro-ide UVA and UVB protection may prevent theevelopment of actinic keratosis invasive squa-ous cell carcinoma and to a lesser extent
asal cell carcinoma66 Most cancer-causing ra-iation is thought to come from the UVB spec-rum and newer broad-spectrum sunscreens pro-ide protection against UVA and UVB radiationounseling about sunscreen and the need for sunvoidance needs to be incorporated into routineffice visits although it may not always beuccessful In a recent study of KTRs in which1 of patients had been informed about theeed for sun protection only 46 used morehan a tube of sunscreen per year67
Dermatology Involvement
There is increased evidence to suggest thatpecialty dermatology clinics for organ trans-lant recipients improve outcome measures in-luding compliance with photoprotection andncreased awareness of skin cancer68 The re-ources required for these specialty clinics makemplementation difficult for community nephrol-gy groups that do not have direct access to aransplant center Transplant patients should bencouraged to have annual visits with their trans-lant center and if dermatology specialty clinicsre available attempt to coordinate a skin cancervaluation annually
UseofRetinoid-likeCompounds
There is a limited scientific basis for KDIGOuggestion recommendation 186 Although reti-oids now are used routinely in KTRs with aigh skin cancer burden our KDOQI work groupelieves that more data are needed before this
uggestion should be accepted as a guideline In
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ARTICLE IN PRESS
ow-immunologic-risk groups and particularlyifficult cases some data suggest that switchingrom CNI to sirolimus therapy may decrease thencidence of skin cancer69 however the riskersus benefit of this maneuver has not been welltudied
DIGORecommendations inChapter 19on-SkinMalignancies
191 Develop an individualized screening plan for eachKTR that takes into account the patientrsquos pastmedical and family history tobacco use compet-ing risks for death and the performance of thescreening methodology (Not Graded)
192 Screen for the following cancers as per localguidelines for the general population (Not Graded)Women cervical breast and colon cancer Menprostate and colon cancer
193 Obtain hepatic ultrasound and alpha feto-proteinevery 12 months in patients with compensatedcirrhosis (Not Graded) [See Recommendations1354 (HCV) and 1365 (HBV)]
DOQIRationale andCommentary
Screening
It is recognized that KTRs have a higher inci-ence of malignancy particularly those associatedith specific viral infections Although cancer
creening may have benefits in this higher riskopulation it should be reinforced that some meth-ds of screening have significant risks which shoulde considered on an individualized basis particu-arly in patients who have projected survival lesshan 5 years
Screening forCancer inPatientsWithHepatitis
Many patients who have underlying cirrhosisn the United States will be followed up by arofessional specializing in liver disease whoay provide additional insight into this cancer
creening recommendation Based on a recentuestionnaire of US gastroenterologists only 50creen patients for hepatocellular carcinoma70
herefore implementation of this guideline byS clinicians is unlikely to be widespread
DIGORecommendations inChapter 20anagingCancerwithReductionof
mmunosuppressiveMedication
201 We suggest consideration be given to reducingimmunosuppressive medications for KTRs with can-
cer (2C)
2011 Important factors for consideration in-clude (Not Graded)bull The stage of cancer at diagnosisbull Whether the cancer is likely to be
exacerbated by immunosuppressionbull The therapies available for the can-
cerbull Whether immunosuppressive medica-
tions interfere with ability to admin-ister the standard chemotherapy
202 For patients with Kaposi sarcoma we suggestusing mTORi along with a reduction in overallimmunosuppression (2C)
DOQIRationale andCommentary
Table 1 (Table 29 in the KDIGO report3 andxcerpted from Grulich et al71) lists cancershat are increased most in immunosuppressedTRs based on standardized incidence ratios
SIRs) which compare the incidence toatched populations Cancers with the highestIRs may be those most likely to respond to aecrease in immunosuppression Except foraposi sarcoma limited evidence is available
or a decrease in immunosuppression in theseettings A strategy to change immunosuppres-ion therapy must occur in consultation withhe transplant center Switching to sirolimusherapy and decreasing immunosuppression inatients who develop Kaposi sarcoma is basedn sound scientific rationale7273
SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
The incidence of cancer posttransplant is 2-20times higher than that in the general population andKDIGO guidelines have been written to outline stepsfor prevention and screening With few exceptions weagree with the recommendations as outlined Skincancer is common in US transplant patients andscreening and prevention are critical However imple-mentation of guidelines for doing so including theKDIGO guidelines is a challenge because of patientpreferences against the routine use of sunscreen aswell as time constraints during office visits Althoughmany posttransplant cancers are viral mediated andrelated to immunosuppression it is less clear how toalter immunosuppression after malignancy has oc-curred We agree that although age-specific screeningfor malignancy should be incorporated into care con-sideration must be given to the risk of screening inpatients with limited life spans (5 years) because of
comorbid conditions
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
ommonPopu
i sarco-Hodgmelanise sm
sophaemia
estima standa10 c
ut esti
0 case
alized t
to guide treatment specifically before the
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
KF
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
REFERENCES1 McCullough KP Keith DS Meyer KH et al Kidney
nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
o2
Tf2
Tfh2
TfcM
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dt
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wad6
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wt
tdp
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op
Mpp
apt
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ar
ti2
mi2
i2
uap
ba5
ra2
cJ
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ml
gt1
p2
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sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
ation Transpl Rev 200923191-19815 Abbud-Filho M Adams PL Alberuacute J et al A report
f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
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ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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KDOQI Commentary 13
ARTICLE IN PRESS
itis B antibody titers annually is a commonractice in the United States Hepatitis B is nots prevalent in the United States as in otherarts of the world and evidence supportingcreening in all patients posttransplant is lack-ng However screening for seroconversion inatients at risk (receiving a hepatitis B corentibodyndashpositive kidney) is appropriate Theseatients may benefit from lamivudine or ente-avir therapy36
LiveVaccineandTimingofVaccine
There is no particular reason for a 6-monthag between transplant and vaccination Theheory is that vaccines are less likely to beffective in the period when immunosuppres-ion is high In the United States most individu-ls are on their baseline maintenance immuno-uppression therapy by 3 months posttransplantecisions regarding the timing of vaccines areade based on immunosuppression exposure
nd risk of infection Recipients also shouldvoid intimate contact with individuals whoave received live vaccines37 This includesvoiding close contact with children who haveeceived oral polio vaccine for 3 weeks anday include close contact with adults receiv-
ng the attenuated varicella vaccine to preventoster Immunosuppressed individuals are ad-ised to avoid contact for 7 days with individu-ls who have received live virus nasal spraysor influenza We concur with the recommenda-ion for flu vaccine but common practice inhe United States is to wait 3-6 months afterransplant before it is administered
DIGORecommendations inChapter 13 Viraliseases
131 BK POLYOMA VIRUS1311 We suggest screening all KTRs for BKV
with quantitative plasma NAT (2C) atleastbull monthly for the first 3-6 months after
transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull whenever there is an unexplained rise
in serum creatinine (2D)bull and after treatment for acute rejection
(2D)1312 We suggest reducing immunosuppressive
medications when BKV plasma NAT is
persistently greater than 10 000 cop-iesmL (107 copiesL) (2D)
132 CYTOMEGALOVIRUS1321 CMV prophylaxis We recommend that
KTRs (except when donor and recipi-ent both have negative CMV serolo-gies) receive chemoprophylaxis forCMV infection with oral ganciclovir orvalganciclovir for at least 3 monthsafter transplantation (1B) and for 6weeks after treatment with a T-cellndashdepleting antibody (1C)
1322 In patients with CMV disease we suggestweekly monitoring of CMV by NAT orpp65 antigenemia (2D)
1323 CMV treatment13231 We recommend that all pa-
tients with serious (includ-ing most patients with tissueinvasive) CMV disease betreated with intravenousganciclovir (1D)
13232 We recommend that CMVdisease in adult KTRs that isnot serious (eg episodes thatare associated with mildclinical symptoms) be treatedwith either intravenous gan-ciclovir or oral valganciclo-vir (1D)
13233 We recommend that allCMV disease in pediatricKTRs be treated with intra-venous ganciclovir (1D)
13234 We suggest continuing therapyuntil CMV is no longer detect-able by plasma NAT or pp65antigenemia (2D)
1324 We suggest reducing immunosuppressivemedication in life-threatening CMV dis-ease and CMV disease that persists in theface of treatment until CMV disease hasresolved (2D)13241 We suggest monitoring graft
function closely during CMVdisease (2D)
133 EPSTEIN-BARR VIRUS AND POST-TRANS-PLANT LYMPHOPROLIFERATIVE DISEASE1331 We suggest monitoring high-risk (donor
EBV seropositiverecipient seronegative)KTRs for EBV by NAT (2C)bull once in the first week after transplanta-
tion (2D)bull then at least monthly for the first 3-6
months after transplantation (2D)bull then every 3 months until the end of
the first post-transplant year (2D)bull and additionally after treatment for
acute rejection (2D)
Bia et al14
ARTICLE IN PRESS
1332 We suggest that EBV-seronegative pa-tients with an increasing EBV load haveimmunosuppressive medication reduced(2D)
1333 We recommend that patients with EBVdisease including PTLD have a reduc-tion or cessation of immunosuppres-sive medication (1C)
134 HERPES SIMPLEX VIRUS 1 2 AND VARI-CELLA ZOSTER VIRUS1341 We recommend that KTRs who de-
velop a superficial HSV 1 2 infectionbe treated (1B) with an appropriateoral antiviral agent (eg acyclovir vala-cyclovir or famciclovir) until all le-sions have resolved (1D)
1342 We recommend that KTRs with sys-temic HSV 1 2 infection be treated(1B) with intravenous acyclovir and areduction in immunosuppressive medi-cation (1D)13421 We recommend that intrave-
nous acyclovir continue un-til the patient has a clinicalresponse (1B) then switch toan appropriate oral antiviralagent (eg acyclovir valacy-clovir or famciclovir) to com-plete a total treatment durationof 14-21 days (2D)
1343 We suggest using a prophylactic antiviralagent for KTRs experiencing frequentrecurrences of HSV 12 infection (2D)
1344 We recommend that primary VZV infec-tion (chicken pox) in KTRs be treated(1C) with either intravenous or oral acy-clovir or valacyclovir and a temporaryreduction in amount of immunosuppres-sive medication (2D)
135 HEPATITIS C VIRUS1351 We suggest that HCV-infected KTRs be
treated only when the benefits of treat-ment clearly outweigh the risk of allo-graft rejection due to interferon-basedtherapy (eg fibrosing cholestatic hepati-tis life-threatening vasculitis) (2D)[Based on KDIGO Hepatitis C Recom-mendation 215]
1352 We suggest monotherapy with standardinterferon for HCV-infected KTRs inwhom the benefits of antiviral treatmentclearly outweigh the risks (2D) [Basedon KDIGO Hepatitis C Recommenda-tions 224 and 442]
1353 We suggest that all conventional currentinduction and maintenance immunosup-pressive regimens can be used in HCVinfected patients (2D) [Based on KDIGO
Hepatitis C Recommendation 43]
1354 Measure ALT in HCV-infected patientsmonthly for the first 6 months and every3-6 months thereafter Perform imagingannually to look for cirrhosis and hepato-cellular carcinoma (Not Graded) [Basedon KDIGO Hepatitis C Recommendation441] (See Recommendation 193)
1355 Test HCV-infected patients at least every3-6 months for proteinuria (Not Graded)[Based on KDIGO Hepatitis C Recom-mendation 444]13551 For patients who develop new
onset proteinuria (either urineproteincreatinine ratio 1 or24-hour urine protein 1 g ontwo or more occasions) per-form an allograft biopsy withimmunofluorescence and elec-tron microscopy (Not Graded)[Based on KDIGO Hepatitis CRecommendation 444]
1356 We suggest that patients with HCV asso-ciated glomerulopathy not receive inter-feron (2D) [Based on KDIGO HepatitisC Recommendation 445]
136 HEPATITIS B VIRUS1361 We suggest that any currently available
induction and maintenance immunosup-pressive medication can be used in HBV-infected KTRs (2D)
1362 We suggest that interferon treatmentshould generally be avoided in HBVinfected KTRs (2C)
1363 We suggest that all HBsAg-positive KTRsreceive prophylaxis with tenofovir ente-cavir or lamivudine (2B)13631 Tenofovir or entecavir are pref-
erable to lamivudine to mini-mize development of potentialdrug resistance unless medica-tion cost requires that lami-vudinebe used (Not Graded)
13632 During therapy with antivi-rals measure HBV DNA andALT levels every 3 months tomonitor efficacy and to detectdrug resistance (Not Graded)
1364 We suggest treatment with adefovir ortenofovir for KTRs with lamivudine resis-tance (5 log10 copiesmL rebound ofHBV-DNA) (2D)
1365 Screen HBsAg-positive patients with cir-rhosis for hepatocellular carcinoma every12 months with liver ultrasound andalpha feto-protein (Not Graded) (SeeRecommendation 193)
1366 We suggest that patients who are negativefor HBsAg and have HBsAb titer 10mIUmL receive booster vaccination to
raise the titer to 100 mIUmL (2D)
K
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KDOQI Commentary 15
ARTICLE IN PRESS
137 HUMAN IMMUNODEFICIENCY VIRUS1371 If not already done screen for HIV
infection (Not Graded)1372 To determine antiretroviral therapy refer
HIV-infected KTRs to an HIV specialistwho should pay special attention to drugndashdrug interactions and appropriate dosingof medications (Not Graded)
DOQIRationale andCommentary
Viral infections are particularly problematic inransplant recipients because of the preferentialnhibition of T-lymphocyte function by both induc-ion and maintenance immunosuppression Use ofnduction immunosuppression with lymphocyte-epleting agents (thymoglobulin or alemtuzumab)s associated with a greater risk of viral infectionosttransplant In general the greater the cumula-ive exposure to immunosuppression the greaterhe risk of infectious complications The presenta-ion of viral infections can be asymptomatic vaguend nonspecific or life-threatening acute illnessany viral infections seen in KTRs are rarely seen
n immunocompetent patients and therefore do notnter into the differential diagnosis for physiciansnfamiliar with transplant recipients Close commu-ication with the transplant center is crucial inaring for the transplant population Early detectionnd institution of therapy provide the best chanceor viral eradication
BKVirus
Although the work group agreed with KDIGOuggestions for BK virus screening posttransplante did not think it was practical to require screen-
ng exclusively with quantitative plasma nucleiccid testing (NAT) because many US centers usenitial urinary screening and then test plasma onlyf urine screening results are positive Howeverhere is no disagreement that some type of screen-ng for BK virus is critical to avoid BK nephropa-hy for which there is no specific treatment when its established Complicating screening for BK vi-us is the variability in results between laboratoriesnd uncertainty about the level of viremia thathould trigger a response to decrease in immunosup-ression In the presence of viremia and increase inerum creatinine level a renal allograft biopsy isndicated to confirm the presence of BK nephropa-
hy Because BK viremia and viruria certainly can b
e detected beyond the first year it is not clear howong screening should be continued posttransplantlthough most centers screen for the first year onlyngoing clinical trials are exploring effective treat-ent for BK nephropathy3839 Decisions about
ecreases in immunosuppression currently theainstay of BK viremia management always
hould be made in consultation with the transplantenter
Cytomegalovirus
KDIGO recommendation 1321 regarding cyto-egalovirus (CMV) prophylaxis is reasonable and
pplicable to the US population Universal prophy-axis for CMV now is recommended over initiatingre-emptive treatment after CMV develops40 Aajor concern for US patients is the cost of CMV
rophylaxis with oral valgancyclovir Leukopeniaan be observed in patients using mycophenolatereparations when prophylaxis with valgancyclo-ir is used Screening for CMV is best performedsing NAT methods (1322) CMV antigenemiassays are still in use in many facilities but are nots sensitive as PCR assays41 There is no utility inhecking for serologic response to CMV with IgGr IgM titers posttransplant because the immuneesponse is not predictable Patients with CMVisease should be cared for by clinicians familiarith treating this disease It is recommended that
reatment be continued until viral load is undetect-ble followed by prophylactic doses of valgancy-lovir for an additional 3 months35
Epstein-BarrVirus
Current practice regarding EBV screening variesmong centers in the United States and many doot routinely screen for EBV posttransplant evenn recipient-negative donor-positive cases In con-rast to KDIGO recommendation 1311 routineBV screening is not recommended in AST infec-
ious disease guidelines35 In many centers EBVcreening is reserved for children who are muchore commonly EBV negative pretransplant than
dults EBV-induced posttransplant lymphoprolif-rative disorder (PTLD) affects many more pediat-ic than adult KTRs If screening is someday to beoutinely implemented in US centers details regard-ng the best method of screening and levels ofiremia above which a clinical intervention should
e triggered need to be better defined
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ARTICLE IN PRESS
HerpesandVaricella
Systemic herpesvirus infections can be lifehreatening in transplant recipients and should bereated aggressively with intravenous antiviralgents as described in the KDIGO recommenda-ions Less aggressive cutaneous infection can bereated with oral antiviral agents as outlined inhe KDIGO guidelines
Varicella exposure is particularly concerning inransplant recipients The work group disputes theecommended dosing of acyclovir for varicellaxposure Acyclovir at a dose of 10 mgkg or about00 mg 4 times daily of oral acyclovir would betandard dosing We agree with the use of varicellammune globulin and emphasize the need to avoidhe varicella vaccine because it is a live virushould a transplant recipient develop a systemicaricella infection hospitalization and high-dosentravenous acyclovir therapy are warranted
Hepatitis C
Hepatitis C management posttransplant is ahallenge The KDIGO guidelines cited hereere based on the recently published KDIGOuideline for hepatitis C in CKD4 Hepatitis Cypically is not treated posttransplant because ofhe risk (50) of rejection precipitated bynterferon therapy particularly in US KTRs inhom hepatitis C commonly is genotype 1 which
s more resistant to treatment with interferon42
owever should hepatitis Cndashrelated glomerulo-ephritis develop the risk-benefit ratio may fa-or treatment in selected patients Such decisionslways should be made in consultation withepatology and infectious disease experts andhe transplant center Monitoring liver enzymeevels specifically alanine aminotransferaseALT) may reflect a change in hepatitis activityut monitoring hepatitis C viral load is not recom-ended because it does not seem to correlateith outcome Annual monitoring for hepatocel-
ular carcinoma using -fetoprotein and imagings encouraged but not often practiced
Hepatitis B
KDIGO recommendations for hepatitis B areeasonable and currently are followed in mostS centers except for recommendation 1366
see previous recommendation under vaccina-ions) KTRs with hepatitis C or hepatitis B also
hould be followed up by a hepatologist
Human ImmunodeficiencyVirus
Human immunodeficiency virus (HIV)-posi-ive individuals are now acceptable for transplantf CD4 count is 200 cellsL and viral loadVL) is undetectable3543 Transplant should beerformed at centers with expertise in managingIV-positive individuals and care should be co-rdinated carefully with HIV specialists Somentiretroviral agents in particular the proteasenhibitors have potentially serious drug interac-ions with immunosuppressive agents35
DIGORecommendations inChapter 14Othernfections
141 URINARY TRACT INFECTION1411 We suggest that all KTRs receive UTI
prophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 monthsafter transplantation (2B)
1412 For allograft pyelonephritis we suggestinitial hospitalization and treatment withintravenous antibiotics (2C)
142 PNEUMOCYSTIS JIROVECII PNEUMONIA1421 We recommend that all KTRs receive
PCP prophylaxis with daily tri-methoprimndashsulfamethoxazole for 3-6months after transplantation (1B)
1422 We suggest that all KTRs receive PCPprophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 weeksduring and after treatment for acute rejec-tion (2C)
1423 We recommend that KTRs with PCPdiagnosed by bronchial alveolar lavageandor lung biopsy be treated withhigh-dose intravenous trimethoprimndashsulfamethoxazole corticosteroids anda reduction in immunosuppressivemedication (1C)
1424 We recommend treatment with cortico-steroids for KTRs with moderate tosevere PCP (as defined by PaO2 lt70mm Hg in room air or an alveolargradient of gt35 mm Hg) (1C)
143 TUBERCULOSIS1431 We suggest that TB prophylaxis and
treatment regimens be the same in KTRsas would be used in the local generalpopulation who require therapy (2D)
1432 We recommend monitoring CNI andmTORi [mTOR inhibitor] blood levels inpatients receiving rifampin (1C)14321 Consider substituting rifabu-
tin for rifampin to minimize
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KDOQI Commentary 17
ARTICLE IN PRESS
interactions with CNIs andmTORi (Not Graded)
144 CANDIDA PROPHYLAXIS1441 We suggest oral and esophageal Candida
prophylaxis with oral clotrimazole loz-enges nystatin or fluconazole for 1-3months after transplantation and for 1month after treatment with an antilympho-cyte antibody (2C)
DOQIRationale andCommentary
UrinaryTract Infection
Urinary tract infections (UTIs) after kidneyransplant are very common and account for aarge percentage of readmissions posttransplantTIs are common because of multiple factors
ncluding the disrupted anatomy of the urinaryract with a ureteroneocystotomy incompleteladder emptying because of diabetes or pros-atic hypertrophy and impaired immune re-ponses Prophylaxis of UTIs usually is under-aken with trimethoprim-sulfamethoxazole for 6onths posttransplant although infections often
ccur despite therapy because of the develop-ent of drug resistance Although native kidney
yelonephritis does not always require hospital-zation it is recommended that all KTRs withhis diagnosis be hospitalized because the graftysfunction that usually accompanies transplantyelonephritis requires aggressive investigationnd treatment Individuals with recurrent UTIsarrant evaluation with urologic assessment Pa-
ients with recurrent UTIs may benefit fromong-term suppressive therapy
Pneumocystic Pneumonia
We agree that Pneumocystis jirovecii pneumoniaPCP) prophylaxis is important for the first 3-6onths posttransplant (1421)After the first month
very-other-day dosing of trimethoprim-sulfame-hoxazole or atovaquone is believed to be adequaterophylaxis In cases in which neither of thesegents can be used an individual may be treatedrophylactically with inhaled pentamidine OurDOQI work group emphasized that patients whoevelop PCP should be transferred to the transplantenter promptly for management and adjustmentsn immunosuppression
Tuberculosis
Monitoring for latent tuberculosis has posed a
hallenge in the immunosuppressed population be-
ause of the unreliable nature of skin testing Newerechniques involving interferon release assays aremerging as the new gold standard for detection ofatent tuberculosis4445
CandidaProphylaxis
Oral candidiasis must be screened for usingral mucosa examination on follow-up visitsn KTRs This is especially true in the earlyosttransplant period when immunosuppres-ive medication dosage is the highest Wegree with these recommendations and empha-ize that if fluconazole is used there is aotential for serious drug interactions becausef cytochrome P-450 3A4 inhibition
SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
Improvement in short-term outcomes has not trans-lated into significant improvements in long-term out-comes in KTRs The lack of significant improvement inlong-term survival may be related to post-transplantcomplications Frequent posttransplant monitoring mayimprove long-term outcomes by decreasing chronic graftfailure or death with a functioning graft Our work groupconcurred with the recommendation and schedules ofroutine screening in monitoring kidney allograft functionafter kidney transplant with a low threshold for perform-ing kidney biopsy in cases of graft dysfunction or protein-uria Expert tissue processing and interpretation of trans-plant biopsy specimens by pathologists with transplantexperience are critical Regular surveillance of the pa-tientrsquos kidney function at the transplant center or in thenephrologistrsquos office offers an opportunity to enhancepatient adherence to medication diet and healthy life-style Although CKD in KTRs progresses more slowlythan CKD in other patients the work group agreed thatthe KDIGO guidelines on CKD should be followed inKTRs
Opportunistic infections are common in KTRs al-though advances in diagnosis and treatment have led toimproved survival in KTRs with infection It is nowstandard of care to use vaccinations in KTRs as long asthe vaccine does not contain live or attenuated virus Italso is routine to screen for or use prophylaxis to preventseveral posttransplant viral infections With few excep-tions (related to EBV and BK virus screening andhepatitis B vaccination posttransplant) we concurredwith KDIGO guidelines for vaccination screening and
treatment of infection posttransplant
KD
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COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULAR
DISEASE
DIGORecommendations inChapter 15iabetesMellitus
151 Screening for New-Onset Diabetes after Transplan-tation1511 We recommend screening all nondia-
betic KTRs with fasting plasma glu-cose oral glucose tolerance testingandor HbA1c (1C) at leastbull weekly for 4 weeks (2D)bull every 3 months for 1 year (2D)bull and annually thereafter (2D)
1512 We suggest screening for NODAT withfasting glucose oral glucose tolerancetesting andor after starting or substan-tially increasing the dose of CNIsmTORi or corticosteroids (2D)
152 Managing NODAT or Diabetes Present at Trans-plantation1521 If NODAT develops consider modifying
the immunosuppressive drug regimen toreverse or ameliorate diabetes afterweighing the risk of rejection and otherpotential adverse effects (Not Graded)
1522 Consider targeting HbA1c 70-75and avoid targeting HbA1c 60 espe-cially if hypoglycemic reactions are com-mon (Not Graded)
1523 We suggest that in patients with diabetesaspirin (65-100 mgd) use for the primaryprevention of CVD be based on patientpreferences and values balancing the riskfor ischemic events to that of bleeding(2D)
DOQIRationale andCommentary
Diabetic Screening
We agree with screening for new-onset diabetesfter transplantation (NODAT) as outlined by theDIGO work group Definitions used are similar
o those of the American Diabetes AssociationADA) The greater frequency of testing initially isustified by the high risk of NODAT in the earlyosttransplant period however ongoing screenings required because the risk of the development ofODAT continues to increase over time4647 We
lso point out that prediabetic states (impairedasting glucose level and impaired glucose toler-nce) occur even more commonly than overt diabe-es48 and may be associated with metabolic syn-rome as well as with increased cardiovascular
ortality49-51 Potential implications of these predia-
etic states emphasize the importance of perform-ng blood tests under fasting conditions For pa-ients with fasting hyperglycemia an oral glucoseolerance test or hemoglobinA1c (HbA1c) test shoulde performed Although more cumbersome to per-orm data suggest that an oral glucose toleranceest is a more sensitive indicator of NODAT inyperglycemic KTRs52 This may allow earlieretection of overt diabetes and more prompt institu-ion of treatment
DiabetesManagement
Data supporting a substantial benefit in themelioration or reversal of NODAT using immu-osuppression modification in KTRs are veryimited There was consensus in our work grouphat considering the paucity of data for reversingODAT by changing immunosuppression and
he potential risk of an adverse outcome withuch a maneuver KDIGO suggestion 1521 couldot be supported Certainly if such a step waseing considered it should be done in conjunc-ion with the transplant center Targeting an HbA1c
evel of 7-75 and avoiding levels 6 isased on data showing increased cardiovascularvents with the lower HbA1c target5354
DIGORecommendations inChapter 16ypertensionDyslipidemias TobaccoUse andbesity
161 Hypertension1611 We recommend measuring blood pres-
sure at each clinic visit (1C)1612 We suggest maintaining blood pressure at
130 mm Hg systolic and 80 mm Hgdiastolic if 18 years of age and 90th
percentile for sex age and height if 18years old (2C)
1613 To treat hypertension (Not Graded)bull Use any class of antihypertensive
agentbull Monitor closely for adverse effects
and drug-drug interactions and whenurine protein excretion 1 gd for18 years old and 600 mgm224 hfor 18 years old consider an ACE-Ior an ARB as first-line therapy
162 Dyslipidemias (These recommendations are basedon KDOQI Dyslipidemia Guidelines and are thusnot graded)1621 Measure a complete lipid profile in all
adult (18 years old) and adolescent
(puberty to 18 years old) KTRs [Based on
K
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KDOQI Commentary 19
ARTICLE IN PRESS
KDOQI Dyslipidemia Recommendation1]bull 2-3 months after transplantationbull 2-3 months after a change in treatment
or other conditions known to causedyslipidemias
bull at least annually thereafter1622 Evaluate KTRs with dyslipidemias for
secondary causes [Based on KDOQI Dys-lipidemia Recommendation 3]16221 For KTRs with fasting triglyc-
erides 500 mgdL (565mmolL) that cannot be cor-rected by removing an under-lying cause treat withbull Adults therapeutic lifestyle
changes and a triglyceride-lowering agent [Based onKDOQI Recommendation41]
bull Adolescents therapeutic life-style changes [Based onKDOQI Recommendation51]
16222 For KTRs with elevatedLDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)treat to reduce LDL-C to100 mgdL (259mmolL) [Based on KDOQIGuideline 42]
bull Adolescents If LDL-C130 mgdL (336 mmolL) treat to reduce LDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 52]
16223 For KTRs with normalLDL-C elevated triglyceridesand elevated non-HDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)fasting triglycerides 200mgdL (226 mmolL)and non-HDL-C 130mgdL (336 mmolL)treat to reduce non-HDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 43]
bull Adolescents If LDL-C130 mgdL (336 mmolL) fasting triglycerides200 mgdL (226 mmolL) and non-HDL-C 160mgdL (414 mmolL)treat to reduce non-HDL-C
to 160 mgdL (414 i
mmolL) [Based on KDOQIGuideline 53]
163 Tobacco Use1631 Screen and counsel all KTRs including
adolescents and children for tobacco useand record the results in the medicalrecord (Not Graded)bull Screen during initial transplant hospi-
talizationbull Screen at least annually thereafter
1632 Offer treatment to all patients who usetobacco (Not Graded)
164 Obesity1641 Assess obesity at each visit (Not Graded)
bull Measure height and weight at eachvisit in adults and children
bull Calculate BMI at each visitbull Measure waist circumference when
weight and physical appearance sug-gest obesity but BMI is 35 kgm2
1642 Offer a weight-reduction program to allobese KTRs (Not Graded)
DOQIRationale andCommentary
Hypertension
The KDIGO work group adapted the KDOQI004 recommendations for target blood pres-ure in KTRs55 Self measurement is useful inssessing response to therapy and enhancesdherence56 In general we agree that the classf antihypertensive agent does not matter inhe treatment of blood pressure elevation inhis population and that attention should beiven to potential side effects of antihyperten-ive agents as well as possible interactionsith the immunosuppressive regimen (eg non-ihydropyridine calcium channel blockers andNIs) In the absence of adequate randomizedontrolled trials it is not known whether angio-ensin-converting enzyme (ACE) inhibitors andngiotensin receptor blockers (ARBs) prolongecipient or allograft survival Some but notll retrospective studies suggest a benefitowever all these studies are limited by selec-ion bias5758 Although ACE inhibitors andRBs commonly lead to some decrease inFR treatment with these drugs should be
ontinued unless serum creatinine level in-reases by 25 to 30 in keeping withDOQI recommendations55 In KTRs receiv-
ng ACE inhibitors or ARBs it is important toducate patients to maintain adequate fluid
ntake during illness to prevent a prerenal
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ARTICLE IN PRESS
nsult to the allograft Similarly awareness isecessary when using diuretics in conjunctionith therapies that block the renin-angiotensin-
ldosterone-system59
Dyslipidemia
The KDIGO work group based their recom-endations for evaluation and treatment of
yperlipidemia on the KDOQI dyslipidemiauidelines for KTRs60 We agree with theseecommendations CNIs potentiate the toxicityf statins by slowing their metabolism throughhe cytochrome P-450 system This interactionccurs more commonly with cyclosporine61
han with tacrolimus Dyslipidemia especiallyypertriglyceridemia frequently complicatesTOR-inhibitor use and lipid-lowering therapy
s required in most patients using these agents
TobaccoUse
Not surprisingly tobacco use at the time ofransplant is associated with decreased patientnd graft survival as well as increased risk ofosttransplant cardiovascular disease (CVD)lthough the KDIGO work group recom-ends initial screening and intervention dur-
ng the hospitalization for transplant we be-ieve there may be benefit gained by startingounseling in the pretransplant period duringhe evaluation phase Unfortunately this doesot occur often because of time and personnelonstraints in transplant centers Ideally allransplant centers should have smoking-cessa-ion programs available to patients either in-ouse or through referral Ideally systemshould be created to continue to screen andonitor for smoking cessation at yearly inter-
als after transplant because there is a highate of relapse with this addiction As outlinedn KDIGO Table 253 although all pharmaco-ogic therapies for smoking cessation can besed in KTRs the starting dose of vareniclinehould be decreased in patients with GFR 30Lmin
Obesity
Obesity is an epidemic in the United Statesnd the proportion of obese kidney transplantandidates continues to grow In additioneight gain after transplant is very commonly
bserved Obesity in KTRs is associated with w
ncreased risks of wound complications de-ayed graft function acute rejection and NO-AT resulting in inferior patient and graftutcomes Attention to this potential complica-ion and counseling should be initiated duringhe pretransplant evaluation phase Informa-ion regarding pharmacologic therapies foreight loss in KTRs is not available and we
gree with the KDIGO work group that thera-eutic lifestyle measures should be encour-ged Data regarding steroid therapy with-rawal and weight gain are controversial Aecent double-blind randomized controlled trialxamining early steroid therapy withdrawalid not show a difference in weight gain at 5ears posttransplant compared with the cohortemaining on standard maintenance corticoste-oid therapy62
DIGORecommendations inChapter 17ardiovascularManagement
171 Consider managing CVD at least as intensively inKTRs as in the general population with appropri-ate diagnostic tests and treatments (Not Graded)
172 We suggest using aspirin (65-100 mgd) in allpatients with atherosclerotic CVD unless there arecontraindications (2B)
DOQIRationale andCommentary
Although outcomes are favorable comparedith remaining on the waiting list the risk of
ardiovascular mortality in KTRs is several-foldigher than observed in the general population63
specially in younger age groups and patientsith decreasing allograft function64 CVD is aajor cause of graft loss after the first post-
ransplant year In this context we strongly agreehat CVD should be managed in KTRs at least asntensively as in the general population Ideallyecreasing CVD risk in KTRs requires a multifac-ted and multidisciplinary approach Based onurrent practice models in the United States theransplant and nephrology community has notet been able to achieve these desirable goals65
his clearly deserves more attention becauseontrol of CVD has the potential to contributeore to long-term kidney graft survival than the
iscovery of newer drugs that decrease the ratef allograft rejection Our KDOQI working groupgreed with the use of low-dose aspirin in KTRs
ith evidence of atherosclerosis
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KDOQI Commentary 21
ARTICLE IN PRESS
SUMMARY OF COMMENTARY ONSECTION III CVD
COMMENTARY ON SECTION IV OF KDIGO
TRANSPLANT GUIDELINE MALIGNANCY
DIGORecommendations inChapter 18 Cancerf the Skin andLip
181 We recommend that KTRs especially thosewho have fair skin live in high sun-exposureclimates have occupations requiring sun expo-sure have had significant sun exposure as achild or have a history of skin cancer be toldthat their risk of skin and lip cancer is veryhigh (1C)
182 We recommend that KTRs minimize life-longsun exposure and use appropriate ultravioletlight blocking agents (1D)
183 We suggest that adult KTRs perform skin andlip self-examinations and report new lesions toa health-care provider (2D)
184 For adult KTRs we suggest that a qualified healthprofessional with experience in diagnosing skincancer perform annual skin and lip examinationon KTRs except possibly for KTRs with dark skinpigmentation (2D)
185 We suggest that patients with a history of skin orlip cancer or premalignant lesions be referred to andfollowed by a qualified health professional withexperience in diagnosing and treating skin cancer
With the decrease in acute rejection during the pastdecade in association with improved immunosuppres-sion regimens patient death now rivals chronic graftdysfunction as one of the leading causes of long-termgraft loss Because CVD is the most common cause ofpatient death in KTRs a concerted effort at minimizingrisk factors for heart disease likely will have as great oreven greater impact on optimizing patient and graftoutcomes than the discovery of new antirejection thera-pies CVD risk reduction strategies should include regularscreening for new-onset diabetes (using ADA-based defini-tions) in the posttransplant period in previously nondiabeticpatients good glycemic regulation for diabetic patients accord-ing to current ADA guidelines and lipid management andblood pressure control according to KDOQI recommenda-tions In addition promotion of a healthy lifestyle throughweight control exercise and smoking cessation should be acentral part of posttransplant counseling and care Whenimmunosuppression modification is being considered to miti-gate cardiovascular risk we recommend that this be inconjunction with the transplant center In summary we gener-ally concurred with the suggestions of the work group in thissection but based on current practice standards in the UnitedStateschallengesremainwith implementationof thisguideline
(2D) s
186 We suggest that patients with a history of skincancer be offered treatment with oral acitretin ifthere are no contraindications (2B)
DOQIRationale andCommentary
CounselingandSunscreen
We concur with recommendations 181 and82 because skin cancer is a major source oforbidity and sometimes mortality in KTRsarning patients at risk of the high danger of
kin cancer a 1C recommendation is reinforcedy a recent prospective case-control study ofrgan transplant recipients that showed that regu-ar use of broad-spectrum sunscreens that pro-ide UVA and UVB protection may prevent theevelopment of actinic keratosis invasive squa-ous cell carcinoma and to a lesser extent
asal cell carcinoma66 Most cancer-causing ra-iation is thought to come from the UVB spec-rum and newer broad-spectrum sunscreens pro-ide protection against UVA and UVB radiationounseling about sunscreen and the need for sunvoidance needs to be incorporated into routineffice visits although it may not always beuccessful In a recent study of KTRs in which1 of patients had been informed about theeed for sun protection only 46 used morehan a tube of sunscreen per year67
Dermatology Involvement
There is increased evidence to suggest thatpecialty dermatology clinics for organ trans-lant recipients improve outcome measures in-luding compliance with photoprotection andncreased awareness of skin cancer68 The re-ources required for these specialty clinics makemplementation difficult for community nephrol-gy groups that do not have direct access to aransplant center Transplant patients should bencouraged to have annual visits with their trans-lant center and if dermatology specialty clinicsre available attempt to coordinate a skin cancervaluation annually
UseofRetinoid-likeCompounds
There is a limited scientific basis for KDIGOuggestion recommendation 186 Although reti-oids now are used routinely in KTRs with aigh skin cancer burden our KDOQI work groupelieves that more data are needed before this
uggestion should be accepted as a guideline In
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ARTICLE IN PRESS
ow-immunologic-risk groups and particularlyifficult cases some data suggest that switchingrom CNI to sirolimus therapy may decrease thencidence of skin cancer69 however the riskersus benefit of this maneuver has not been welltudied
DIGORecommendations inChapter 19on-SkinMalignancies
191 Develop an individualized screening plan for eachKTR that takes into account the patientrsquos pastmedical and family history tobacco use compet-ing risks for death and the performance of thescreening methodology (Not Graded)
192 Screen for the following cancers as per localguidelines for the general population (Not Graded)Women cervical breast and colon cancer Menprostate and colon cancer
193 Obtain hepatic ultrasound and alpha feto-proteinevery 12 months in patients with compensatedcirrhosis (Not Graded) [See Recommendations1354 (HCV) and 1365 (HBV)]
DOQIRationale andCommentary
Screening
It is recognized that KTRs have a higher inci-ence of malignancy particularly those associatedith specific viral infections Although cancer
creening may have benefits in this higher riskopulation it should be reinforced that some meth-ds of screening have significant risks which shoulde considered on an individualized basis particu-arly in patients who have projected survival lesshan 5 years
Screening forCancer inPatientsWithHepatitis
Many patients who have underlying cirrhosisn the United States will be followed up by arofessional specializing in liver disease whoay provide additional insight into this cancer
creening recommendation Based on a recentuestionnaire of US gastroenterologists only 50creen patients for hepatocellular carcinoma70
herefore implementation of this guideline byS clinicians is unlikely to be widespread
DIGORecommendations inChapter 20anagingCancerwithReductionof
mmunosuppressiveMedication
201 We suggest consideration be given to reducingimmunosuppressive medications for KTRs with can-
cer (2C)
2011 Important factors for consideration in-clude (Not Graded)bull The stage of cancer at diagnosisbull Whether the cancer is likely to be
exacerbated by immunosuppressionbull The therapies available for the can-
cerbull Whether immunosuppressive medica-
tions interfere with ability to admin-ister the standard chemotherapy
202 For patients with Kaposi sarcoma we suggestusing mTORi along with a reduction in overallimmunosuppression (2C)
DOQIRationale andCommentary
Table 1 (Table 29 in the KDIGO report3 andxcerpted from Grulich et al71) lists cancershat are increased most in immunosuppressedTRs based on standardized incidence ratios
SIRs) which compare the incidence toatched populations Cancers with the highestIRs may be those most likely to respond to aecrease in immunosuppression Except foraposi sarcoma limited evidence is available
or a decrease in immunosuppression in theseettings A strategy to change immunosuppres-ion therapy must occur in consultation withhe transplant center Switching to sirolimusherapy and decreasing immunosuppression inatients who develop Kaposi sarcoma is basedn sound scientific rationale7273
SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
The incidence of cancer posttransplant is 2-20times higher than that in the general population andKDIGO guidelines have been written to outline stepsfor prevention and screening With few exceptions weagree with the recommendations as outlined Skincancer is common in US transplant patients andscreening and prevention are critical However imple-mentation of guidelines for doing so including theKDIGO guidelines is a challenge because of patientpreferences against the routine use of sunscreen aswell as time constraints during office visits Althoughmany posttransplant cancers are viral mediated andrelated to immunosuppression it is less clear how toalter immunosuppression after malignancy has oc-curred We agree that although age-specific screeningfor malignancy should be incorporated into care con-sideration must be given to the risk of screening inpatients with limited life spans (5 years) because of
comorbid conditions
KT
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
ommonPopu
i sarco-Hodgmelanise sm
sophaemia
estima standa10 c
ut esti
0 case
alized t
to guide treatment specifically before the
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
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m J Transplant 20099894-906
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sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
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uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
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f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
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18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
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orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
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ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
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ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
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elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
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81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
Bia et al14
ARTICLE IN PRESS
1332 We suggest that EBV-seronegative pa-tients with an increasing EBV load haveimmunosuppressive medication reduced(2D)
1333 We recommend that patients with EBVdisease including PTLD have a reduc-tion or cessation of immunosuppres-sive medication (1C)
134 HERPES SIMPLEX VIRUS 1 2 AND VARI-CELLA ZOSTER VIRUS1341 We recommend that KTRs who de-
velop a superficial HSV 1 2 infectionbe treated (1B) with an appropriateoral antiviral agent (eg acyclovir vala-cyclovir or famciclovir) until all le-sions have resolved (1D)
1342 We recommend that KTRs with sys-temic HSV 1 2 infection be treated(1B) with intravenous acyclovir and areduction in immunosuppressive medi-cation (1D)13421 We recommend that intrave-
nous acyclovir continue un-til the patient has a clinicalresponse (1B) then switch toan appropriate oral antiviralagent (eg acyclovir valacy-clovir or famciclovir) to com-plete a total treatment durationof 14-21 days (2D)
1343 We suggest using a prophylactic antiviralagent for KTRs experiencing frequentrecurrences of HSV 12 infection (2D)
1344 We recommend that primary VZV infec-tion (chicken pox) in KTRs be treated(1C) with either intravenous or oral acy-clovir or valacyclovir and a temporaryreduction in amount of immunosuppres-sive medication (2D)
135 HEPATITIS C VIRUS1351 We suggest that HCV-infected KTRs be
treated only when the benefits of treat-ment clearly outweigh the risk of allo-graft rejection due to interferon-basedtherapy (eg fibrosing cholestatic hepati-tis life-threatening vasculitis) (2D)[Based on KDIGO Hepatitis C Recom-mendation 215]
1352 We suggest monotherapy with standardinterferon for HCV-infected KTRs inwhom the benefits of antiviral treatmentclearly outweigh the risks (2D) [Basedon KDIGO Hepatitis C Recommenda-tions 224 and 442]
1353 We suggest that all conventional currentinduction and maintenance immunosup-pressive regimens can be used in HCVinfected patients (2D) [Based on KDIGO
Hepatitis C Recommendation 43]
1354 Measure ALT in HCV-infected patientsmonthly for the first 6 months and every3-6 months thereafter Perform imagingannually to look for cirrhosis and hepato-cellular carcinoma (Not Graded) [Basedon KDIGO Hepatitis C Recommendation441] (See Recommendation 193)
1355 Test HCV-infected patients at least every3-6 months for proteinuria (Not Graded)[Based on KDIGO Hepatitis C Recom-mendation 444]13551 For patients who develop new
onset proteinuria (either urineproteincreatinine ratio 1 or24-hour urine protein 1 g ontwo or more occasions) per-form an allograft biopsy withimmunofluorescence and elec-tron microscopy (Not Graded)[Based on KDIGO Hepatitis CRecommendation 444]
1356 We suggest that patients with HCV asso-ciated glomerulopathy not receive inter-feron (2D) [Based on KDIGO HepatitisC Recommendation 445]
136 HEPATITIS B VIRUS1361 We suggest that any currently available
induction and maintenance immunosup-pressive medication can be used in HBV-infected KTRs (2D)
1362 We suggest that interferon treatmentshould generally be avoided in HBVinfected KTRs (2C)
1363 We suggest that all HBsAg-positive KTRsreceive prophylaxis with tenofovir ente-cavir or lamivudine (2B)13631 Tenofovir or entecavir are pref-
erable to lamivudine to mini-mize development of potentialdrug resistance unless medica-tion cost requires that lami-vudinebe used (Not Graded)
13632 During therapy with antivi-rals measure HBV DNA andALT levels every 3 months tomonitor efficacy and to detectdrug resistance (Not Graded)
1364 We suggest treatment with adefovir ortenofovir for KTRs with lamivudine resis-tance (5 log10 copiesmL rebound ofHBV-DNA) (2D)
1365 Screen HBsAg-positive patients with cir-rhosis for hepatocellular carcinoma every12 months with liver ultrasound andalpha feto-protein (Not Graded) (SeeRecommendation 193)
1366 We suggest that patients who are negativefor HBsAg and have HBsAb titer 10mIUmL receive booster vaccination to
raise the titer to 100 mIUmL (2D)
K
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anitEtsmaerriv
KDOQI Commentary 15
ARTICLE IN PRESS
137 HUMAN IMMUNODEFICIENCY VIRUS1371 If not already done screen for HIV
infection (Not Graded)1372 To determine antiretroviral therapy refer
HIV-infected KTRs to an HIV specialistwho should pay special attention to drugndashdrug interactions and appropriate dosingof medications (Not Graded)
DOQIRationale andCommentary
Viral infections are particularly problematic inransplant recipients because of the preferentialnhibition of T-lymphocyte function by both induc-ion and maintenance immunosuppression Use ofnduction immunosuppression with lymphocyte-epleting agents (thymoglobulin or alemtuzumab)s associated with a greater risk of viral infectionosttransplant In general the greater the cumula-ive exposure to immunosuppression the greaterhe risk of infectious complications The presenta-ion of viral infections can be asymptomatic vaguend nonspecific or life-threatening acute illnessany viral infections seen in KTRs are rarely seen
n immunocompetent patients and therefore do notnter into the differential diagnosis for physiciansnfamiliar with transplant recipients Close commu-ication with the transplant center is crucial inaring for the transplant population Early detectionnd institution of therapy provide the best chanceor viral eradication
BKVirus
Although the work group agreed with KDIGOuggestions for BK virus screening posttransplante did not think it was practical to require screen-
ng exclusively with quantitative plasma nucleiccid testing (NAT) because many US centers usenitial urinary screening and then test plasma onlyf urine screening results are positive Howeverhere is no disagreement that some type of screen-ng for BK virus is critical to avoid BK nephropa-hy for which there is no specific treatment when its established Complicating screening for BK vi-us is the variability in results between laboratoriesnd uncertainty about the level of viremia thathould trigger a response to decrease in immunosup-ression In the presence of viremia and increase inerum creatinine level a renal allograft biopsy isndicated to confirm the presence of BK nephropa-
hy Because BK viremia and viruria certainly can b
e detected beyond the first year it is not clear howong screening should be continued posttransplantlthough most centers screen for the first year onlyngoing clinical trials are exploring effective treat-ent for BK nephropathy3839 Decisions about
ecreases in immunosuppression currently theainstay of BK viremia management always
hould be made in consultation with the transplantenter
Cytomegalovirus
KDIGO recommendation 1321 regarding cyto-egalovirus (CMV) prophylaxis is reasonable and
pplicable to the US population Universal prophy-axis for CMV now is recommended over initiatingre-emptive treatment after CMV develops40 Aajor concern for US patients is the cost of CMV
rophylaxis with oral valgancyclovir Leukopeniaan be observed in patients using mycophenolatereparations when prophylaxis with valgancyclo-ir is used Screening for CMV is best performedsing NAT methods (1322) CMV antigenemiassays are still in use in many facilities but are nots sensitive as PCR assays41 There is no utility inhecking for serologic response to CMV with IgGr IgM titers posttransplant because the immuneesponse is not predictable Patients with CMVisease should be cared for by clinicians familiarith treating this disease It is recommended that
reatment be continued until viral load is undetect-ble followed by prophylactic doses of valgancy-lovir for an additional 3 months35
Epstein-BarrVirus
Current practice regarding EBV screening variesmong centers in the United States and many doot routinely screen for EBV posttransplant evenn recipient-negative donor-positive cases In con-rast to KDIGO recommendation 1311 routineBV screening is not recommended in AST infec-
ious disease guidelines35 In many centers EBVcreening is reserved for children who are muchore commonly EBV negative pretransplant than
dults EBV-induced posttransplant lymphoprolif-rative disorder (PTLD) affects many more pediat-ic than adult KTRs If screening is someday to beoutinely implemented in US centers details regard-ng the best method of screening and levels ofiremia above which a clinical intervention should
e triggered need to be better defined
ttattt
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Bia et al16
ARTICLE IN PRESS
HerpesandVaricella
Systemic herpesvirus infections can be lifehreatening in transplant recipients and should bereated aggressively with intravenous antiviralgents as described in the KDIGO recommenda-ions Less aggressive cutaneous infection can bereated with oral antiviral agents as outlined inhe KDIGO guidelines
Varicella exposure is particularly concerning inransplant recipients The work group disputes theecommended dosing of acyclovir for varicellaxposure Acyclovir at a dose of 10 mgkg or about00 mg 4 times daily of oral acyclovir would betandard dosing We agree with the use of varicellammune globulin and emphasize the need to avoidhe varicella vaccine because it is a live virushould a transplant recipient develop a systemicaricella infection hospitalization and high-dosentravenous acyclovir therapy are warranted
Hepatitis C
Hepatitis C management posttransplant is ahallenge The KDIGO guidelines cited hereere based on the recently published KDIGOuideline for hepatitis C in CKD4 Hepatitis Cypically is not treated posttransplant because ofhe risk (50) of rejection precipitated bynterferon therapy particularly in US KTRs inhom hepatitis C commonly is genotype 1 which
s more resistant to treatment with interferon42
owever should hepatitis Cndashrelated glomerulo-ephritis develop the risk-benefit ratio may fa-or treatment in selected patients Such decisionslways should be made in consultation withepatology and infectious disease experts andhe transplant center Monitoring liver enzymeevels specifically alanine aminotransferaseALT) may reflect a change in hepatitis activityut monitoring hepatitis C viral load is not recom-ended because it does not seem to correlateith outcome Annual monitoring for hepatocel-
ular carcinoma using -fetoprotein and imagings encouraged but not often practiced
Hepatitis B
KDIGO recommendations for hepatitis B areeasonable and currently are followed in mostS centers except for recommendation 1366
see previous recommendation under vaccina-ions) KTRs with hepatitis C or hepatitis B also
hould be followed up by a hepatologist
Human ImmunodeficiencyVirus
Human immunodeficiency virus (HIV)-posi-ive individuals are now acceptable for transplantf CD4 count is 200 cellsL and viral loadVL) is undetectable3543 Transplant should beerformed at centers with expertise in managingIV-positive individuals and care should be co-rdinated carefully with HIV specialists Somentiretroviral agents in particular the proteasenhibitors have potentially serious drug interac-ions with immunosuppressive agents35
DIGORecommendations inChapter 14Othernfections
141 URINARY TRACT INFECTION1411 We suggest that all KTRs receive UTI
prophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 monthsafter transplantation (2B)
1412 For allograft pyelonephritis we suggestinitial hospitalization and treatment withintravenous antibiotics (2C)
142 PNEUMOCYSTIS JIROVECII PNEUMONIA1421 We recommend that all KTRs receive
PCP prophylaxis with daily tri-methoprimndashsulfamethoxazole for 3-6months after transplantation (1B)
1422 We suggest that all KTRs receive PCPprophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 weeksduring and after treatment for acute rejec-tion (2C)
1423 We recommend that KTRs with PCPdiagnosed by bronchial alveolar lavageandor lung biopsy be treated withhigh-dose intravenous trimethoprimndashsulfamethoxazole corticosteroids anda reduction in immunosuppressivemedication (1C)
1424 We recommend treatment with cortico-steroids for KTRs with moderate tosevere PCP (as defined by PaO2 lt70mm Hg in room air or an alveolargradient of gt35 mm Hg) (1C)
143 TUBERCULOSIS1431 We suggest that TB prophylaxis and
treatment regimens be the same in KTRsas would be used in the local generalpopulation who require therapy (2D)
1432 We recommend monitoring CNI andmTORi [mTOR inhibitor] blood levels inpatients receiving rifampin (1C)14321 Consider substituting rifabu-
tin for rifampin to minimize
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KDOQI Commentary 17
ARTICLE IN PRESS
interactions with CNIs andmTORi (Not Graded)
144 CANDIDA PROPHYLAXIS1441 We suggest oral and esophageal Candida
prophylaxis with oral clotrimazole loz-enges nystatin or fluconazole for 1-3months after transplantation and for 1month after treatment with an antilympho-cyte antibody (2C)
DOQIRationale andCommentary
UrinaryTract Infection
Urinary tract infections (UTIs) after kidneyransplant are very common and account for aarge percentage of readmissions posttransplantTIs are common because of multiple factors
ncluding the disrupted anatomy of the urinaryract with a ureteroneocystotomy incompleteladder emptying because of diabetes or pros-atic hypertrophy and impaired immune re-ponses Prophylaxis of UTIs usually is under-aken with trimethoprim-sulfamethoxazole for 6onths posttransplant although infections often
ccur despite therapy because of the develop-ent of drug resistance Although native kidney
yelonephritis does not always require hospital-zation it is recommended that all KTRs withhis diagnosis be hospitalized because the graftysfunction that usually accompanies transplantyelonephritis requires aggressive investigationnd treatment Individuals with recurrent UTIsarrant evaluation with urologic assessment Pa-
ients with recurrent UTIs may benefit fromong-term suppressive therapy
Pneumocystic Pneumonia
We agree that Pneumocystis jirovecii pneumoniaPCP) prophylaxis is important for the first 3-6onths posttransplant (1421)After the first month
very-other-day dosing of trimethoprim-sulfame-hoxazole or atovaquone is believed to be adequaterophylaxis In cases in which neither of thesegents can be used an individual may be treatedrophylactically with inhaled pentamidine OurDOQI work group emphasized that patients whoevelop PCP should be transferred to the transplantenter promptly for management and adjustmentsn immunosuppression
Tuberculosis
Monitoring for latent tuberculosis has posed a
hallenge in the immunosuppressed population be-
ause of the unreliable nature of skin testing Newerechniques involving interferon release assays aremerging as the new gold standard for detection ofatent tuberculosis4445
CandidaProphylaxis
Oral candidiasis must be screened for usingral mucosa examination on follow-up visitsn KTRs This is especially true in the earlyosttransplant period when immunosuppres-ive medication dosage is the highest Wegree with these recommendations and empha-ize that if fluconazole is used there is aotential for serious drug interactions becausef cytochrome P-450 3A4 inhibition
SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
Improvement in short-term outcomes has not trans-lated into significant improvements in long-term out-comes in KTRs The lack of significant improvement inlong-term survival may be related to post-transplantcomplications Frequent posttransplant monitoring mayimprove long-term outcomes by decreasing chronic graftfailure or death with a functioning graft Our work groupconcurred with the recommendation and schedules ofroutine screening in monitoring kidney allograft functionafter kidney transplant with a low threshold for perform-ing kidney biopsy in cases of graft dysfunction or protein-uria Expert tissue processing and interpretation of trans-plant biopsy specimens by pathologists with transplantexperience are critical Regular surveillance of the pa-tientrsquos kidney function at the transplant center or in thenephrologistrsquos office offers an opportunity to enhancepatient adherence to medication diet and healthy life-style Although CKD in KTRs progresses more slowlythan CKD in other patients the work group agreed thatthe KDIGO guidelines on CKD should be followed inKTRs
Opportunistic infections are common in KTRs al-though advances in diagnosis and treatment have led toimproved survival in KTRs with infection It is nowstandard of care to use vaccinations in KTRs as long asthe vaccine does not contain live or attenuated virus Italso is routine to screen for or use prophylaxis to preventseveral posttransplant viral infections With few excep-tions (related to EBV and BK virus screening andhepatitis B vaccination posttransplant) we concurredwith KDIGO guidelines for vaccination screening and
treatment of infection posttransplant
KD
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Bia et al18
ARTICLE IN PRESS
COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULAR
DISEASE
DIGORecommendations inChapter 15iabetesMellitus
151 Screening for New-Onset Diabetes after Transplan-tation1511 We recommend screening all nondia-
betic KTRs with fasting plasma glu-cose oral glucose tolerance testingandor HbA1c (1C) at leastbull weekly for 4 weeks (2D)bull every 3 months for 1 year (2D)bull and annually thereafter (2D)
1512 We suggest screening for NODAT withfasting glucose oral glucose tolerancetesting andor after starting or substan-tially increasing the dose of CNIsmTORi or corticosteroids (2D)
152 Managing NODAT or Diabetes Present at Trans-plantation1521 If NODAT develops consider modifying
the immunosuppressive drug regimen toreverse or ameliorate diabetes afterweighing the risk of rejection and otherpotential adverse effects (Not Graded)
1522 Consider targeting HbA1c 70-75and avoid targeting HbA1c 60 espe-cially if hypoglycemic reactions are com-mon (Not Graded)
1523 We suggest that in patients with diabetesaspirin (65-100 mgd) use for the primaryprevention of CVD be based on patientpreferences and values balancing the riskfor ischemic events to that of bleeding(2D)
DOQIRationale andCommentary
Diabetic Screening
We agree with screening for new-onset diabetesfter transplantation (NODAT) as outlined by theDIGO work group Definitions used are similar
o those of the American Diabetes AssociationADA) The greater frequency of testing initially isustified by the high risk of NODAT in the earlyosttransplant period however ongoing screenings required because the risk of the development ofODAT continues to increase over time4647 We
lso point out that prediabetic states (impairedasting glucose level and impaired glucose toler-nce) occur even more commonly than overt diabe-es48 and may be associated with metabolic syn-rome as well as with increased cardiovascular
ortality49-51 Potential implications of these predia-
etic states emphasize the importance of perform-ng blood tests under fasting conditions For pa-ients with fasting hyperglycemia an oral glucoseolerance test or hemoglobinA1c (HbA1c) test shoulde performed Although more cumbersome to per-orm data suggest that an oral glucose toleranceest is a more sensitive indicator of NODAT inyperglycemic KTRs52 This may allow earlieretection of overt diabetes and more prompt institu-ion of treatment
DiabetesManagement
Data supporting a substantial benefit in themelioration or reversal of NODAT using immu-osuppression modification in KTRs are veryimited There was consensus in our work grouphat considering the paucity of data for reversingODAT by changing immunosuppression and
he potential risk of an adverse outcome withuch a maneuver KDIGO suggestion 1521 couldot be supported Certainly if such a step waseing considered it should be done in conjunc-ion with the transplant center Targeting an HbA1c
evel of 7-75 and avoiding levels 6 isased on data showing increased cardiovascularvents with the lower HbA1c target5354
DIGORecommendations inChapter 16ypertensionDyslipidemias TobaccoUse andbesity
161 Hypertension1611 We recommend measuring blood pres-
sure at each clinic visit (1C)1612 We suggest maintaining blood pressure at
130 mm Hg systolic and 80 mm Hgdiastolic if 18 years of age and 90th
percentile for sex age and height if 18years old (2C)
1613 To treat hypertension (Not Graded)bull Use any class of antihypertensive
agentbull Monitor closely for adverse effects
and drug-drug interactions and whenurine protein excretion 1 gd for18 years old and 600 mgm224 hfor 18 years old consider an ACE-Ior an ARB as first-line therapy
162 Dyslipidemias (These recommendations are basedon KDOQI Dyslipidemia Guidelines and are thusnot graded)1621 Measure a complete lipid profile in all
adult (18 years old) and adolescent
(puberty to 18 years old) KTRs [Based on
K
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KDOQI Commentary 19
ARTICLE IN PRESS
KDOQI Dyslipidemia Recommendation1]bull 2-3 months after transplantationbull 2-3 months after a change in treatment
or other conditions known to causedyslipidemias
bull at least annually thereafter1622 Evaluate KTRs with dyslipidemias for
secondary causes [Based on KDOQI Dys-lipidemia Recommendation 3]16221 For KTRs with fasting triglyc-
erides 500 mgdL (565mmolL) that cannot be cor-rected by removing an under-lying cause treat withbull Adults therapeutic lifestyle
changes and a triglyceride-lowering agent [Based onKDOQI Recommendation41]
bull Adolescents therapeutic life-style changes [Based onKDOQI Recommendation51]
16222 For KTRs with elevatedLDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)treat to reduce LDL-C to100 mgdL (259mmolL) [Based on KDOQIGuideline 42]
bull Adolescents If LDL-C130 mgdL (336 mmolL) treat to reduce LDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 52]
16223 For KTRs with normalLDL-C elevated triglyceridesand elevated non-HDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)fasting triglycerides 200mgdL (226 mmolL)and non-HDL-C 130mgdL (336 mmolL)treat to reduce non-HDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 43]
bull Adolescents If LDL-C130 mgdL (336 mmolL) fasting triglycerides200 mgdL (226 mmolL) and non-HDL-C 160mgdL (414 mmolL)treat to reduce non-HDL-C
to 160 mgdL (414 i
mmolL) [Based on KDOQIGuideline 53]
163 Tobacco Use1631 Screen and counsel all KTRs including
adolescents and children for tobacco useand record the results in the medicalrecord (Not Graded)bull Screen during initial transplant hospi-
talizationbull Screen at least annually thereafter
1632 Offer treatment to all patients who usetobacco (Not Graded)
164 Obesity1641 Assess obesity at each visit (Not Graded)
bull Measure height and weight at eachvisit in adults and children
bull Calculate BMI at each visitbull Measure waist circumference when
weight and physical appearance sug-gest obesity but BMI is 35 kgm2
1642 Offer a weight-reduction program to allobese KTRs (Not Graded)
DOQIRationale andCommentary
Hypertension
The KDIGO work group adapted the KDOQI004 recommendations for target blood pres-ure in KTRs55 Self measurement is useful inssessing response to therapy and enhancesdherence56 In general we agree that the classf antihypertensive agent does not matter inhe treatment of blood pressure elevation inhis population and that attention should beiven to potential side effects of antihyperten-ive agents as well as possible interactionsith the immunosuppressive regimen (eg non-ihydropyridine calcium channel blockers andNIs) In the absence of adequate randomizedontrolled trials it is not known whether angio-ensin-converting enzyme (ACE) inhibitors andngiotensin receptor blockers (ARBs) prolongecipient or allograft survival Some but notll retrospective studies suggest a benefitowever all these studies are limited by selec-ion bias5758 Although ACE inhibitors andRBs commonly lead to some decrease inFR treatment with these drugs should be
ontinued unless serum creatinine level in-reases by 25 to 30 in keeping withDOQI recommendations55 In KTRs receiv-
ng ACE inhibitors or ARBs it is important toducate patients to maintain adequate fluid
ntake during illness to prevent a prerenal
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ARTICLE IN PRESS
nsult to the allograft Similarly awareness isecessary when using diuretics in conjunctionith therapies that block the renin-angiotensin-
ldosterone-system59
Dyslipidemia
The KDIGO work group based their recom-endations for evaluation and treatment of
yperlipidemia on the KDOQI dyslipidemiauidelines for KTRs60 We agree with theseecommendations CNIs potentiate the toxicityf statins by slowing their metabolism throughhe cytochrome P-450 system This interactionccurs more commonly with cyclosporine61
han with tacrolimus Dyslipidemia especiallyypertriglyceridemia frequently complicatesTOR-inhibitor use and lipid-lowering therapy
s required in most patients using these agents
TobaccoUse
Not surprisingly tobacco use at the time ofransplant is associated with decreased patientnd graft survival as well as increased risk ofosttransplant cardiovascular disease (CVD)lthough the KDIGO work group recom-ends initial screening and intervention dur-
ng the hospitalization for transplant we be-ieve there may be benefit gained by startingounseling in the pretransplant period duringhe evaluation phase Unfortunately this doesot occur often because of time and personnelonstraints in transplant centers Ideally allransplant centers should have smoking-cessa-ion programs available to patients either in-ouse or through referral Ideally systemshould be created to continue to screen andonitor for smoking cessation at yearly inter-
als after transplant because there is a highate of relapse with this addiction As outlinedn KDIGO Table 253 although all pharmaco-ogic therapies for smoking cessation can besed in KTRs the starting dose of vareniclinehould be decreased in patients with GFR 30Lmin
Obesity
Obesity is an epidemic in the United Statesnd the proportion of obese kidney transplantandidates continues to grow In additioneight gain after transplant is very commonly
bserved Obesity in KTRs is associated with w
ncreased risks of wound complications de-ayed graft function acute rejection and NO-AT resulting in inferior patient and graftutcomes Attention to this potential complica-ion and counseling should be initiated duringhe pretransplant evaluation phase Informa-ion regarding pharmacologic therapies foreight loss in KTRs is not available and we
gree with the KDIGO work group that thera-eutic lifestyle measures should be encour-ged Data regarding steroid therapy with-rawal and weight gain are controversial Aecent double-blind randomized controlled trialxamining early steroid therapy withdrawalid not show a difference in weight gain at 5ears posttransplant compared with the cohortemaining on standard maintenance corticoste-oid therapy62
DIGORecommendations inChapter 17ardiovascularManagement
171 Consider managing CVD at least as intensively inKTRs as in the general population with appropri-ate diagnostic tests and treatments (Not Graded)
172 We suggest using aspirin (65-100 mgd) in allpatients with atherosclerotic CVD unless there arecontraindications (2B)
DOQIRationale andCommentary
Although outcomes are favorable comparedith remaining on the waiting list the risk of
ardiovascular mortality in KTRs is several-foldigher than observed in the general population63
specially in younger age groups and patientsith decreasing allograft function64 CVD is aajor cause of graft loss after the first post-
ransplant year In this context we strongly agreehat CVD should be managed in KTRs at least asntensively as in the general population Ideallyecreasing CVD risk in KTRs requires a multifac-ted and multidisciplinary approach Based onurrent practice models in the United States theransplant and nephrology community has notet been able to achieve these desirable goals65
his clearly deserves more attention becauseontrol of CVD has the potential to contributeore to long-term kidney graft survival than the
iscovery of newer drugs that decrease the ratef allograft rejection Our KDOQI working groupgreed with the use of low-dose aspirin in KTRs
ith evidence of atherosclerosis
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KDOQI Commentary 21
ARTICLE IN PRESS
SUMMARY OF COMMENTARY ONSECTION III CVD
COMMENTARY ON SECTION IV OF KDIGO
TRANSPLANT GUIDELINE MALIGNANCY
DIGORecommendations inChapter 18 Cancerf the Skin andLip
181 We recommend that KTRs especially thosewho have fair skin live in high sun-exposureclimates have occupations requiring sun expo-sure have had significant sun exposure as achild or have a history of skin cancer be toldthat their risk of skin and lip cancer is veryhigh (1C)
182 We recommend that KTRs minimize life-longsun exposure and use appropriate ultravioletlight blocking agents (1D)
183 We suggest that adult KTRs perform skin andlip self-examinations and report new lesions toa health-care provider (2D)
184 For adult KTRs we suggest that a qualified healthprofessional with experience in diagnosing skincancer perform annual skin and lip examinationon KTRs except possibly for KTRs with dark skinpigmentation (2D)
185 We suggest that patients with a history of skin orlip cancer or premalignant lesions be referred to andfollowed by a qualified health professional withexperience in diagnosing and treating skin cancer
With the decrease in acute rejection during the pastdecade in association with improved immunosuppres-sion regimens patient death now rivals chronic graftdysfunction as one of the leading causes of long-termgraft loss Because CVD is the most common cause ofpatient death in KTRs a concerted effort at minimizingrisk factors for heart disease likely will have as great oreven greater impact on optimizing patient and graftoutcomes than the discovery of new antirejection thera-pies CVD risk reduction strategies should include regularscreening for new-onset diabetes (using ADA-based defini-tions) in the posttransplant period in previously nondiabeticpatients good glycemic regulation for diabetic patients accord-ing to current ADA guidelines and lipid management andblood pressure control according to KDOQI recommenda-tions In addition promotion of a healthy lifestyle throughweight control exercise and smoking cessation should be acentral part of posttransplant counseling and care Whenimmunosuppression modification is being considered to miti-gate cardiovascular risk we recommend that this be inconjunction with the transplant center In summary we gener-ally concurred with the suggestions of the work group in thissection but based on current practice standards in the UnitedStateschallengesremainwith implementationof thisguideline
(2D) s
186 We suggest that patients with a history of skincancer be offered treatment with oral acitretin ifthere are no contraindications (2B)
DOQIRationale andCommentary
CounselingandSunscreen
We concur with recommendations 181 and82 because skin cancer is a major source oforbidity and sometimes mortality in KTRsarning patients at risk of the high danger of
kin cancer a 1C recommendation is reinforcedy a recent prospective case-control study ofrgan transplant recipients that showed that regu-ar use of broad-spectrum sunscreens that pro-ide UVA and UVB protection may prevent theevelopment of actinic keratosis invasive squa-ous cell carcinoma and to a lesser extent
asal cell carcinoma66 Most cancer-causing ra-iation is thought to come from the UVB spec-rum and newer broad-spectrum sunscreens pro-ide protection against UVA and UVB radiationounseling about sunscreen and the need for sunvoidance needs to be incorporated into routineffice visits although it may not always beuccessful In a recent study of KTRs in which1 of patients had been informed about theeed for sun protection only 46 used morehan a tube of sunscreen per year67
Dermatology Involvement
There is increased evidence to suggest thatpecialty dermatology clinics for organ trans-lant recipients improve outcome measures in-luding compliance with photoprotection andncreased awareness of skin cancer68 The re-ources required for these specialty clinics makemplementation difficult for community nephrol-gy groups that do not have direct access to aransplant center Transplant patients should bencouraged to have annual visits with their trans-lant center and if dermatology specialty clinicsre available attempt to coordinate a skin cancervaluation annually
UseofRetinoid-likeCompounds
There is a limited scientific basis for KDIGOuggestion recommendation 186 Although reti-oids now are used routinely in KTRs with aigh skin cancer burden our KDOQI work groupelieves that more data are needed before this
uggestion should be accepted as a guideline In
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ARTICLE IN PRESS
ow-immunologic-risk groups and particularlyifficult cases some data suggest that switchingrom CNI to sirolimus therapy may decrease thencidence of skin cancer69 however the riskersus benefit of this maneuver has not been welltudied
DIGORecommendations inChapter 19on-SkinMalignancies
191 Develop an individualized screening plan for eachKTR that takes into account the patientrsquos pastmedical and family history tobacco use compet-ing risks for death and the performance of thescreening methodology (Not Graded)
192 Screen for the following cancers as per localguidelines for the general population (Not Graded)Women cervical breast and colon cancer Menprostate and colon cancer
193 Obtain hepatic ultrasound and alpha feto-proteinevery 12 months in patients with compensatedcirrhosis (Not Graded) [See Recommendations1354 (HCV) and 1365 (HBV)]
DOQIRationale andCommentary
Screening
It is recognized that KTRs have a higher inci-ence of malignancy particularly those associatedith specific viral infections Although cancer
creening may have benefits in this higher riskopulation it should be reinforced that some meth-ds of screening have significant risks which shoulde considered on an individualized basis particu-arly in patients who have projected survival lesshan 5 years
Screening forCancer inPatientsWithHepatitis
Many patients who have underlying cirrhosisn the United States will be followed up by arofessional specializing in liver disease whoay provide additional insight into this cancer
creening recommendation Based on a recentuestionnaire of US gastroenterologists only 50creen patients for hepatocellular carcinoma70
herefore implementation of this guideline byS clinicians is unlikely to be widespread
DIGORecommendations inChapter 20anagingCancerwithReductionof
mmunosuppressiveMedication
201 We suggest consideration be given to reducingimmunosuppressive medications for KTRs with can-
cer (2C)
2011 Important factors for consideration in-clude (Not Graded)bull The stage of cancer at diagnosisbull Whether the cancer is likely to be
exacerbated by immunosuppressionbull The therapies available for the can-
cerbull Whether immunosuppressive medica-
tions interfere with ability to admin-ister the standard chemotherapy
202 For patients with Kaposi sarcoma we suggestusing mTORi along with a reduction in overallimmunosuppression (2C)
DOQIRationale andCommentary
Table 1 (Table 29 in the KDIGO report3 andxcerpted from Grulich et al71) lists cancershat are increased most in immunosuppressedTRs based on standardized incidence ratios
SIRs) which compare the incidence toatched populations Cancers with the highestIRs may be those most likely to respond to aecrease in immunosuppression Except foraposi sarcoma limited evidence is available
or a decrease in immunosuppression in theseettings A strategy to change immunosuppres-ion therapy must occur in consultation withhe transplant center Switching to sirolimusherapy and decreasing immunosuppression inatients who develop Kaposi sarcoma is basedn sound scientific rationale7273
SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
The incidence of cancer posttransplant is 2-20times higher than that in the general population andKDIGO guidelines have been written to outline stepsfor prevention and screening With few exceptions weagree with the recommendations as outlined Skincancer is common in US transplant patients andscreening and prevention are critical However imple-mentation of guidelines for doing so including theKDIGO guidelines is a challenge because of patientpreferences against the routine use of sunscreen aswell as time constraints during office visits Althoughmany posttransplant cancers are viral mediated andrelated to immunosuppression it is less clear how toalter immunosuppression after malignancy has oc-curred We agree that although age-specific screeningfor malignancy should be incorporated into care con-sideration must be given to the risk of screening inpatients with limited life spans (5 years) because of
comorbid conditions
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
ommonPopu
i sarco-Hodgmelanise sm
sophaemia
estima standa10 c
ut esti
0 case
alized t
to guide treatment specifically before the
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
REFERENCES1 McCullough KP Keith DS Meyer KH et al Kidney
nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
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ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
ation Transpl Rev 200923191-19815 Abbud-Filho M Adams PL Alberuacute J et al A report
f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
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ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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KDOQI Commentary 15
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137 HUMAN IMMUNODEFICIENCY VIRUS1371 If not already done screen for HIV
infection (Not Graded)1372 To determine antiretroviral therapy refer
HIV-infected KTRs to an HIV specialistwho should pay special attention to drugndashdrug interactions and appropriate dosingof medications (Not Graded)
DOQIRationale andCommentary
Viral infections are particularly problematic inransplant recipients because of the preferentialnhibition of T-lymphocyte function by both induc-ion and maintenance immunosuppression Use ofnduction immunosuppression with lymphocyte-epleting agents (thymoglobulin or alemtuzumab)s associated with a greater risk of viral infectionosttransplant In general the greater the cumula-ive exposure to immunosuppression the greaterhe risk of infectious complications The presenta-ion of viral infections can be asymptomatic vaguend nonspecific or life-threatening acute illnessany viral infections seen in KTRs are rarely seen
n immunocompetent patients and therefore do notnter into the differential diagnosis for physiciansnfamiliar with transplant recipients Close commu-ication with the transplant center is crucial inaring for the transplant population Early detectionnd institution of therapy provide the best chanceor viral eradication
BKVirus
Although the work group agreed with KDIGOuggestions for BK virus screening posttransplante did not think it was practical to require screen-
ng exclusively with quantitative plasma nucleiccid testing (NAT) because many US centers usenitial urinary screening and then test plasma onlyf urine screening results are positive Howeverhere is no disagreement that some type of screen-ng for BK virus is critical to avoid BK nephropa-hy for which there is no specific treatment when its established Complicating screening for BK vi-us is the variability in results between laboratoriesnd uncertainty about the level of viremia thathould trigger a response to decrease in immunosup-ression In the presence of viremia and increase inerum creatinine level a renal allograft biopsy isndicated to confirm the presence of BK nephropa-
hy Because BK viremia and viruria certainly can b
e detected beyond the first year it is not clear howong screening should be continued posttransplantlthough most centers screen for the first year onlyngoing clinical trials are exploring effective treat-ent for BK nephropathy3839 Decisions about
ecreases in immunosuppression currently theainstay of BK viremia management always
hould be made in consultation with the transplantenter
Cytomegalovirus
KDIGO recommendation 1321 regarding cyto-egalovirus (CMV) prophylaxis is reasonable and
pplicable to the US population Universal prophy-axis for CMV now is recommended over initiatingre-emptive treatment after CMV develops40 Aajor concern for US patients is the cost of CMV
rophylaxis with oral valgancyclovir Leukopeniaan be observed in patients using mycophenolatereparations when prophylaxis with valgancyclo-ir is used Screening for CMV is best performedsing NAT methods (1322) CMV antigenemiassays are still in use in many facilities but are nots sensitive as PCR assays41 There is no utility inhecking for serologic response to CMV with IgGr IgM titers posttransplant because the immuneesponse is not predictable Patients with CMVisease should be cared for by clinicians familiarith treating this disease It is recommended that
reatment be continued until viral load is undetect-ble followed by prophylactic doses of valgancy-lovir for an additional 3 months35
Epstein-BarrVirus
Current practice regarding EBV screening variesmong centers in the United States and many doot routinely screen for EBV posttransplant evenn recipient-negative donor-positive cases In con-rast to KDIGO recommendation 1311 routineBV screening is not recommended in AST infec-
ious disease guidelines35 In many centers EBVcreening is reserved for children who are muchore commonly EBV negative pretransplant than
dults EBV-induced posttransplant lymphoprolif-rative disorder (PTLD) affects many more pediat-ic than adult KTRs If screening is someday to beoutinely implemented in US centers details regard-ng the best method of screening and levels ofiremia above which a clinical intervention should
e triggered need to be better defined
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HerpesandVaricella
Systemic herpesvirus infections can be lifehreatening in transplant recipients and should bereated aggressively with intravenous antiviralgents as described in the KDIGO recommenda-ions Less aggressive cutaneous infection can bereated with oral antiviral agents as outlined inhe KDIGO guidelines
Varicella exposure is particularly concerning inransplant recipients The work group disputes theecommended dosing of acyclovir for varicellaxposure Acyclovir at a dose of 10 mgkg or about00 mg 4 times daily of oral acyclovir would betandard dosing We agree with the use of varicellammune globulin and emphasize the need to avoidhe varicella vaccine because it is a live virushould a transplant recipient develop a systemicaricella infection hospitalization and high-dosentravenous acyclovir therapy are warranted
Hepatitis C
Hepatitis C management posttransplant is ahallenge The KDIGO guidelines cited hereere based on the recently published KDIGOuideline for hepatitis C in CKD4 Hepatitis Cypically is not treated posttransplant because ofhe risk (50) of rejection precipitated bynterferon therapy particularly in US KTRs inhom hepatitis C commonly is genotype 1 which
s more resistant to treatment with interferon42
owever should hepatitis Cndashrelated glomerulo-ephritis develop the risk-benefit ratio may fa-or treatment in selected patients Such decisionslways should be made in consultation withepatology and infectious disease experts andhe transplant center Monitoring liver enzymeevels specifically alanine aminotransferaseALT) may reflect a change in hepatitis activityut monitoring hepatitis C viral load is not recom-ended because it does not seem to correlateith outcome Annual monitoring for hepatocel-
ular carcinoma using -fetoprotein and imagings encouraged but not often practiced
Hepatitis B
KDIGO recommendations for hepatitis B areeasonable and currently are followed in mostS centers except for recommendation 1366
see previous recommendation under vaccina-ions) KTRs with hepatitis C or hepatitis B also
hould be followed up by a hepatologist
Human ImmunodeficiencyVirus
Human immunodeficiency virus (HIV)-posi-ive individuals are now acceptable for transplantf CD4 count is 200 cellsL and viral loadVL) is undetectable3543 Transplant should beerformed at centers with expertise in managingIV-positive individuals and care should be co-rdinated carefully with HIV specialists Somentiretroviral agents in particular the proteasenhibitors have potentially serious drug interac-ions with immunosuppressive agents35
DIGORecommendations inChapter 14Othernfections
141 URINARY TRACT INFECTION1411 We suggest that all KTRs receive UTI
prophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 monthsafter transplantation (2B)
1412 For allograft pyelonephritis we suggestinitial hospitalization and treatment withintravenous antibiotics (2C)
142 PNEUMOCYSTIS JIROVECII PNEUMONIA1421 We recommend that all KTRs receive
PCP prophylaxis with daily tri-methoprimndashsulfamethoxazole for 3-6months after transplantation (1B)
1422 We suggest that all KTRs receive PCPprophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 weeksduring and after treatment for acute rejec-tion (2C)
1423 We recommend that KTRs with PCPdiagnosed by bronchial alveolar lavageandor lung biopsy be treated withhigh-dose intravenous trimethoprimndashsulfamethoxazole corticosteroids anda reduction in immunosuppressivemedication (1C)
1424 We recommend treatment with cortico-steroids for KTRs with moderate tosevere PCP (as defined by PaO2 lt70mm Hg in room air or an alveolargradient of gt35 mm Hg) (1C)
143 TUBERCULOSIS1431 We suggest that TB prophylaxis and
treatment regimens be the same in KTRsas would be used in the local generalpopulation who require therapy (2D)
1432 We recommend monitoring CNI andmTORi [mTOR inhibitor] blood levels inpatients receiving rifampin (1C)14321 Consider substituting rifabu-
tin for rifampin to minimize
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KDOQI Commentary 17
ARTICLE IN PRESS
interactions with CNIs andmTORi (Not Graded)
144 CANDIDA PROPHYLAXIS1441 We suggest oral and esophageal Candida
prophylaxis with oral clotrimazole loz-enges nystatin or fluconazole for 1-3months after transplantation and for 1month after treatment with an antilympho-cyte antibody (2C)
DOQIRationale andCommentary
UrinaryTract Infection
Urinary tract infections (UTIs) after kidneyransplant are very common and account for aarge percentage of readmissions posttransplantTIs are common because of multiple factors
ncluding the disrupted anatomy of the urinaryract with a ureteroneocystotomy incompleteladder emptying because of diabetes or pros-atic hypertrophy and impaired immune re-ponses Prophylaxis of UTIs usually is under-aken with trimethoprim-sulfamethoxazole for 6onths posttransplant although infections often
ccur despite therapy because of the develop-ent of drug resistance Although native kidney
yelonephritis does not always require hospital-zation it is recommended that all KTRs withhis diagnosis be hospitalized because the graftysfunction that usually accompanies transplantyelonephritis requires aggressive investigationnd treatment Individuals with recurrent UTIsarrant evaluation with urologic assessment Pa-
ients with recurrent UTIs may benefit fromong-term suppressive therapy
Pneumocystic Pneumonia
We agree that Pneumocystis jirovecii pneumoniaPCP) prophylaxis is important for the first 3-6onths posttransplant (1421)After the first month
very-other-day dosing of trimethoprim-sulfame-hoxazole or atovaquone is believed to be adequaterophylaxis In cases in which neither of thesegents can be used an individual may be treatedrophylactically with inhaled pentamidine OurDOQI work group emphasized that patients whoevelop PCP should be transferred to the transplantenter promptly for management and adjustmentsn immunosuppression
Tuberculosis
Monitoring for latent tuberculosis has posed a
hallenge in the immunosuppressed population be-
ause of the unreliable nature of skin testing Newerechniques involving interferon release assays aremerging as the new gold standard for detection ofatent tuberculosis4445
CandidaProphylaxis
Oral candidiasis must be screened for usingral mucosa examination on follow-up visitsn KTRs This is especially true in the earlyosttransplant period when immunosuppres-ive medication dosage is the highest Wegree with these recommendations and empha-ize that if fluconazole is used there is aotential for serious drug interactions becausef cytochrome P-450 3A4 inhibition
SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
Improvement in short-term outcomes has not trans-lated into significant improvements in long-term out-comes in KTRs The lack of significant improvement inlong-term survival may be related to post-transplantcomplications Frequent posttransplant monitoring mayimprove long-term outcomes by decreasing chronic graftfailure or death with a functioning graft Our work groupconcurred with the recommendation and schedules ofroutine screening in monitoring kidney allograft functionafter kidney transplant with a low threshold for perform-ing kidney biopsy in cases of graft dysfunction or protein-uria Expert tissue processing and interpretation of trans-plant biopsy specimens by pathologists with transplantexperience are critical Regular surveillance of the pa-tientrsquos kidney function at the transplant center or in thenephrologistrsquos office offers an opportunity to enhancepatient adherence to medication diet and healthy life-style Although CKD in KTRs progresses more slowlythan CKD in other patients the work group agreed thatthe KDIGO guidelines on CKD should be followed inKTRs
Opportunistic infections are common in KTRs al-though advances in diagnosis and treatment have led toimproved survival in KTRs with infection It is nowstandard of care to use vaccinations in KTRs as long asthe vaccine does not contain live or attenuated virus Italso is routine to screen for or use prophylaxis to preventseveral posttransplant viral infections With few excep-tions (related to EBV and BK virus screening andhepatitis B vaccination posttransplant) we concurredwith KDIGO guidelines for vaccination screening and
treatment of infection posttransplant
KD
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ARTICLE IN PRESS
COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULAR
DISEASE
DIGORecommendations inChapter 15iabetesMellitus
151 Screening for New-Onset Diabetes after Transplan-tation1511 We recommend screening all nondia-
betic KTRs with fasting plasma glu-cose oral glucose tolerance testingandor HbA1c (1C) at leastbull weekly for 4 weeks (2D)bull every 3 months for 1 year (2D)bull and annually thereafter (2D)
1512 We suggest screening for NODAT withfasting glucose oral glucose tolerancetesting andor after starting or substan-tially increasing the dose of CNIsmTORi or corticosteroids (2D)
152 Managing NODAT or Diabetes Present at Trans-plantation1521 If NODAT develops consider modifying
the immunosuppressive drug regimen toreverse or ameliorate diabetes afterweighing the risk of rejection and otherpotential adverse effects (Not Graded)
1522 Consider targeting HbA1c 70-75and avoid targeting HbA1c 60 espe-cially if hypoglycemic reactions are com-mon (Not Graded)
1523 We suggest that in patients with diabetesaspirin (65-100 mgd) use for the primaryprevention of CVD be based on patientpreferences and values balancing the riskfor ischemic events to that of bleeding(2D)
DOQIRationale andCommentary
Diabetic Screening
We agree with screening for new-onset diabetesfter transplantation (NODAT) as outlined by theDIGO work group Definitions used are similar
o those of the American Diabetes AssociationADA) The greater frequency of testing initially isustified by the high risk of NODAT in the earlyosttransplant period however ongoing screenings required because the risk of the development ofODAT continues to increase over time4647 We
lso point out that prediabetic states (impairedasting glucose level and impaired glucose toler-nce) occur even more commonly than overt diabe-es48 and may be associated with metabolic syn-rome as well as with increased cardiovascular
ortality49-51 Potential implications of these predia-
etic states emphasize the importance of perform-ng blood tests under fasting conditions For pa-ients with fasting hyperglycemia an oral glucoseolerance test or hemoglobinA1c (HbA1c) test shoulde performed Although more cumbersome to per-orm data suggest that an oral glucose toleranceest is a more sensitive indicator of NODAT inyperglycemic KTRs52 This may allow earlieretection of overt diabetes and more prompt institu-ion of treatment
DiabetesManagement
Data supporting a substantial benefit in themelioration or reversal of NODAT using immu-osuppression modification in KTRs are veryimited There was consensus in our work grouphat considering the paucity of data for reversingODAT by changing immunosuppression and
he potential risk of an adverse outcome withuch a maneuver KDIGO suggestion 1521 couldot be supported Certainly if such a step waseing considered it should be done in conjunc-ion with the transplant center Targeting an HbA1c
evel of 7-75 and avoiding levels 6 isased on data showing increased cardiovascularvents with the lower HbA1c target5354
DIGORecommendations inChapter 16ypertensionDyslipidemias TobaccoUse andbesity
161 Hypertension1611 We recommend measuring blood pres-
sure at each clinic visit (1C)1612 We suggest maintaining blood pressure at
130 mm Hg systolic and 80 mm Hgdiastolic if 18 years of age and 90th
percentile for sex age and height if 18years old (2C)
1613 To treat hypertension (Not Graded)bull Use any class of antihypertensive
agentbull Monitor closely for adverse effects
and drug-drug interactions and whenurine protein excretion 1 gd for18 years old and 600 mgm224 hfor 18 years old consider an ACE-Ior an ARB as first-line therapy
162 Dyslipidemias (These recommendations are basedon KDOQI Dyslipidemia Guidelines and are thusnot graded)1621 Measure a complete lipid profile in all
adult (18 years old) and adolescent
(puberty to 18 years old) KTRs [Based on
K
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KDOQI Commentary 19
ARTICLE IN PRESS
KDOQI Dyslipidemia Recommendation1]bull 2-3 months after transplantationbull 2-3 months after a change in treatment
or other conditions known to causedyslipidemias
bull at least annually thereafter1622 Evaluate KTRs with dyslipidemias for
secondary causes [Based on KDOQI Dys-lipidemia Recommendation 3]16221 For KTRs with fasting triglyc-
erides 500 mgdL (565mmolL) that cannot be cor-rected by removing an under-lying cause treat withbull Adults therapeutic lifestyle
changes and a triglyceride-lowering agent [Based onKDOQI Recommendation41]
bull Adolescents therapeutic life-style changes [Based onKDOQI Recommendation51]
16222 For KTRs with elevatedLDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)treat to reduce LDL-C to100 mgdL (259mmolL) [Based on KDOQIGuideline 42]
bull Adolescents If LDL-C130 mgdL (336 mmolL) treat to reduce LDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 52]
16223 For KTRs with normalLDL-C elevated triglyceridesand elevated non-HDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)fasting triglycerides 200mgdL (226 mmolL)and non-HDL-C 130mgdL (336 mmolL)treat to reduce non-HDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 43]
bull Adolescents If LDL-C130 mgdL (336 mmolL) fasting triglycerides200 mgdL (226 mmolL) and non-HDL-C 160mgdL (414 mmolL)treat to reduce non-HDL-C
to 160 mgdL (414 i
mmolL) [Based on KDOQIGuideline 53]
163 Tobacco Use1631 Screen and counsel all KTRs including
adolescents and children for tobacco useand record the results in the medicalrecord (Not Graded)bull Screen during initial transplant hospi-
talizationbull Screen at least annually thereafter
1632 Offer treatment to all patients who usetobacco (Not Graded)
164 Obesity1641 Assess obesity at each visit (Not Graded)
bull Measure height and weight at eachvisit in adults and children
bull Calculate BMI at each visitbull Measure waist circumference when
weight and physical appearance sug-gest obesity but BMI is 35 kgm2
1642 Offer a weight-reduction program to allobese KTRs (Not Graded)
DOQIRationale andCommentary
Hypertension
The KDIGO work group adapted the KDOQI004 recommendations for target blood pres-ure in KTRs55 Self measurement is useful inssessing response to therapy and enhancesdherence56 In general we agree that the classf antihypertensive agent does not matter inhe treatment of blood pressure elevation inhis population and that attention should beiven to potential side effects of antihyperten-ive agents as well as possible interactionsith the immunosuppressive regimen (eg non-ihydropyridine calcium channel blockers andNIs) In the absence of adequate randomizedontrolled trials it is not known whether angio-ensin-converting enzyme (ACE) inhibitors andngiotensin receptor blockers (ARBs) prolongecipient or allograft survival Some but notll retrospective studies suggest a benefitowever all these studies are limited by selec-ion bias5758 Although ACE inhibitors andRBs commonly lead to some decrease inFR treatment with these drugs should be
ontinued unless serum creatinine level in-reases by 25 to 30 in keeping withDOQI recommendations55 In KTRs receiv-
ng ACE inhibitors or ARBs it is important toducate patients to maintain adequate fluid
ntake during illness to prevent a prerenal
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ARTICLE IN PRESS
nsult to the allograft Similarly awareness isecessary when using diuretics in conjunctionith therapies that block the renin-angiotensin-
ldosterone-system59
Dyslipidemia
The KDIGO work group based their recom-endations for evaluation and treatment of
yperlipidemia on the KDOQI dyslipidemiauidelines for KTRs60 We agree with theseecommendations CNIs potentiate the toxicityf statins by slowing their metabolism throughhe cytochrome P-450 system This interactionccurs more commonly with cyclosporine61
han with tacrolimus Dyslipidemia especiallyypertriglyceridemia frequently complicatesTOR-inhibitor use and lipid-lowering therapy
s required in most patients using these agents
TobaccoUse
Not surprisingly tobacco use at the time ofransplant is associated with decreased patientnd graft survival as well as increased risk ofosttransplant cardiovascular disease (CVD)lthough the KDIGO work group recom-ends initial screening and intervention dur-
ng the hospitalization for transplant we be-ieve there may be benefit gained by startingounseling in the pretransplant period duringhe evaluation phase Unfortunately this doesot occur often because of time and personnelonstraints in transplant centers Ideally allransplant centers should have smoking-cessa-ion programs available to patients either in-ouse or through referral Ideally systemshould be created to continue to screen andonitor for smoking cessation at yearly inter-
als after transplant because there is a highate of relapse with this addiction As outlinedn KDIGO Table 253 although all pharmaco-ogic therapies for smoking cessation can besed in KTRs the starting dose of vareniclinehould be decreased in patients with GFR 30Lmin
Obesity
Obesity is an epidemic in the United Statesnd the proportion of obese kidney transplantandidates continues to grow In additioneight gain after transplant is very commonly
bserved Obesity in KTRs is associated with w
ncreased risks of wound complications de-ayed graft function acute rejection and NO-AT resulting in inferior patient and graftutcomes Attention to this potential complica-ion and counseling should be initiated duringhe pretransplant evaluation phase Informa-ion regarding pharmacologic therapies foreight loss in KTRs is not available and we
gree with the KDIGO work group that thera-eutic lifestyle measures should be encour-ged Data regarding steroid therapy with-rawal and weight gain are controversial Aecent double-blind randomized controlled trialxamining early steroid therapy withdrawalid not show a difference in weight gain at 5ears posttransplant compared with the cohortemaining on standard maintenance corticoste-oid therapy62
DIGORecommendations inChapter 17ardiovascularManagement
171 Consider managing CVD at least as intensively inKTRs as in the general population with appropri-ate diagnostic tests and treatments (Not Graded)
172 We suggest using aspirin (65-100 mgd) in allpatients with atherosclerotic CVD unless there arecontraindications (2B)
DOQIRationale andCommentary
Although outcomes are favorable comparedith remaining on the waiting list the risk of
ardiovascular mortality in KTRs is several-foldigher than observed in the general population63
specially in younger age groups and patientsith decreasing allograft function64 CVD is aajor cause of graft loss after the first post-
ransplant year In this context we strongly agreehat CVD should be managed in KTRs at least asntensively as in the general population Ideallyecreasing CVD risk in KTRs requires a multifac-ted and multidisciplinary approach Based onurrent practice models in the United States theransplant and nephrology community has notet been able to achieve these desirable goals65
his clearly deserves more attention becauseontrol of CVD has the potential to contributeore to long-term kidney graft survival than the
iscovery of newer drugs that decrease the ratef allograft rejection Our KDOQI working groupgreed with the use of low-dose aspirin in KTRs
ith evidence of atherosclerosis
Ko
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KDOQI Commentary 21
ARTICLE IN PRESS
SUMMARY OF COMMENTARY ONSECTION III CVD
COMMENTARY ON SECTION IV OF KDIGO
TRANSPLANT GUIDELINE MALIGNANCY
DIGORecommendations inChapter 18 Cancerf the Skin andLip
181 We recommend that KTRs especially thosewho have fair skin live in high sun-exposureclimates have occupations requiring sun expo-sure have had significant sun exposure as achild or have a history of skin cancer be toldthat their risk of skin and lip cancer is veryhigh (1C)
182 We recommend that KTRs minimize life-longsun exposure and use appropriate ultravioletlight blocking agents (1D)
183 We suggest that adult KTRs perform skin andlip self-examinations and report new lesions toa health-care provider (2D)
184 For adult KTRs we suggest that a qualified healthprofessional with experience in diagnosing skincancer perform annual skin and lip examinationon KTRs except possibly for KTRs with dark skinpigmentation (2D)
185 We suggest that patients with a history of skin orlip cancer or premalignant lesions be referred to andfollowed by a qualified health professional withexperience in diagnosing and treating skin cancer
With the decrease in acute rejection during the pastdecade in association with improved immunosuppres-sion regimens patient death now rivals chronic graftdysfunction as one of the leading causes of long-termgraft loss Because CVD is the most common cause ofpatient death in KTRs a concerted effort at minimizingrisk factors for heart disease likely will have as great oreven greater impact on optimizing patient and graftoutcomes than the discovery of new antirejection thera-pies CVD risk reduction strategies should include regularscreening for new-onset diabetes (using ADA-based defini-tions) in the posttransplant period in previously nondiabeticpatients good glycemic regulation for diabetic patients accord-ing to current ADA guidelines and lipid management andblood pressure control according to KDOQI recommenda-tions In addition promotion of a healthy lifestyle throughweight control exercise and smoking cessation should be acentral part of posttransplant counseling and care Whenimmunosuppression modification is being considered to miti-gate cardiovascular risk we recommend that this be inconjunction with the transplant center In summary we gener-ally concurred with the suggestions of the work group in thissection but based on current practice standards in the UnitedStateschallengesremainwith implementationof thisguideline
(2D) s
186 We suggest that patients with a history of skincancer be offered treatment with oral acitretin ifthere are no contraindications (2B)
DOQIRationale andCommentary
CounselingandSunscreen
We concur with recommendations 181 and82 because skin cancer is a major source oforbidity and sometimes mortality in KTRsarning patients at risk of the high danger of
kin cancer a 1C recommendation is reinforcedy a recent prospective case-control study ofrgan transplant recipients that showed that regu-ar use of broad-spectrum sunscreens that pro-ide UVA and UVB protection may prevent theevelopment of actinic keratosis invasive squa-ous cell carcinoma and to a lesser extent
asal cell carcinoma66 Most cancer-causing ra-iation is thought to come from the UVB spec-rum and newer broad-spectrum sunscreens pro-ide protection against UVA and UVB radiationounseling about sunscreen and the need for sunvoidance needs to be incorporated into routineffice visits although it may not always beuccessful In a recent study of KTRs in which1 of patients had been informed about theeed for sun protection only 46 used morehan a tube of sunscreen per year67
Dermatology Involvement
There is increased evidence to suggest thatpecialty dermatology clinics for organ trans-lant recipients improve outcome measures in-luding compliance with photoprotection andncreased awareness of skin cancer68 The re-ources required for these specialty clinics makemplementation difficult for community nephrol-gy groups that do not have direct access to aransplant center Transplant patients should bencouraged to have annual visits with their trans-lant center and if dermatology specialty clinicsre available attempt to coordinate a skin cancervaluation annually
UseofRetinoid-likeCompounds
There is a limited scientific basis for KDIGOuggestion recommendation 186 Although reti-oids now are used routinely in KTRs with aigh skin cancer burden our KDOQI work groupelieves that more data are needed before this
uggestion should be accepted as a guideline In
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ARTICLE IN PRESS
ow-immunologic-risk groups and particularlyifficult cases some data suggest that switchingrom CNI to sirolimus therapy may decrease thencidence of skin cancer69 however the riskersus benefit of this maneuver has not been welltudied
DIGORecommendations inChapter 19on-SkinMalignancies
191 Develop an individualized screening plan for eachKTR that takes into account the patientrsquos pastmedical and family history tobacco use compet-ing risks for death and the performance of thescreening methodology (Not Graded)
192 Screen for the following cancers as per localguidelines for the general population (Not Graded)Women cervical breast and colon cancer Menprostate and colon cancer
193 Obtain hepatic ultrasound and alpha feto-proteinevery 12 months in patients with compensatedcirrhosis (Not Graded) [See Recommendations1354 (HCV) and 1365 (HBV)]
DOQIRationale andCommentary
Screening
It is recognized that KTRs have a higher inci-ence of malignancy particularly those associatedith specific viral infections Although cancer
creening may have benefits in this higher riskopulation it should be reinforced that some meth-ds of screening have significant risks which shoulde considered on an individualized basis particu-arly in patients who have projected survival lesshan 5 years
Screening forCancer inPatientsWithHepatitis
Many patients who have underlying cirrhosisn the United States will be followed up by arofessional specializing in liver disease whoay provide additional insight into this cancer
creening recommendation Based on a recentuestionnaire of US gastroenterologists only 50creen patients for hepatocellular carcinoma70
herefore implementation of this guideline byS clinicians is unlikely to be widespread
DIGORecommendations inChapter 20anagingCancerwithReductionof
mmunosuppressiveMedication
201 We suggest consideration be given to reducingimmunosuppressive medications for KTRs with can-
cer (2C)
2011 Important factors for consideration in-clude (Not Graded)bull The stage of cancer at diagnosisbull Whether the cancer is likely to be
exacerbated by immunosuppressionbull The therapies available for the can-
cerbull Whether immunosuppressive medica-
tions interfere with ability to admin-ister the standard chemotherapy
202 For patients with Kaposi sarcoma we suggestusing mTORi along with a reduction in overallimmunosuppression (2C)
DOQIRationale andCommentary
Table 1 (Table 29 in the KDIGO report3 andxcerpted from Grulich et al71) lists cancershat are increased most in immunosuppressedTRs based on standardized incidence ratios
SIRs) which compare the incidence toatched populations Cancers with the highestIRs may be those most likely to respond to aecrease in immunosuppression Except foraposi sarcoma limited evidence is available
or a decrease in immunosuppression in theseettings A strategy to change immunosuppres-ion therapy must occur in consultation withhe transplant center Switching to sirolimusherapy and decreasing immunosuppression inatients who develop Kaposi sarcoma is basedn sound scientific rationale7273
SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
The incidence of cancer posttransplant is 2-20times higher than that in the general population andKDIGO guidelines have been written to outline stepsfor prevention and screening With few exceptions weagree with the recommendations as outlined Skincancer is common in US transplant patients andscreening and prevention are critical However imple-mentation of guidelines for doing so including theKDIGO guidelines is a challenge because of patientpreferences against the routine use of sunscreen aswell as time constraints during office visits Althoughmany posttransplant cancers are viral mediated andrelated to immunosuppression it is less clear how toalter immunosuppression after malignancy has oc-curred We agree that although age-specific screeningfor malignancy should be incorporated into care con-sideration must be given to the risk of screening inpatients with limited life spans (5 years) because of
comorbid conditions
KT
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
ommonPopu
i sarco-Hodgmelanise sm
sophaemia
estima standa10 c
ut esti
0 case
alized t
to guide treatment specifically before the
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
K
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
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nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
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p2
sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
ation Transpl Rev 200923191-19815 Abbud-Filho M Adams PL Alberuacute J et al A report
f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
cA
nrc
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trN
hUt
Iwa
rl5
mi8
oe1
DA
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hm2
EA
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Bia et al30
ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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ARTICLE IN PRESS
HerpesandVaricella
Systemic herpesvirus infections can be lifehreatening in transplant recipients and should bereated aggressively with intravenous antiviralgents as described in the KDIGO recommenda-ions Less aggressive cutaneous infection can bereated with oral antiviral agents as outlined inhe KDIGO guidelines
Varicella exposure is particularly concerning inransplant recipients The work group disputes theecommended dosing of acyclovir for varicellaxposure Acyclovir at a dose of 10 mgkg or about00 mg 4 times daily of oral acyclovir would betandard dosing We agree with the use of varicellammune globulin and emphasize the need to avoidhe varicella vaccine because it is a live virushould a transplant recipient develop a systemicaricella infection hospitalization and high-dosentravenous acyclovir therapy are warranted
Hepatitis C
Hepatitis C management posttransplant is ahallenge The KDIGO guidelines cited hereere based on the recently published KDIGOuideline for hepatitis C in CKD4 Hepatitis Cypically is not treated posttransplant because ofhe risk (50) of rejection precipitated bynterferon therapy particularly in US KTRs inhom hepatitis C commonly is genotype 1 which
s more resistant to treatment with interferon42
owever should hepatitis Cndashrelated glomerulo-ephritis develop the risk-benefit ratio may fa-or treatment in selected patients Such decisionslways should be made in consultation withepatology and infectious disease experts andhe transplant center Monitoring liver enzymeevels specifically alanine aminotransferaseALT) may reflect a change in hepatitis activityut monitoring hepatitis C viral load is not recom-ended because it does not seem to correlateith outcome Annual monitoring for hepatocel-
ular carcinoma using -fetoprotein and imagings encouraged but not often practiced
Hepatitis B
KDIGO recommendations for hepatitis B areeasonable and currently are followed in mostS centers except for recommendation 1366
see previous recommendation under vaccina-ions) KTRs with hepatitis C or hepatitis B also
hould be followed up by a hepatologist
Human ImmunodeficiencyVirus
Human immunodeficiency virus (HIV)-posi-ive individuals are now acceptable for transplantf CD4 count is 200 cellsL and viral loadVL) is undetectable3543 Transplant should beerformed at centers with expertise in managingIV-positive individuals and care should be co-rdinated carefully with HIV specialists Somentiretroviral agents in particular the proteasenhibitors have potentially serious drug interac-ions with immunosuppressive agents35
DIGORecommendations inChapter 14Othernfections
141 URINARY TRACT INFECTION1411 We suggest that all KTRs receive UTI
prophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 monthsafter transplantation (2B)
1412 For allograft pyelonephritis we suggestinitial hospitalization and treatment withintravenous antibiotics (2C)
142 PNEUMOCYSTIS JIROVECII PNEUMONIA1421 We recommend that all KTRs receive
PCP prophylaxis with daily tri-methoprimndashsulfamethoxazole for 3-6months after transplantation (1B)
1422 We suggest that all KTRs receive PCPprophylaxis with daily trimethoprimndashsulfamethoxazole for at least 6 weeksduring and after treatment for acute rejec-tion (2C)
1423 We recommend that KTRs with PCPdiagnosed by bronchial alveolar lavageandor lung biopsy be treated withhigh-dose intravenous trimethoprimndashsulfamethoxazole corticosteroids anda reduction in immunosuppressivemedication (1C)
1424 We recommend treatment with cortico-steroids for KTRs with moderate tosevere PCP (as defined by PaO2 lt70mm Hg in room air or an alveolargradient of gt35 mm Hg) (1C)
143 TUBERCULOSIS1431 We suggest that TB prophylaxis and
treatment regimens be the same in KTRsas would be used in the local generalpopulation who require therapy (2D)
1432 We recommend monitoring CNI andmTORi [mTOR inhibitor] blood levels inpatients receiving rifampin (1C)14321 Consider substituting rifabu-
tin for rifampin to minimize
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KDOQI Commentary 17
ARTICLE IN PRESS
interactions with CNIs andmTORi (Not Graded)
144 CANDIDA PROPHYLAXIS1441 We suggest oral and esophageal Candida
prophylaxis with oral clotrimazole loz-enges nystatin or fluconazole for 1-3months after transplantation and for 1month after treatment with an antilympho-cyte antibody (2C)
DOQIRationale andCommentary
UrinaryTract Infection
Urinary tract infections (UTIs) after kidneyransplant are very common and account for aarge percentage of readmissions posttransplantTIs are common because of multiple factors
ncluding the disrupted anatomy of the urinaryract with a ureteroneocystotomy incompleteladder emptying because of diabetes or pros-atic hypertrophy and impaired immune re-ponses Prophylaxis of UTIs usually is under-aken with trimethoprim-sulfamethoxazole for 6onths posttransplant although infections often
ccur despite therapy because of the develop-ent of drug resistance Although native kidney
yelonephritis does not always require hospital-zation it is recommended that all KTRs withhis diagnosis be hospitalized because the graftysfunction that usually accompanies transplantyelonephritis requires aggressive investigationnd treatment Individuals with recurrent UTIsarrant evaluation with urologic assessment Pa-
ients with recurrent UTIs may benefit fromong-term suppressive therapy
Pneumocystic Pneumonia
We agree that Pneumocystis jirovecii pneumoniaPCP) prophylaxis is important for the first 3-6onths posttransplant (1421)After the first month
very-other-day dosing of trimethoprim-sulfame-hoxazole or atovaquone is believed to be adequaterophylaxis In cases in which neither of thesegents can be used an individual may be treatedrophylactically with inhaled pentamidine OurDOQI work group emphasized that patients whoevelop PCP should be transferred to the transplantenter promptly for management and adjustmentsn immunosuppression
Tuberculosis
Monitoring for latent tuberculosis has posed a
hallenge in the immunosuppressed population be-
ause of the unreliable nature of skin testing Newerechniques involving interferon release assays aremerging as the new gold standard for detection ofatent tuberculosis4445
CandidaProphylaxis
Oral candidiasis must be screened for usingral mucosa examination on follow-up visitsn KTRs This is especially true in the earlyosttransplant period when immunosuppres-ive medication dosage is the highest Wegree with these recommendations and empha-ize that if fluconazole is used there is aotential for serious drug interactions becausef cytochrome P-450 3A4 inhibition
SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
Improvement in short-term outcomes has not trans-lated into significant improvements in long-term out-comes in KTRs The lack of significant improvement inlong-term survival may be related to post-transplantcomplications Frequent posttransplant monitoring mayimprove long-term outcomes by decreasing chronic graftfailure or death with a functioning graft Our work groupconcurred with the recommendation and schedules ofroutine screening in monitoring kidney allograft functionafter kidney transplant with a low threshold for perform-ing kidney biopsy in cases of graft dysfunction or protein-uria Expert tissue processing and interpretation of trans-plant biopsy specimens by pathologists with transplantexperience are critical Regular surveillance of the pa-tientrsquos kidney function at the transplant center or in thenephrologistrsquos office offers an opportunity to enhancepatient adherence to medication diet and healthy life-style Although CKD in KTRs progresses more slowlythan CKD in other patients the work group agreed thatthe KDIGO guidelines on CKD should be followed inKTRs
Opportunistic infections are common in KTRs al-though advances in diagnosis and treatment have led toimproved survival in KTRs with infection It is nowstandard of care to use vaccinations in KTRs as long asthe vaccine does not contain live or attenuated virus Italso is routine to screen for or use prophylaxis to preventseveral posttransplant viral infections With few excep-tions (related to EBV and BK virus screening andhepatitis B vaccination posttransplant) we concurredwith KDIGO guidelines for vaccination screening and
treatment of infection posttransplant
KD
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Bia et al18
ARTICLE IN PRESS
COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULAR
DISEASE
DIGORecommendations inChapter 15iabetesMellitus
151 Screening for New-Onset Diabetes after Transplan-tation1511 We recommend screening all nondia-
betic KTRs with fasting plasma glu-cose oral glucose tolerance testingandor HbA1c (1C) at leastbull weekly for 4 weeks (2D)bull every 3 months for 1 year (2D)bull and annually thereafter (2D)
1512 We suggest screening for NODAT withfasting glucose oral glucose tolerancetesting andor after starting or substan-tially increasing the dose of CNIsmTORi or corticosteroids (2D)
152 Managing NODAT or Diabetes Present at Trans-plantation1521 If NODAT develops consider modifying
the immunosuppressive drug regimen toreverse or ameliorate diabetes afterweighing the risk of rejection and otherpotential adverse effects (Not Graded)
1522 Consider targeting HbA1c 70-75and avoid targeting HbA1c 60 espe-cially if hypoglycemic reactions are com-mon (Not Graded)
1523 We suggest that in patients with diabetesaspirin (65-100 mgd) use for the primaryprevention of CVD be based on patientpreferences and values balancing the riskfor ischemic events to that of bleeding(2D)
DOQIRationale andCommentary
Diabetic Screening
We agree with screening for new-onset diabetesfter transplantation (NODAT) as outlined by theDIGO work group Definitions used are similar
o those of the American Diabetes AssociationADA) The greater frequency of testing initially isustified by the high risk of NODAT in the earlyosttransplant period however ongoing screenings required because the risk of the development ofODAT continues to increase over time4647 We
lso point out that prediabetic states (impairedasting glucose level and impaired glucose toler-nce) occur even more commonly than overt diabe-es48 and may be associated with metabolic syn-rome as well as with increased cardiovascular
ortality49-51 Potential implications of these predia-
etic states emphasize the importance of perform-ng blood tests under fasting conditions For pa-ients with fasting hyperglycemia an oral glucoseolerance test or hemoglobinA1c (HbA1c) test shoulde performed Although more cumbersome to per-orm data suggest that an oral glucose toleranceest is a more sensitive indicator of NODAT inyperglycemic KTRs52 This may allow earlieretection of overt diabetes and more prompt institu-ion of treatment
DiabetesManagement
Data supporting a substantial benefit in themelioration or reversal of NODAT using immu-osuppression modification in KTRs are veryimited There was consensus in our work grouphat considering the paucity of data for reversingODAT by changing immunosuppression and
he potential risk of an adverse outcome withuch a maneuver KDIGO suggestion 1521 couldot be supported Certainly if such a step waseing considered it should be done in conjunc-ion with the transplant center Targeting an HbA1c
evel of 7-75 and avoiding levels 6 isased on data showing increased cardiovascularvents with the lower HbA1c target5354
DIGORecommendations inChapter 16ypertensionDyslipidemias TobaccoUse andbesity
161 Hypertension1611 We recommend measuring blood pres-
sure at each clinic visit (1C)1612 We suggest maintaining blood pressure at
130 mm Hg systolic and 80 mm Hgdiastolic if 18 years of age and 90th
percentile for sex age and height if 18years old (2C)
1613 To treat hypertension (Not Graded)bull Use any class of antihypertensive
agentbull Monitor closely for adverse effects
and drug-drug interactions and whenurine protein excretion 1 gd for18 years old and 600 mgm224 hfor 18 years old consider an ACE-Ior an ARB as first-line therapy
162 Dyslipidemias (These recommendations are basedon KDOQI Dyslipidemia Guidelines and are thusnot graded)1621 Measure a complete lipid profile in all
adult (18 years old) and adolescent
(puberty to 18 years old) KTRs [Based on
K
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KDOQI Commentary 19
ARTICLE IN PRESS
KDOQI Dyslipidemia Recommendation1]bull 2-3 months after transplantationbull 2-3 months after a change in treatment
or other conditions known to causedyslipidemias
bull at least annually thereafter1622 Evaluate KTRs with dyslipidemias for
secondary causes [Based on KDOQI Dys-lipidemia Recommendation 3]16221 For KTRs with fasting triglyc-
erides 500 mgdL (565mmolL) that cannot be cor-rected by removing an under-lying cause treat withbull Adults therapeutic lifestyle
changes and a triglyceride-lowering agent [Based onKDOQI Recommendation41]
bull Adolescents therapeutic life-style changes [Based onKDOQI Recommendation51]
16222 For KTRs with elevatedLDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)treat to reduce LDL-C to100 mgdL (259mmolL) [Based on KDOQIGuideline 42]
bull Adolescents If LDL-C130 mgdL (336 mmolL) treat to reduce LDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 52]
16223 For KTRs with normalLDL-C elevated triglyceridesand elevated non-HDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)fasting triglycerides 200mgdL (226 mmolL)and non-HDL-C 130mgdL (336 mmolL)treat to reduce non-HDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 43]
bull Adolescents If LDL-C130 mgdL (336 mmolL) fasting triglycerides200 mgdL (226 mmolL) and non-HDL-C 160mgdL (414 mmolL)treat to reduce non-HDL-C
to 160 mgdL (414 i
mmolL) [Based on KDOQIGuideline 53]
163 Tobacco Use1631 Screen and counsel all KTRs including
adolescents and children for tobacco useand record the results in the medicalrecord (Not Graded)bull Screen during initial transplant hospi-
talizationbull Screen at least annually thereafter
1632 Offer treatment to all patients who usetobacco (Not Graded)
164 Obesity1641 Assess obesity at each visit (Not Graded)
bull Measure height and weight at eachvisit in adults and children
bull Calculate BMI at each visitbull Measure waist circumference when
weight and physical appearance sug-gest obesity but BMI is 35 kgm2
1642 Offer a weight-reduction program to allobese KTRs (Not Graded)
DOQIRationale andCommentary
Hypertension
The KDIGO work group adapted the KDOQI004 recommendations for target blood pres-ure in KTRs55 Self measurement is useful inssessing response to therapy and enhancesdherence56 In general we agree that the classf antihypertensive agent does not matter inhe treatment of blood pressure elevation inhis population and that attention should beiven to potential side effects of antihyperten-ive agents as well as possible interactionsith the immunosuppressive regimen (eg non-ihydropyridine calcium channel blockers andNIs) In the absence of adequate randomizedontrolled trials it is not known whether angio-ensin-converting enzyme (ACE) inhibitors andngiotensin receptor blockers (ARBs) prolongecipient or allograft survival Some but notll retrospective studies suggest a benefitowever all these studies are limited by selec-ion bias5758 Although ACE inhibitors andRBs commonly lead to some decrease inFR treatment with these drugs should be
ontinued unless serum creatinine level in-reases by 25 to 30 in keeping withDOQI recommendations55 In KTRs receiv-
ng ACE inhibitors or ARBs it is important toducate patients to maintain adequate fluid
ntake during illness to prevent a prerenal
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Bia et al20
ARTICLE IN PRESS
nsult to the allograft Similarly awareness isecessary when using diuretics in conjunctionith therapies that block the renin-angiotensin-
ldosterone-system59
Dyslipidemia
The KDIGO work group based their recom-endations for evaluation and treatment of
yperlipidemia on the KDOQI dyslipidemiauidelines for KTRs60 We agree with theseecommendations CNIs potentiate the toxicityf statins by slowing their metabolism throughhe cytochrome P-450 system This interactionccurs more commonly with cyclosporine61
han with tacrolimus Dyslipidemia especiallyypertriglyceridemia frequently complicatesTOR-inhibitor use and lipid-lowering therapy
s required in most patients using these agents
TobaccoUse
Not surprisingly tobacco use at the time ofransplant is associated with decreased patientnd graft survival as well as increased risk ofosttransplant cardiovascular disease (CVD)lthough the KDIGO work group recom-ends initial screening and intervention dur-
ng the hospitalization for transplant we be-ieve there may be benefit gained by startingounseling in the pretransplant period duringhe evaluation phase Unfortunately this doesot occur often because of time and personnelonstraints in transplant centers Ideally allransplant centers should have smoking-cessa-ion programs available to patients either in-ouse or through referral Ideally systemshould be created to continue to screen andonitor for smoking cessation at yearly inter-
als after transplant because there is a highate of relapse with this addiction As outlinedn KDIGO Table 253 although all pharmaco-ogic therapies for smoking cessation can besed in KTRs the starting dose of vareniclinehould be decreased in patients with GFR 30Lmin
Obesity
Obesity is an epidemic in the United Statesnd the proportion of obese kidney transplantandidates continues to grow In additioneight gain after transplant is very commonly
bserved Obesity in KTRs is associated with w
ncreased risks of wound complications de-ayed graft function acute rejection and NO-AT resulting in inferior patient and graftutcomes Attention to this potential complica-ion and counseling should be initiated duringhe pretransplant evaluation phase Informa-ion regarding pharmacologic therapies foreight loss in KTRs is not available and we
gree with the KDIGO work group that thera-eutic lifestyle measures should be encour-ged Data regarding steroid therapy with-rawal and weight gain are controversial Aecent double-blind randomized controlled trialxamining early steroid therapy withdrawalid not show a difference in weight gain at 5ears posttransplant compared with the cohortemaining on standard maintenance corticoste-oid therapy62
DIGORecommendations inChapter 17ardiovascularManagement
171 Consider managing CVD at least as intensively inKTRs as in the general population with appropri-ate diagnostic tests and treatments (Not Graded)
172 We suggest using aspirin (65-100 mgd) in allpatients with atherosclerotic CVD unless there arecontraindications (2B)
DOQIRationale andCommentary
Although outcomes are favorable comparedith remaining on the waiting list the risk of
ardiovascular mortality in KTRs is several-foldigher than observed in the general population63
specially in younger age groups and patientsith decreasing allograft function64 CVD is aajor cause of graft loss after the first post-
ransplant year In this context we strongly agreehat CVD should be managed in KTRs at least asntensively as in the general population Ideallyecreasing CVD risk in KTRs requires a multifac-ted and multidisciplinary approach Based onurrent practice models in the United States theransplant and nephrology community has notet been able to achieve these desirable goals65
his clearly deserves more attention becauseontrol of CVD has the potential to contributeore to long-term kidney graft survival than the
iscovery of newer drugs that decrease the ratef allograft rejection Our KDOQI working groupgreed with the use of low-dose aspirin in KTRs
ith evidence of atherosclerosis
Ko
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KDOQI Commentary 21
ARTICLE IN PRESS
SUMMARY OF COMMENTARY ONSECTION III CVD
COMMENTARY ON SECTION IV OF KDIGO
TRANSPLANT GUIDELINE MALIGNANCY
DIGORecommendations inChapter 18 Cancerf the Skin andLip
181 We recommend that KTRs especially thosewho have fair skin live in high sun-exposureclimates have occupations requiring sun expo-sure have had significant sun exposure as achild or have a history of skin cancer be toldthat their risk of skin and lip cancer is veryhigh (1C)
182 We recommend that KTRs minimize life-longsun exposure and use appropriate ultravioletlight blocking agents (1D)
183 We suggest that adult KTRs perform skin andlip self-examinations and report new lesions toa health-care provider (2D)
184 For adult KTRs we suggest that a qualified healthprofessional with experience in diagnosing skincancer perform annual skin and lip examinationon KTRs except possibly for KTRs with dark skinpigmentation (2D)
185 We suggest that patients with a history of skin orlip cancer or premalignant lesions be referred to andfollowed by a qualified health professional withexperience in diagnosing and treating skin cancer
With the decrease in acute rejection during the pastdecade in association with improved immunosuppres-sion regimens patient death now rivals chronic graftdysfunction as one of the leading causes of long-termgraft loss Because CVD is the most common cause ofpatient death in KTRs a concerted effort at minimizingrisk factors for heart disease likely will have as great oreven greater impact on optimizing patient and graftoutcomes than the discovery of new antirejection thera-pies CVD risk reduction strategies should include regularscreening for new-onset diabetes (using ADA-based defini-tions) in the posttransplant period in previously nondiabeticpatients good glycemic regulation for diabetic patients accord-ing to current ADA guidelines and lipid management andblood pressure control according to KDOQI recommenda-tions In addition promotion of a healthy lifestyle throughweight control exercise and smoking cessation should be acentral part of posttransplant counseling and care Whenimmunosuppression modification is being considered to miti-gate cardiovascular risk we recommend that this be inconjunction with the transplant center In summary we gener-ally concurred with the suggestions of the work group in thissection but based on current practice standards in the UnitedStateschallengesremainwith implementationof thisguideline
(2D) s
186 We suggest that patients with a history of skincancer be offered treatment with oral acitretin ifthere are no contraindications (2B)
DOQIRationale andCommentary
CounselingandSunscreen
We concur with recommendations 181 and82 because skin cancer is a major source oforbidity and sometimes mortality in KTRsarning patients at risk of the high danger of
kin cancer a 1C recommendation is reinforcedy a recent prospective case-control study ofrgan transplant recipients that showed that regu-ar use of broad-spectrum sunscreens that pro-ide UVA and UVB protection may prevent theevelopment of actinic keratosis invasive squa-ous cell carcinoma and to a lesser extent
asal cell carcinoma66 Most cancer-causing ra-iation is thought to come from the UVB spec-rum and newer broad-spectrum sunscreens pro-ide protection against UVA and UVB radiationounseling about sunscreen and the need for sunvoidance needs to be incorporated into routineffice visits although it may not always beuccessful In a recent study of KTRs in which1 of patients had been informed about theeed for sun protection only 46 used morehan a tube of sunscreen per year67
Dermatology Involvement
There is increased evidence to suggest thatpecialty dermatology clinics for organ trans-lant recipients improve outcome measures in-luding compliance with photoprotection andncreased awareness of skin cancer68 The re-ources required for these specialty clinics makemplementation difficult for community nephrol-gy groups that do not have direct access to aransplant center Transplant patients should bencouraged to have annual visits with their trans-lant center and if dermatology specialty clinicsre available attempt to coordinate a skin cancervaluation annually
UseofRetinoid-likeCompounds
There is a limited scientific basis for KDIGOuggestion recommendation 186 Although reti-oids now are used routinely in KTRs with aigh skin cancer burden our KDOQI work groupelieves that more data are needed before this
uggestion should be accepted as a guideline In
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ARTICLE IN PRESS
ow-immunologic-risk groups and particularlyifficult cases some data suggest that switchingrom CNI to sirolimus therapy may decrease thencidence of skin cancer69 however the riskersus benefit of this maneuver has not been welltudied
DIGORecommendations inChapter 19on-SkinMalignancies
191 Develop an individualized screening plan for eachKTR that takes into account the patientrsquos pastmedical and family history tobacco use compet-ing risks for death and the performance of thescreening methodology (Not Graded)
192 Screen for the following cancers as per localguidelines for the general population (Not Graded)Women cervical breast and colon cancer Menprostate and colon cancer
193 Obtain hepatic ultrasound and alpha feto-proteinevery 12 months in patients with compensatedcirrhosis (Not Graded) [See Recommendations1354 (HCV) and 1365 (HBV)]
DOQIRationale andCommentary
Screening
It is recognized that KTRs have a higher inci-ence of malignancy particularly those associatedith specific viral infections Although cancer
creening may have benefits in this higher riskopulation it should be reinforced that some meth-ds of screening have significant risks which shoulde considered on an individualized basis particu-arly in patients who have projected survival lesshan 5 years
Screening forCancer inPatientsWithHepatitis
Many patients who have underlying cirrhosisn the United States will be followed up by arofessional specializing in liver disease whoay provide additional insight into this cancer
creening recommendation Based on a recentuestionnaire of US gastroenterologists only 50creen patients for hepatocellular carcinoma70
herefore implementation of this guideline byS clinicians is unlikely to be widespread
DIGORecommendations inChapter 20anagingCancerwithReductionof
mmunosuppressiveMedication
201 We suggest consideration be given to reducingimmunosuppressive medications for KTRs with can-
cer (2C)
2011 Important factors for consideration in-clude (Not Graded)bull The stage of cancer at diagnosisbull Whether the cancer is likely to be
exacerbated by immunosuppressionbull The therapies available for the can-
cerbull Whether immunosuppressive medica-
tions interfere with ability to admin-ister the standard chemotherapy
202 For patients with Kaposi sarcoma we suggestusing mTORi along with a reduction in overallimmunosuppression (2C)
DOQIRationale andCommentary
Table 1 (Table 29 in the KDIGO report3 andxcerpted from Grulich et al71) lists cancershat are increased most in immunosuppressedTRs based on standardized incidence ratios
SIRs) which compare the incidence toatched populations Cancers with the highestIRs may be those most likely to respond to aecrease in immunosuppression Except foraposi sarcoma limited evidence is available
or a decrease in immunosuppression in theseettings A strategy to change immunosuppres-ion therapy must occur in consultation withhe transplant center Switching to sirolimusherapy and decreasing immunosuppression inatients who develop Kaposi sarcoma is basedn sound scientific rationale7273
SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
The incidence of cancer posttransplant is 2-20times higher than that in the general population andKDIGO guidelines have been written to outline stepsfor prevention and screening With few exceptions weagree with the recommendations as outlined Skincancer is common in US transplant patients andscreening and prevention are critical However imple-mentation of guidelines for doing so including theKDIGO guidelines is a challenge because of patientpreferences against the routine use of sunscreen aswell as time constraints during office visits Althoughmany posttransplant cancers are viral mediated andrelated to immunosuppression it is less clear how toalter immunosuppression after malignancy has oc-curred We agree that although age-specific screeningfor malignancy should be incorporated into care con-sideration must be given to the risk of screening inpatients with limited life spans (5 years) because of
comorbid conditions
KT
H
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
ommonPopu
i sarco-Hodgmelanise sm
sophaemia
estima standa10 c
ut esti
0 case
alized t
to guide treatment specifically before the
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
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nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
o2
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ml
gt1
p2
ps2
c2
p2
sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
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M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
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f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
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Bia et al30
ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
K
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KDOQI Commentary 17
ARTICLE IN PRESS
interactions with CNIs andmTORi (Not Graded)
144 CANDIDA PROPHYLAXIS1441 We suggest oral and esophageal Candida
prophylaxis with oral clotrimazole loz-enges nystatin or fluconazole for 1-3months after transplantation and for 1month after treatment with an antilympho-cyte antibody (2C)
DOQIRationale andCommentary
UrinaryTract Infection
Urinary tract infections (UTIs) after kidneyransplant are very common and account for aarge percentage of readmissions posttransplantTIs are common because of multiple factors
ncluding the disrupted anatomy of the urinaryract with a ureteroneocystotomy incompleteladder emptying because of diabetes or pros-atic hypertrophy and impaired immune re-ponses Prophylaxis of UTIs usually is under-aken with trimethoprim-sulfamethoxazole for 6onths posttransplant although infections often
ccur despite therapy because of the develop-ent of drug resistance Although native kidney
yelonephritis does not always require hospital-zation it is recommended that all KTRs withhis diagnosis be hospitalized because the graftysfunction that usually accompanies transplantyelonephritis requires aggressive investigationnd treatment Individuals with recurrent UTIsarrant evaluation with urologic assessment Pa-
ients with recurrent UTIs may benefit fromong-term suppressive therapy
Pneumocystic Pneumonia
We agree that Pneumocystis jirovecii pneumoniaPCP) prophylaxis is important for the first 3-6onths posttransplant (1421)After the first month
very-other-day dosing of trimethoprim-sulfame-hoxazole or atovaquone is believed to be adequaterophylaxis In cases in which neither of thesegents can be used an individual may be treatedrophylactically with inhaled pentamidine OurDOQI work group emphasized that patients whoevelop PCP should be transferred to the transplantenter promptly for management and adjustmentsn immunosuppression
Tuberculosis
Monitoring for latent tuberculosis has posed a
hallenge in the immunosuppressed population be-
ause of the unreliable nature of skin testing Newerechniques involving interferon release assays aremerging as the new gold standard for detection ofatent tuberculosis4445
CandidaProphylaxis
Oral candidiasis must be screened for usingral mucosa examination on follow-up visitsn KTRs This is especially true in the earlyosttransplant period when immunosuppres-ive medication dosage is the highest Wegree with these recommendations and empha-ize that if fluconazole is used there is aotential for serious drug interactions becausef cytochrome P-450 3A4 inhibition
SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
Improvement in short-term outcomes has not trans-lated into significant improvements in long-term out-comes in KTRs The lack of significant improvement inlong-term survival may be related to post-transplantcomplications Frequent posttransplant monitoring mayimprove long-term outcomes by decreasing chronic graftfailure or death with a functioning graft Our work groupconcurred with the recommendation and schedules ofroutine screening in monitoring kidney allograft functionafter kidney transplant with a low threshold for perform-ing kidney biopsy in cases of graft dysfunction or protein-uria Expert tissue processing and interpretation of trans-plant biopsy specimens by pathologists with transplantexperience are critical Regular surveillance of the pa-tientrsquos kidney function at the transplant center or in thenephrologistrsquos office offers an opportunity to enhancepatient adherence to medication diet and healthy life-style Although CKD in KTRs progresses more slowlythan CKD in other patients the work group agreed thatthe KDIGO guidelines on CKD should be followed inKTRs
Opportunistic infections are common in KTRs al-though advances in diagnosis and treatment have led toimproved survival in KTRs with infection It is nowstandard of care to use vaccinations in KTRs as long asthe vaccine does not contain live or attenuated virus Italso is routine to screen for or use prophylaxis to preventseveral posttransplant viral infections With few excep-tions (related to EBV and BK virus screening andhepatitis B vaccination posttransplant) we concurredwith KDIGO guidelines for vaccination screening and
treatment of infection posttransplant
KD
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ARTICLE IN PRESS
COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULAR
DISEASE
DIGORecommendations inChapter 15iabetesMellitus
151 Screening for New-Onset Diabetes after Transplan-tation1511 We recommend screening all nondia-
betic KTRs with fasting plasma glu-cose oral glucose tolerance testingandor HbA1c (1C) at leastbull weekly for 4 weeks (2D)bull every 3 months for 1 year (2D)bull and annually thereafter (2D)
1512 We suggest screening for NODAT withfasting glucose oral glucose tolerancetesting andor after starting or substan-tially increasing the dose of CNIsmTORi or corticosteroids (2D)
152 Managing NODAT or Diabetes Present at Trans-plantation1521 If NODAT develops consider modifying
the immunosuppressive drug regimen toreverse or ameliorate diabetes afterweighing the risk of rejection and otherpotential adverse effects (Not Graded)
1522 Consider targeting HbA1c 70-75and avoid targeting HbA1c 60 espe-cially if hypoglycemic reactions are com-mon (Not Graded)
1523 We suggest that in patients with diabetesaspirin (65-100 mgd) use for the primaryprevention of CVD be based on patientpreferences and values balancing the riskfor ischemic events to that of bleeding(2D)
DOQIRationale andCommentary
Diabetic Screening
We agree with screening for new-onset diabetesfter transplantation (NODAT) as outlined by theDIGO work group Definitions used are similar
o those of the American Diabetes AssociationADA) The greater frequency of testing initially isustified by the high risk of NODAT in the earlyosttransplant period however ongoing screenings required because the risk of the development ofODAT continues to increase over time4647 We
lso point out that prediabetic states (impairedasting glucose level and impaired glucose toler-nce) occur even more commonly than overt diabe-es48 and may be associated with metabolic syn-rome as well as with increased cardiovascular
ortality49-51 Potential implications of these predia-
etic states emphasize the importance of perform-ng blood tests under fasting conditions For pa-ients with fasting hyperglycemia an oral glucoseolerance test or hemoglobinA1c (HbA1c) test shoulde performed Although more cumbersome to per-orm data suggest that an oral glucose toleranceest is a more sensitive indicator of NODAT inyperglycemic KTRs52 This may allow earlieretection of overt diabetes and more prompt institu-ion of treatment
DiabetesManagement
Data supporting a substantial benefit in themelioration or reversal of NODAT using immu-osuppression modification in KTRs are veryimited There was consensus in our work grouphat considering the paucity of data for reversingODAT by changing immunosuppression and
he potential risk of an adverse outcome withuch a maneuver KDIGO suggestion 1521 couldot be supported Certainly if such a step waseing considered it should be done in conjunc-ion with the transplant center Targeting an HbA1c
evel of 7-75 and avoiding levels 6 isased on data showing increased cardiovascularvents with the lower HbA1c target5354
DIGORecommendations inChapter 16ypertensionDyslipidemias TobaccoUse andbesity
161 Hypertension1611 We recommend measuring blood pres-
sure at each clinic visit (1C)1612 We suggest maintaining blood pressure at
130 mm Hg systolic and 80 mm Hgdiastolic if 18 years of age and 90th
percentile for sex age and height if 18years old (2C)
1613 To treat hypertension (Not Graded)bull Use any class of antihypertensive
agentbull Monitor closely for adverse effects
and drug-drug interactions and whenurine protein excretion 1 gd for18 years old and 600 mgm224 hfor 18 years old consider an ACE-Ior an ARB as first-line therapy
162 Dyslipidemias (These recommendations are basedon KDOQI Dyslipidemia Guidelines and are thusnot graded)1621 Measure a complete lipid profile in all
adult (18 years old) and adolescent
(puberty to 18 years old) KTRs [Based on
K
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KDOQI Commentary 19
ARTICLE IN PRESS
KDOQI Dyslipidemia Recommendation1]bull 2-3 months after transplantationbull 2-3 months after a change in treatment
or other conditions known to causedyslipidemias
bull at least annually thereafter1622 Evaluate KTRs with dyslipidemias for
secondary causes [Based on KDOQI Dys-lipidemia Recommendation 3]16221 For KTRs with fasting triglyc-
erides 500 mgdL (565mmolL) that cannot be cor-rected by removing an under-lying cause treat withbull Adults therapeutic lifestyle
changes and a triglyceride-lowering agent [Based onKDOQI Recommendation41]
bull Adolescents therapeutic life-style changes [Based onKDOQI Recommendation51]
16222 For KTRs with elevatedLDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)treat to reduce LDL-C to100 mgdL (259mmolL) [Based on KDOQIGuideline 42]
bull Adolescents If LDL-C130 mgdL (336 mmolL) treat to reduce LDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 52]
16223 For KTRs with normalLDL-C elevated triglyceridesand elevated non-HDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)fasting triglycerides 200mgdL (226 mmolL)and non-HDL-C 130mgdL (336 mmolL)treat to reduce non-HDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 43]
bull Adolescents If LDL-C130 mgdL (336 mmolL) fasting triglycerides200 mgdL (226 mmolL) and non-HDL-C 160mgdL (414 mmolL)treat to reduce non-HDL-C
to 160 mgdL (414 i
mmolL) [Based on KDOQIGuideline 53]
163 Tobacco Use1631 Screen and counsel all KTRs including
adolescents and children for tobacco useand record the results in the medicalrecord (Not Graded)bull Screen during initial transplant hospi-
talizationbull Screen at least annually thereafter
1632 Offer treatment to all patients who usetobacco (Not Graded)
164 Obesity1641 Assess obesity at each visit (Not Graded)
bull Measure height and weight at eachvisit in adults and children
bull Calculate BMI at each visitbull Measure waist circumference when
weight and physical appearance sug-gest obesity but BMI is 35 kgm2
1642 Offer a weight-reduction program to allobese KTRs (Not Graded)
DOQIRationale andCommentary
Hypertension
The KDIGO work group adapted the KDOQI004 recommendations for target blood pres-ure in KTRs55 Self measurement is useful inssessing response to therapy and enhancesdherence56 In general we agree that the classf antihypertensive agent does not matter inhe treatment of blood pressure elevation inhis population and that attention should beiven to potential side effects of antihyperten-ive agents as well as possible interactionsith the immunosuppressive regimen (eg non-ihydropyridine calcium channel blockers andNIs) In the absence of adequate randomizedontrolled trials it is not known whether angio-ensin-converting enzyme (ACE) inhibitors andngiotensin receptor blockers (ARBs) prolongecipient or allograft survival Some but notll retrospective studies suggest a benefitowever all these studies are limited by selec-ion bias5758 Although ACE inhibitors andRBs commonly lead to some decrease inFR treatment with these drugs should be
ontinued unless serum creatinine level in-reases by 25 to 30 in keeping withDOQI recommendations55 In KTRs receiv-
ng ACE inhibitors or ARBs it is important toducate patients to maintain adequate fluid
ntake during illness to prevent a prerenal
inwa
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Bia et al20
ARTICLE IN PRESS
nsult to the allograft Similarly awareness isecessary when using diuretics in conjunctionith therapies that block the renin-angiotensin-
ldosterone-system59
Dyslipidemia
The KDIGO work group based their recom-endations for evaluation and treatment of
yperlipidemia on the KDOQI dyslipidemiauidelines for KTRs60 We agree with theseecommendations CNIs potentiate the toxicityf statins by slowing their metabolism throughhe cytochrome P-450 system This interactionccurs more commonly with cyclosporine61
han with tacrolimus Dyslipidemia especiallyypertriglyceridemia frequently complicatesTOR-inhibitor use and lipid-lowering therapy
s required in most patients using these agents
TobaccoUse
Not surprisingly tobacco use at the time ofransplant is associated with decreased patientnd graft survival as well as increased risk ofosttransplant cardiovascular disease (CVD)lthough the KDIGO work group recom-ends initial screening and intervention dur-
ng the hospitalization for transplant we be-ieve there may be benefit gained by startingounseling in the pretransplant period duringhe evaluation phase Unfortunately this doesot occur often because of time and personnelonstraints in transplant centers Ideally allransplant centers should have smoking-cessa-ion programs available to patients either in-ouse or through referral Ideally systemshould be created to continue to screen andonitor for smoking cessation at yearly inter-
als after transplant because there is a highate of relapse with this addiction As outlinedn KDIGO Table 253 although all pharmaco-ogic therapies for smoking cessation can besed in KTRs the starting dose of vareniclinehould be decreased in patients with GFR 30Lmin
Obesity
Obesity is an epidemic in the United Statesnd the proportion of obese kidney transplantandidates continues to grow In additioneight gain after transplant is very commonly
bserved Obesity in KTRs is associated with w
ncreased risks of wound complications de-ayed graft function acute rejection and NO-AT resulting in inferior patient and graftutcomes Attention to this potential complica-ion and counseling should be initiated duringhe pretransplant evaluation phase Informa-ion regarding pharmacologic therapies foreight loss in KTRs is not available and we
gree with the KDIGO work group that thera-eutic lifestyle measures should be encour-ged Data regarding steroid therapy with-rawal and weight gain are controversial Aecent double-blind randomized controlled trialxamining early steroid therapy withdrawalid not show a difference in weight gain at 5ears posttransplant compared with the cohortemaining on standard maintenance corticoste-oid therapy62
DIGORecommendations inChapter 17ardiovascularManagement
171 Consider managing CVD at least as intensively inKTRs as in the general population with appropri-ate diagnostic tests and treatments (Not Graded)
172 We suggest using aspirin (65-100 mgd) in allpatients with atherosclerotic CVD unless there arecontraindications (2B)
DOQIRationale andCommentary
Although outcomes are favorable comparedith remaining on the waiting list the risk of
ardiovascular mortality in KTRs is several-foldigher than observed in the general population63
specially in younger age groups and patientsith decreasing allograft function64 CVD is aajor cause of graft loss after the first post-
ransplant year In this context we strongly agreehat CVD should be managed in KTRs at least asntensively as in the general population Ideallyecreasing CVD risk in KTRs requires a multifac-ted and multidisciplinary approach Based onurrent practice models in the United States theransplant and nephrology community has notet been able to achieve these desirable goals65
his clearly deserves more attention becauseontrol of CVD has the potential to contributeore to long-term kidney graft survival than the
iscovery of newer drugs that decrease the ratef allograft rejection Our KDOQI working groupgreed with the use of low-dose aspirin in KTRs
ith evidence of atherosclerosis
Ko
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KDOQI Commentary 21
ARTICLE IN PRESS
SUMMARY OF COMMENTARY ONSECTION III CVD
COMMENTARY ON SECTION IV OF KDIGO
TRANSPLANT GUIDELINE MALIGNANCY
DIGORecommendations inChapter 18 Cancerf the Skin andLip
181 We recommend that KTRs especially thosewho have fair skin live in high sun-exposureclimates have occupations requiring sun expo-sure have had significant sun exposure as achild or have a history of skin cancer be toldthat their risk of skin and lip cancer is veryhigh (1C)
182 We recommend that KTRs minimize life-longsun exposure and use appropriate ultravioletlight blocking agents (1D)
183 We suggest that adult KTRs perform skin andlip self-examinations and report new lesions toa health-care provider (2D)
184 For adult KTRs we suggest that a qualified healthprofessional with experience in diagnosing skincancer perform annual skin and lip examinationon KTRs except possibly for KTRs with dark skinpigmentation (2D)
185 We suggest that patients with a history of skin orlip cancer or premalignant lesions be referred to andfollowed by a qualified health professional withexperience in diagnosing and treating skin cancer
With the decrease in acute rejection during the pastdecade in association with improved immunosuppres-sion regimens patient death now rivals chronic graftdysfunction as one of the leading causes of long-termgraft loss Because CVD is the most common cause ofpatient death in KTRs a concerted effort at minimizingrisk factors for heart disease likely will have as great oreven greater impact on optimizing patient and graftoutcomes than the discovery of new antirejection thera-pies CVD risk reduction strategies should include regularscreening for new-onset diabetes (using ADA-based defini-tions) in the posttransplant period in previously nondiabeticpatients good glycemic regulation for diabetic patients accord-ing to current ADA guidelines and lipid management andblood pressure control according to KDOQI recommenda-tions In addition promotion of a healthy lifestyle throughweight control exercise and smoking cessation should be acentral part of posttransplant counseling and care Whenimmunosuppression modification is being considered to miti-gate cardiovascular risk we recommend that this be inconjunction with the transplant center In summary we gener-ally concurred with the suggestions of the work group in thissection but based on current practice standards in the UnitedStateschallengesremainwith implementationof thisguideline
(2D) s
186 We suggest that patients with a history of skincancer be offered treatment with oral acitretin ifthere are no contraindications (2B)
DOQIRationale andCommentary
CounselingandSunscreen
We concur with recommendations 181 and82 because skin cancer is a major source oforbidity and sometimes mortality in KTRsarning patients at risk of the high danger of
kin cancer a 1C recommendation is reinforcedy a recent prospective case-control study ofrgan transplant recipients that showed that regu-ar use of broad-spectrum sunscreens that pro-ide UVA and UVB protection may prevent theevelopment of actinic keratosis invasive squa-ous cell carcinoma and to a lesser extent
asal cell carcinoma66 Most cancer-causing ra-iation is thought to come from the UVB spec-rum and newer broad-spectrum sunscreens pro-ide protection against UVA and UVB radiationounseling about sunscreen and the need for sunvoidance needs to be incorporated into routineffice visits although it may not always beuccessful In a recent study of KTRs in which1 of patients had been informed about theeed for sun protection only 46 used morehan a tube of sunscreen per year67
Dermatology Involvement
There is increased evidence to suggest thatpecialty dermatology clinics for organ trans-lant recipients improve outcome measures in-luding compliance with photoprotection andncreased awareness of skin cancer68 The re-ources required for these specialty clinics makemplementation difficult for community nephrol-gy groups that do not have direct access to aransplant center Transplant patients should bencouraged to have annual visits with their trans-lant center and if dermatology specialty clinicsre available attempt to coordinate a skin cancervaluation annually
UseofRetinoid-likeCompounds
There is a limited scientific basis for KDIGOuggestion recommendation 186 Although reti-oids now are used routinely in KTRs with aigh skin cancer burden our KDOQI work groupelieves that more data are needed before this
uggestion should be accepted as a guideline In
ldfivs
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Bia et al22
ARTICLE IN PRESS
ow-immunologic-risk groups and particularlyifficult cases some data suggest that switchingrom CNI to sirolimus therapy may decrease thencidence of skin cancer69 however the riskersus benefit of this maneuver has not been welltudied
DIGORecommendations inChapter 19on-SkinMalignancies
191 Develop an individualized screening plan for eachKTR that takes into account the patientrsquos pastmedical and family history tobacco use compet-ing risks for death and the performance of thescreening methodology (Not Graded)
192 Screen for the following cancers as per localguidelines for the general population (Not Graded)Women cervical breast and colon cancer Menprostate and colon cancer
193 Obtain hepatic ultrasound and alpha feto-proteinevery 12 months in patients with compensatedcirrhosis (Not Graded) [See Recommendations1354 (HCV) and 1365 (HBV)]
DOQIRationale andCommentary
Screening
It is recognized that KTRs have a higher inci-ence of malignancy particularly those associatedith specific viral infections Although cancer
creening may have benefits in this higher riskopulation it should be reinforced that some meth-ds of screening have significant risks which shoulde considered on an individualized basis particu-arly in patients who have projected survival lesshan 5 years
Screening forCancer inPatientsWithHepatitis
Many patients who have underlying cirrhosisn the United States will be followed up by arofessional specializing in liver disease whoay provide additional insight into this cancer
creening recommendation Based on a recentuestionnaire of US gastroenterologists only 50creen patients for hepatocellular carcinoma70
herefore implementation of this guideline byS clinicians is unlikely to be widespread
DIGORecommendations inChapter 20anagingCancerwithReductionof
mmunosuppressiveMedication
201 We suggest consideration be given to reducingimmunosuppressive medications for KTRs with can-
cer (2C)
2011 Important factors for consideration in-clude (Not Graded)bull The stage of cancer at diagnosisbull Whether the cancer is likely to be
exacerbated by immunosuppressionbull The therapies available for the can-
cerbull Whether immunosuppressive medica-
tions interfere with ability to admin-ister the standard chemotherapy
202 For patients with Kaposi sarcoma we suggestusing mTORi along with a reduction in overallimmunosuppression (2C)
DOQIRationale andCommentary
Table 1 (Table 29 in the KDIGO report3 andxcerpted from Grulich et al71) lists cancershat are increased most in immunosuppressedTRs based on standardized incidence ratios
SIRs) which compare the incidence toatched populations Cancers with the highestIRs may be those most likely to respond to aecrease in immunosuppression Except foraposi sarcoma limited evidence is available
or a decrease in immunosuppression in theseettings A strategy to change immunosuppres-ion therapy must occur in consultation withhe transplant center Switching to sirolimusherapy and decreasing immunosuppression inatients who develop Kaposi sarcoma is basedn sound scientific rationale7273
SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
The incidence of cancer posttransplant is 2-20times higher than that in the general population andKDIGO guidelines have been written to outline stepsfor prevention and screening With few exceptions weagree with the recommendations as outlined Skincancer is common in US transplant patients andscreening and prevention are critical However imple-mentation of guidelines for doing so including theKDIGO guidelines is a challenge because of patientpreferences against the routine use of sunscreen aswell as time constraints during office visits Althoughmany posttransplant cancers are viral mediated andrelated to immunosuppression it is less clear how toalter immunosuppression after malignancy has oc-curred We agree that although age-specific screeningfor malignancy should be incorporated into care con-sideration must be given to the risk of screening inpatients with limited life spans (5 years) because of
comorbid conditions
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
ommonPopu
i sarco-Hodgmelanise sm
sophaemia
estima standa10 c
ut esti
0 case
alized t
to guide treatment specifically before the
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
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nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
o2
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Tfh2
TfcM
CU1
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op
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ar
ti2
mi2
i2
uap
ba5
ra2
cJ
sir
ml
gt1
p2
ps2
c2
p2
sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
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M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
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f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
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ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
KD
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ARTICLE IN PRESS
COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULAR
DISEASE
DIGORecommendations inChapter 15iabetesMellitus
151 Screening for New-Onset Diabetes after Transplan-tation1511 We recommend screening all nondia-
betic KTRs with fasting plasma glu-cose oral glucose tolerance testingandor HbA1c (1C) at leastbull weekly for 4 weeks (2D)bull every 3 months for 1 year (2D)bull and annually thereafter (2D)
1512 We suggest screening for NODAT withfasting glucose oral glucose tolerancetesting andor after starting or substan-tially increasing the dose of CNIsmTORi or corticosteroids (2D)
152 Managing NODAT or Diabetes Present at Trans-plantation1521 If NODAT develops consider modifying
the immunosuppressive drug regimen toreverse or ameliorate diabetes afterweighing the risk of rejection and otherpotential adverse effects (Not Graded)
1522 Consider targeting HbA1c 70-75and avoid targeting HbA1c 60 espe-cially if hypoglycemic reactions are com-mon (Not Graded)
1523 We suggest that in patients with diabetesaspirin (65-100 mgd) use for the primaryprevention of CVD be based on patientpreferences and values balancing the riskfor ischemic events to that of bleeding(2D)
DOQIRationale andCommentary
Diabetic Screening
We agree with screening for new-onset diabetesfter transplantation (NODAT) as outlined by theDIGO work group Definitions used are similar
o those of the American Diabetes AssociationADA) The greater frequency of testing initially isustified by the high risk of NODAT in the earlyosttransplant period however ongoing screenings required because the risk of the development ofODAT continues to increase over time4647 We
lso point out that prediabetic states (impairedasting glucose level and impaired glucose toler-nce) occur even more commonly than overt diabe-es48 and may be associated with metabolic syn-rome as well as with increased cardiovascular
ortality49-51 Potential implications of these predia-
etic states emphasize the importance of perform-ng blood tests under fasting conditions For pa-ients with fasting hyperglycemia an oral glucoseolerance test or hemoglobinA1c (HbA1c) test shoulde performed Although more cumbersome to per-orm data suggest that an oral glucose toleranceest is a more sensitive indicator of NODAT inyperglycemic KTRs52 This may allow earlieretection of overt diabetes and more prompt institu-ion of treatment
DiabetesManagement
Data supporting a substantial benefit in themelioration or reversal of NODAT using immu-osuppression modification in KTRs are veryimited There was consensus in our work grouphat considering the paucity of data for reversingODAT by changing immunosuppression and
he potential risk of an adverse outcome withuch a maneuver KDIGO suggestion 1521 couldot be supported Certainly if such a step waseing considered it should be done in conjunc-ion with the transplant center Targeting an HbA1c
evel of 7-75 and avoiding levels 6 isased on data showing increased cardiovascularvents with the lower HbA1c target5354
DIGORecommendations inChapter 16ypertensionDyslipidemias TobaccoUse andbesity
161 Hypertension1611 We recommend measuring blood pres-
sure at each clinic visit (1C)1612 We suggest maintaining blood pressure at
130 mm Hg systolic and 80 mm Hgdiastolic if 18 years of age and 90th
percentile for sex age and height if 18years old (2C)
1613 To treat hypertension (Not Graded)bull Use any class of antihypertensive
agentbull Monitor closely for adverse effects
and drug-drug interactions and whenurine protein excretion 1 gd for18 years old and 600 mgm224 hfor 18 years old consider an ACE-Ior an ARB as first-line therapy
162 Dyslipidemias (These recommendations are basedon KDOQI Dyslipidemia Guidelines and are thusnot graded)1621 Measure a complete lipid profile in all
adult (18 years old) and adolescent
(puberty to 18 years old) KTRs [Based on
K
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KDOQI Commentary 19
ARTICLE IN PRESS
KDOQI Dyslipidemia Recommendation1]bull 2-3 months after transplantationbull 2-3 months after a change in treatment
or other conditions known to causedyslipidemias
bull at least annually thereafter1622 Evaluate KTRs with dyslipidemias for
secondary causes [Based on KDOQI Dys-lipidemia Recommendation 3]16221 For KTRs with fasting triglyc-
erides 500 mgdL (565mmolL) that cannot be cor-rected by removing an under-lying cause treat withbull Adults therapeutic lifestyle
changes and a triglyceride-lowering agent [Based onKDOQI Recommendation41]
bull Adolescents therapeutic life-style changes [Based onKDOQI Recommendation51]
16222 For KTRs with elevatedLDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)treat to reduce LDL-C to100 mgdL (259mmolL) [Based on KDOQIGuideline 42]
bull Adolescents If LDL-C130 mgdL (336 mmolL) treat to reduce LDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 52]
16223 For KTRs with normalLDL-C elevated triglyceridesand elevated non-HDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)fasting triglycerides 200mgdL (226 mmolL)and non-HDL-C 130mgdL (336 mmolL)treat to reduce non-HDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 43]
bull Adolescents If LDL-C130 mgdL (336 mmolL) fasting triglycerides200 mgdL (226 mmolL) and non-HDL-C 160mgdL (414 mmolL)treat to reduce non-HDL-C
to 160 mgdL (414 i
mmolL) [Based on KDOQIGuideline 53]
163 Tobacco Use1631 Screen and counsel all KTRs including
adolescents and children for tobacco useand record the results in the medicalrecord (Not Graded)bull Screen during initial transplant hospi-
talizationbull Screen at least annually thereafter
1632 Offer treatment to all patients who usetobacco (Not Graded)
164 Obesity1641 Assess obesity at each visit (Not Graded)
bull Measure height and weight at eachvisit in adults and children
bull Calculate BMI at each visitbull Measure waist circumference when
weight and physical appearance sug-gest obesity but BMI is 35 kgm2
1642 Offer a weight-reduction program to allobese KTRs (Not Graded)
DOQIRationale andCommentary
Hypertension
The KDIGO work group adapted the KDOQI004 recommendations for target blood pres-ure in KTRs55 Self measurement is useful inssessing response to therapy and enhancesdherence56 In general we agree that the classf antihypertensive agent does not matter inhe treatment of blood pressure elevation inhis population and that attention should beiven to potential side effects of antihyperten-ive agents as well as possible interactionsith the immunosuppressive regimen (eg non-ihydropyridine calcium channel blockers andNIs) In the absence of adequate randomizedontrolled trials it is not known whether angio-ensin-converting enzyme (ACE) inhibitors andngiotensin receptor blockers (ARBs) prolongecipient or allograft survival Some but notll retrospective studies suggest a benefitowever all these studies are limited by selec-ion bias5758 Although ACE inhibitors andRBs commonly lead to some decrease inFR treatment with these drugs should be
ontinued unless serum creatinine level in-reases by 25 to 30 in keeping withDOQI recommendations55 In KTRs receiv-
ng ACE inhibitors or ARBs it is important toducate patients to maintain adequate fluid
ntake during illness to prevent a prerenal
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ARTICLE IN PRESS
nsult to the allograft Similarly awareness isecessary when using diuretics in conjunctionith therapies that block the renin-angiotensin-
ldosterone-system59
Dyslipidemia
The KDIGO work group based their recom-endations for evaluation and treatment of
yperlipidemia on the KDOQI dyslipidemiauidelines for KTRs60 We agree with theseecommendations CNIs potentiate the toxicityf statins by slowing their metabolism throughhe cytochrome P-450 system This interactionccurs more commonly with cyclosporine61
han with tacrolimus Dyslipidemia especiallyypertriglyceridemia frequently complicatesTOR-inhibitor use and lipid-lowering therapy
s required in most patients using these agents
TobaccoUse
Not surprisingly tobacco use at the time ofransplant is associated with decreased patientnd graft survival as well as increased risk ofosttransplant cardiovascular disease (CVD)lthough the KDIGO work group recom-ends initial screening and intervention dur-
ng the hospitalization for transplant we be-ieve there may be benefit gained by startingounseling in the pretransplant period duringhe evaluation phase Unfortunately this doesot occur often because of time and personnelonstraints in transplant centers Ideally allransplant centers should have smoking-cessa-ion programs available to patients either in-ouse or through referral Ideally systemshould be created to continue to screen andonitor for smoking cessation at yearly inter-
als after transplant because there is a highate of relapse with this addiction As outlinedn KDIGO Table 253 although all pharmaco-ogic therapies for smoking cessation can besed in KTRs the starting dose of vareniclinehould be decreased in patients with GFR 30Lmin
Obesity
Obesity is an epidemic in the United Statesnd the proportion of obese kidney transplantandidates continues to grow In additioneight gain after transplant is very commonly
bserved Obesity in KTRs is associated with w
ncreased risks of wound complications de-ayed graft function acute rejection and NO-AT resulting in inferior patient and graftutcomes Attention to this potential complica-ion and counseling should be initiated duringhe pretransplant evaluation phase Informa-ion regarding pharmacologic therapies foreight loss in KTRs is not available and we
gree with the KDIGO work group that thera-eutic lifestyle measures should be encour-ged Data regarding steroid therapy with-rawal and weight gain are controversial Aecent double-blind randomized controlled trialxamining early steroid therapy withdrawalid not show a difference in weight gain at 5ears posttransplant compared with the cohortemaining on standard maintenance corticoste-oid therapy62
DIGORecommendations inChapter 17ardiovascularManagement
171 Consider managing CVD at least as intensively inKTRs as in the general population with appropri-ate diagnostic tests and treatments (Not Graded)
172 We suggest using aspirin (65-100 mgd) in allpatients with atherosclerotic CVD unless there arecontraindications (2B)
DOQIRationale andCommentary
Although outcomes are favorable comparedith remaining on the waiting list the risk of
ardiovascular mortality in KTRs is several-foldigher than observed in the general population63
specially in younger age groups and patientsith decreasing allograft function64 CVD is aajor cause of graft loss after the first post-
ransplant year In this context we strongly agreehat CVD should be managed in KTRs at least asntensively as in the general population Ideallyecreasing CVD risk in KTRs requires a multifac-ted and multidisciplinary approach Based onurrent practice models in the United States theransplant and nephrology community has notet been able to achieve these desirable goals65
his clearly deserves more attention becauseontrol of CVD has the potential to contributeore to long-term kidney graft survival than the
iscovery of newer drugs that decrease the ratef allograft rejection Our KDOQI working groupgreed with the use of low-dose aspirin in KTRs
ith evidence of atherosclerosis
Ko
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KDOQI Commentary 21
ARTICLE IN PRESS
SUMMARY OF COMMENTARY ONSECTION III CVD
COMMENTARY ON SECTION IV OF KDIGO
TRANSPLANT GUIDELINE MALIGNANCY
DIGORecommendations inChapter 18 Cancerf the Skin andLip
181 We recommend that KTRs especially thosewho have fair skin live in high sun-exposureclimates have occupations requiring sun expo-sure have had significant sun exposure as achild or have a history of skin cancer be toldthat their risk of skin and lip cancer is veryhigh (1C)
182 We recommend that KTRs minimize life-longsun exposure and use appropriate ultravioletlight blocking agents (1D)
183 We suggest that adult KTRs perform skin andlip self-examinations and report new lesions toa health-care provider (2D)
184 For adult KTRs we suggest that a qualified healthprofessional with experience in diagnosing skincancer perform annual skin and lip examinationon KTRs except possibly for KTRs with dark skinpigmentation (2D)
185 We suggest that patients with a history of skin orlip cancer or premalignant lesions be referred to andfollowed by a qualified health professional withexperience in diagnosing and treating skin cancer
With the decrease in acute rejection during the pastdecade in association with improved immunosuppres-sion regimens patient death now rivals chronic graftdysfunction as one of the leading causes of long-termgraft loss Because CVD is the most common cause ofpatient death in KTRs a concerted effort at minimizingrisk factors for heart disease likely will have as great oreven greater impact on optimizing patient and graftoutcomes than the discovery of new antirejection thera-pies CVD risk reduction strategies should include regularscreening for new-onset diabetes (using ADA-based defini-tions) in the posttransplant period in previously nondiabeticpatients good glycemic regulation for diabetic patients accord-ing to current ADA guidelines and lipid management andblood pressure control according to KDOQI recommenda-tions In addition promotion of a healthy lifestyle throughweight control exercise and smoking cessation should be acentral part of posttransplant counseling and care Whenimmunosuppression modification is being considered to miti-gate cardiovascular risk we recommend that this be inconjunction with the transplant center In summary we gener-ally concurred with the suggestions of the work group in thissection but based on current practice standards in the UnitedStateschallengesremainwith implementationof thisguideline
(2D) s
186 We suggest that patients with a history of skincancer be offered treatment with oral acitretin ifthere are no contraindications (2B)
DOQIRationale andCommentary
CounselingandSunscreen
We concur with recommendations 181 and82 because skin cancer is a major source oforbidity and sometimes mortality in KTRsarning patients at risk of the high danger of
kin cancer a 1C recommendation is reinforcedy a recent prospective case-control study ofrgan transplant recipients that showed that regu-ar use of broad-spectrum sunscreens that pro-ide UVA and UVB protection may prevent theevelopment of actinic keratosis invasive squa-ous cell carcinoma and to a lesser extent
asal cell carcinoma66 Most cancer-causing ra-iation is thought to come from the UVB spec-rum and newer broad-spectrum sunscreens pro-ide protection against UVA and UVB radiationounseling about sunscreen and the need for sunvoidance needs to be incorporated into routineffice visits although it may not always beuccessful In a recent study of KTRs in which1 of patients had been informed about theeed for sun protection only 46 used morehan a tube of sunscreen per year67
Dermatology Involvement
There is increased evidence to suggest thatpecialty dermatology clinics for organ trans-lant recipients improve outcome measures in-luding compliance with photoprotection andncreased awareness of skin cancer68 The re-ources required for these specialty clinics makemplementation difficult for community nephrol-gy groups that do not have direct access to aransplant center Transplant patients should bencouraged to have annual visits with their trans-lant center and if dermatology specialty clinicsre available attempt to coordinate a skin cancervaluation annually
UseofRetinoid-likeCompounds
There is a limited scientific basis for KDIGOuggestion recommendation 186 Although reti-oids now are used routinely in KTRs with aigh skin cancer burden our KDOQI work groupelieves that more data are needed before this
uggestion should be accepted as a guideline In
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ow-immunologic-risk groups and particularlyifficult cases some data suggest that switchingrom CNI to sirolimus therapy may decrease thencidence of skin cancer69 however the riskersus benefit of this maneuver has not been welltudied
DIGORecommendations inChapter 19on-SkinMalignancies
191 Develop an individualized screening plan for eachKTR that takes into account the patientrsquos pastmedical and family history tobacco use compet-ing risks for death and the performance of thescreening methodology (Not Graded)
192 Screen for the following cancers as per localguidelines for the general population (Not Graded)Women cervical breast and colon cancer Menprostate and colon cancer
193 Obtain hepatic ultrasound and alpha feto-proteinevery 12 months in patients with compensatedcirrhosis (Not Graded) [See Recommendations1354 (HCV) and 1365 (HBV)]
DOQIRationale andCommentary
Screening
It is recognized that KTRs have a higher inci-ence of malignancy particularly those associatedith specific viral infections Although cancer
creening may have benefits in this higher riskopulation it should be reinforced that some meth-ds of screening have significant risks which shoulde considered on an individualized basis particu-arly in patients who have projected survival lesshan 5 years
Screening forCancer inPatientsWithHepatitis
Many patients who have underlying cirrhosisn the United States will be followed up by arofessional specializing in liver disease whoay provide additional insight into this cancer
creening recommendation Based on a recentuestionnaire of US gastroenterologists only 50creen patients for hepatocellular carcinoma70
herefore implementation of this guideline byS clinicians is unlikely to be widespread
DIGORecommendations inChapter 20anagingCancerwithReductionof
mmunosuppressiveMedication
201 We suggest consideration be given to reducingimmunosuppressive medications for KTRs with can-
cer (2C)
2011 Important factors for consideration in-clude (Not Graded)bull The stage of cancer at diagnosisbull Whether the cancer is likely to be
exacerbated by immunosuppressionbull The therapies available for the can-
cerbull Whether immunosuppressive medica-
tions interfere with ability to admin-ister the standard chemotherapy
202 For patients with Kaposi sarcoma we suggestusing mTORi along with a reduction in overallimmunosuppression (2C)
DOQIRationale andCommentary
Table 1 (Table 29 in the KDIGO report3 andxcerpted from Grulich et al71) lists cancershat are increased most in immunosuppressedTRs based on standardized incidence ratios
SIRs) which compare the incidence toatched populations Cancers with the highestIRs may be those most likely to respond to aecrease in immunosuppression Except foraposi sarcoma limited evidence is available
or a decrease in immunosuppression in theseettings A strategy to change immunosuppres-ion therapy must occur in consultation withhe transplant center Switching to sirolimusherapy and decreasing immunosuppression inatients who develop Kaposi sarcoma is basedn sound scientific rationale7273
SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
The incidence of cancer posttransplant is 2-20times higher than that in the general population andKDIGO guidelines have been written to outline stepsfor prevention and screening With few exceptions weagree with the recommendations as outlined Skincancer is common in US transplant patients andscreening and prevention are critical However imple-mentation of guidelines for doing so including theKDIGO guidelines is a challenge because of patientpreferences against the routine use of sunscreen aswell as time constraints during office visits Althoughmany posttransplant cancers are viral mediated andrelated to immunosuppression it is less clear how toalter immunosuppression after malignancy has oc-curred We agree that although age-specific screeningfor malignancy should be incorporated into care con-sideration must be given to the risk of screening inpatients with limited life spans (5 years) because of
comorbid conditions
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
ommonPopu
i sarco-Hodgmelanise sm
sophaemia
estima standa10 c
ut esti
0 case
alized t
to guide treatment specifically before the
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
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nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
o2
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Tfh2
TfcM
CU1
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op
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ar
ti2
mi2
i2
uap
ba5
ra2
cJ
sir
ml
gt1
p2
ps2
c2
p2
sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
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M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
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f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
cA
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ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
K
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KDOQI Commentary 19
ARTICLE IN PRESS
KDOQI Dyslipidemia Recommendation1]bull 2-3 months after transplantationbull 2-3 months after a change in treatment
or other conditions known to causedyslipidemias
bull at least annually thereafter1622 Evaluate KTRs with dyslipidemias for
secondary causes [Based on KDOQI Dys-lipidemia Recommendation 3]16221 For KTRs with fasting triglyc-
erides 500 mgdL (565mmolL) that cannot be cor-rected by removing an under-lying cause treat withbull Adults therapeutic lifestyle
changes and a triglyceride-lowering agent [Based onKDOQI Recommendation41]
bull Adolescents therapeutic life-style changes [Based onKDOQI Recommendation51]
16222 For KTRs with elevatedLDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)treat to reduce LDL-C to100 mgdL (259mmolL) [Based on KDOQIGuideline 42]
bull Adolescents If LDL-C130 mgdL (336 mmolL) treat to reduce LDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 52]
16223 For KTRs with normalLDL-C elevated triglyceridesand elevated non-HDL-Cbull Adults If LDL-C 100
mgdL (259 mmolL)fasting triglycerides 200mgdL (226 mmolL)and non-HDL-C 130mgdL (336 mmolL)treat to reduce non-HDL-Cto 130 mgdL (336mmolL) [Based on KDOQIGuideline 43]
bull Adolescents If LDL-C130 mgdL (336 mmolL) fasting triglycerides200 mgdL (226 mmolL) and non-HDL-C 160mgdL (414 mmolL)treat to reduce non-HDL-C
to 160 mgdL (414 i
mmolL) [Based on KDOQIGuideline 53]
163 Tobacco Use1631 Screen and counsel all KTRs including
adolescents and children for tobacco useand record the results in the medicalrecord (Not Graded)bull Screen during initial transplant hospi-
talizationbull Screen at least annually thereafter
1632 Offer treatment to all patients who usetobacco (Not Graded)
164 Obesity1641 Assess obesity at each visit (Not Graded)
bull Measure height and weight at eachvisit in adults and children
bull Calculate BMI at each visitbull Measure waist circumference when
weight and physical appearance sug-gest obesity but BMI is 35 kgm2
1642 Offer a weight-reduction program to allobese KTRs (Not Graded)
DOQIRationale andCommentary
Hypertension
The KDIGO work group adapted the KDOQI004 recommendations for target blood pres-ure in KTRs55 Self measurement is useful inssessing response to therapy and enhancesdherence56 In general we agree that the classf antihypertensive agent does not matter inhe treatment of blood pressure elevation inhis population and that attention should beiven to potential side effects of antihyperten-ive agents as well as possible interactionsith the immunosuppressive regimen (eg non-ihydropyridine calcium channel blockers andNIs) In the absence of adequate randomizedontrolled trials it is not known whether angio-ensin-converting enzyme (ACE) inhibitors andngiotensin receptor blockers (ARBs) prolongecipient or allograft survival Some but notll retrospective studies suggest a benefitowever all these studies are limited by selec-ion bias5758 Although ACE inhibitors andRBs commonly lead to some decrease inFR treatment with these drugs should be
ontinued unless serum creatinine level in-reases by 25 to 30 in keeping withDOQI recommendations55 In KTRs receiv-
ng ACE inhibitors or ARBs it is important toducate patients to maintain adequate fluid
ntake during illness to prevent a prerenal
inwa
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ARTICLE IN PRESS
nsult to the allograft Similarly awareness isecessary when using diuretics in conjunctionith therapies that block the renin-angiotensin-
ldosterone-system59
Dyslipidemia
The KDIGO work group based their recom-endations for evaluation and treatment of
yperlipidemia on the KDOQI dyslipidemiauidelines for KTRs60 We agree with theseecommendations CNIs potentiate the toxicityf statins by slowing their metabolism throughhe cytochrome P-450 system This interactionccurs more commonly with cyclosporine61
han with tacrolimus Dyslipidemia especiallyypertriglyceridemia frequently complicatesTOR-inhibitor use and lipid-lowering therapy
s required in most patients using these agents
TobaccoUse
Not surprisingly tobacco use at the time ofransplant is associated with decreased patientnd graft survival as well as increased risk ofosttransplant cardiovascular disease (CVD)lthough the KDIGO work group recom-ends initial screening and intervention dur-
ng the hospitalization for transplant we be-ieve there may be benefit gained by startingounseling in the pretransplant period duringhe evaluation phase Unfortunately this doesot occur often because of time and personnelonstraints in transplant centers Ideally allransplant centers should have smoking-cessa-ion programs available to patients either in-ouse or through referral Ideally systemshould be created to continue to screen andonitor for smoking cessation at yearly inter-
als after transplant because there is a highate of relapse with this addiction As outlinedn KDIGO Table 253 although all pharmaco-ogic therapies for smoking cessation can besed in KTRs the starting dose of vareniclinehould be decreased in patients with GFR 30Lmin
Obesity
Obesity is an epidemic in the United Statesnd the proportion of obese kidney transplantandidates continues to grow In additioneight gain after transplant is very commonly
bserved Obesity in KTRs is associated with w
ncreased risks of wound complications de-ayed graft function acute rejection and NO-AT resulting in inferior patient and graftutcomes Attention to this potential complica-ion and counseling should be initiated duringhe pretransplant evaluation phase Informa-ion regarding pharmacologic therapies foreight loss in KTRs is not available and we
gree with the KDIGO work group that thera-eutic lifestyle measures should be encour-ged Data regarding steroid therapy with-rawal and weight gain are controversial Aecent double-blind randomized controlled trialxamining early steroid therapy withdrawalid not show a difference in weight gain at 5ears posttransplant compared with the cohortemaining on standard maintenance corticoste-oid therapy62
DIGORecommendations inChapter 17ardiovascularManagement
171 Consider managing CVD at least as intensively inKTRs as in the general population with appropri-ate diagnostic tests and treatments (Not Graded)
172 We suggest using aspirin (65-100 mgd) in allpatients with atherosclerotic CVD unless there arecontraindications (2B)
DOQIRationale andCommentary
Although outcomes are favorable comparedith remaining on the waiting list the risk of
ardiovascular mortality in KTRs is several-foldigher than observed in the general population63
specially in younger age groups and patientsith decreasing allograft function64 CVD is aajor cause of graft loss after the first post-
ransplant year In this context we strongly agreehat CVD should be managed in KTRs at least asntensively as in the general population Ideallyecreasing CVD risk in KTRs requires a multifac-ted and multidisciplinary approach Based onurrent practice models in the United States theransplant and nephrology community has notet been able to achieve these desirable goals65
his clearly deserves more attention becauseontrol of CVD has the potential to contributeore to long-term kidney graft survival than the
iscovery of newer drugs that decrease the ratef allograft rejection Our KDOQI working groupgreed with the use of low-dose aspirin in KTRs
ith evidence of atherosclerosis
Ko
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KDOQI Commentary 21
ARTICLE IN PRESS
SUMMARY OF COMMENTARY ONSECTION III CVD
COMMENTARY ON SECTION IV OF KDIGO
TRANSPLANT GUIDELINE MALIGNANCY
DIGORecommendations inChapter 18 Cancerf the Skin andLip
181 We recommend that KTRs especially thosewho have fair skin live in high sun-exposureclimates have occupations requiring sun expo-sure have had significant sun exposure as achild or have a history of skin cancer be toldthat their risk of skin and lip cancer is veryhigh (1C)
182 We recommend that KTRs minimize life-longsun exposure and use appropriate ultravioletlight blocking agents (1D)
183 We suggest that adult KTRs perform skin andlip self-examinations and report new lesions toa health-care provider (2D)
184 For adult KTRs we suggest that a qualified healthprofessional with experience in diagnosing skincancer perform annual skin and lip examinationon KTRs except possibly for KTRs with dark skinpigmentation (2D)
185 We suggest that patients with a history of skin orlip cancer or premalignant lesions be referred to andfollowed by a qualified health professional withexperience in diagnosing and treating skin cancer
With the decrease in acute rejection during the pastdecade in association with improved immunosuppres-sion regimens patient death now rivals chronic graftdysfunction as one of the leading causes of long-termgraft loss Because CVD is the most common cause ofpatient death in KTRs a concerted effort at minimizingrisk factors for heart disease likely will have as great oreven greater impact on optimizing patient and graftoutcomes than the discovery of new antirejection thera-pies CVD risk reduction strategies should include regularscreening for new-onset diabetes (using ADA-based defini-tions) in the posttransplant period in previously nondiabeticpatients good glycemic regulation for diabetic patients accord-ing to current ADA guidelines and lipid management andblood pressure control according to KDOQI recommenda-tions In addition promotion of a healthy lifestyle throughweight control exercise and smoking cessation should be acentral part of posttransplant counseling and care Whenimmunosuppression modification is being considered to miti-gate cardiovascular risk we recommend that this be inconjunction with the transplant center In summary we gener-ally concurred with the suggestions of the work group in thissection but based on current practice standards in the UnitedStateschallengesremainwith implementationof thisguideline
(2D) s
186 We suggest that patients with a history of skincancer be offered treatment with oral acitretin ifthere are no contraindications (2B)
DOQIRationale andCommentary
CounselingandSunscreen
We concur with recommendations 181 and82 because skin cancer is a major source oforbidity and sometimes mortality in KTRsarning patients at risk of the high danger of
kin cancer a 1C recommendation is reinforcedy a recent prospective case-control study ofrgan transplant recipients that showed that regu-ar use of broad-spectrum sunscreens that pro-ide UVA and UVB protection may prevent theevelopment of actinic keratosis invasive squa-ous cell carcinoma and to a lesser extent
asal cell carcinoma66 Most cancer-causing ra-iation is thought to come from the UVB spec-rum and newer broad-spectrum sunscreens pro-ide protection against UVA and UVB radiationounseling about sunscreen and the need for sunvoidance needs to be incorporated into routineffice visits although it may not always beuccessful In a recent study of KTRs in which1 of patients had been informed about theeed for sun protection only 46 used morehan a tube of sunscreen per year67
Dermatology Involvement
There is increased evidence to suggest thatpecialty dermatology clinics for organ trans-lant recipients improve outcome measures in-luding compliance with photoprotection andncreased awareness of skin cancer68 The re-ources required for these specialty clinics makemplementation difficult for community nephrol-gy groups that do not have direct access to aransplant center Transplant patients should bencouraged to have annual visits with their trans-lant center and if dermatology specialty clinicsre available attempt to coordinate a skin cancervaluation annually
UseofRetinoid-likeCompounds
There is a limited scientific basis for KDIGOuggestion recommendation 186 Although reti-oids now are used routinely in KTRs with aigh skin cancer burden our KDOQI work groupelieves that more data are needed before this
uggestion should be accepted as a guideline In
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ARTICLE IN PRESS
ow-immunologic-risk groups and particularlyifficult cases some data suggest that switchingrom CNI to sirolimus therapy may decrease thencidence of skin cancer69 however the riskersus benefit of this maneuver has not been welltudied
DIGORecommendations inChapter 19on-SkinMalignancies
191 Develop an individualized screening plan for eachKTR that takes into account the patientrsquos pastmedical and family history tobacco use compet-ing risks for death and the performance of thescreening methodology (Not Graded)
192 Screen for the following cancers as per localguidelines for the general population (Not Graded)Women cervical breast and colon cancer Menprostate and colon cancer
193 Obtain hepatic ultrasound and alpha feto-proteinevery 12 months in patients with compensatedcirrhosis (Not Graded) [See Recommendations1354 (HCV) and 1365 (HBV)]
DOQIRationale andCommentary
Screening
It is recognized that KTRs have a higher inci-ence of malignancy particularly those associatedith specific viral infections Although cancer
creening may have benefits in this higher riskopulation it should be reinforced that some meth-ds of screening have significant risks which shoulde considered on an individualized basis particu-arly in patients who have projected survival lesshan 5 years
Screening forCancer inPatientsWithHepatitis
Many patients who have underlying cirrhosisn the United States will be followed up by arofessional specializing in liver disease whoay provide additional insight into this cancer
creening recommendation Based on a recentuestionnaire of US gastroenterologists only 50creen patients for hepatocellular carcinoma70
herefore implementation of this guideline byS clinicians is unlikely to be widespread
DIGORecommendations inChapter 20anagingCancerwithReductionof
mmunosuppressiveMedication
201 We suggest consideration be given to reducingimmunosuppressive medications for KTRs with can-
cer (2C)
2011 Important factors for consideration in-clude (Not Graded)bull The stage of cancer at diagnosisbull Whether the cancer is likely to be
exacerbated by immunosuppressionbull The therapies available for the can-
cerbull Whether immunosuppressive medica-
tions interfere with ability to admin-ister the standard chemotherapy
202 For patients with Kaposi sarcoma we suggestusing mTORi along with a reduction in overallimmunosuppression (2C)
DOQIRationale andCommentary
Table 1 (Table 29 in the KDIGO report3 andxcerpted from Grulich et al71) lists cancershat are increased most in immunosuppressedTRs based on standardized incidence ratios
SIRs) which compare the incidence toatched populations Cancers with the highestIRs may be those most likely to respond to aecrease in immunosuppression Except foraposi sarcoma limited evidence is available
or a decrease in immunosuppression in theseettings A strategy to change immunosuppres-ion therapy must occur in consultation withhe transplant center Switching to sirolimusherapy and decreasing immunosuppression inatients who develop Kaposi sarcoma is basedn sound scientific rationale7273
SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
The incidence of cancer posttransplant is 2-20times higher than that in the general population andKDIGO guidelines have been written to outline stepsfor prevention and screening With few exceptions weagree with the recommendations as outlined Skincancer is common in US transplant patients andscreening and prevention are critical However imple-mentation of guidelines for doing so including theKDIGO guidelines is a challenge because of patientpreferences against the routine use of sunscreen aswell as time constraints during office visits Althoughmany posttransplant cancers are viral mediated andrelated to immunosuppression it is less clear how toalter immunosuppression after malignancy has oc-curred We agree that although age-specific screeningfor malignancy should be incorporated into care con-sideration must be given to the risk of screening inpatients with limited life spans (5 years) because of
comorbid conditions
KT
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
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use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
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nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
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sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
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M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
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f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
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ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
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ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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ARTICLE IN PRESS
nsult to the allograft Similarly awareness isecessary when using diuretics in conjunctionith therapies that block the renin-angiotensin-
ldosterone-system59
Dyslipidemia
The KDIGO work group based their recom-endations for evaluation and treatment of
yperlipidemia on the KDOQI dyslipidemiauidelines for KTRs60 We agree with theseecommendations CNIs potentiate the toxicityf statins by slowing their metabolism throughhe cytochrome P-450 system This interactionccurs more commonly with cyclosporine61
han with tacrolimus Dyslipidemia especiallyypertriglyceridemia frequently complicatesTOR-inhibitor use and lipid-lowering therapy
s required in most patients using these agents
TobaccoUse
Not surprisingly tobacco use at the time ofransplant is associated with decreased patientnd graft survival as well as increased risk ofosttransplant cardiovascular disease (CVD)lthough the KDIGO work group recom-ends initial screening and intervention dur-
ng the hospitalization for transplant we be-ieve there may be benefit gained by startingounseling in the pretransplant period duringhe evaluation phase Unfortunately this doesot occur often because of time and personnelonstraints in transplant centers Ideally allransplant centers should have smoking-cessa-ion programs available to patients either in-ouse or through referral Ideally systemshould be created to continue to screen andonitor for smoking cessation at yearly inter-
als after transplant because there is a highate of relapse with this addiction As outlinedn KDIGO Table 253 although all pharmaco-ogic therapies for smoking cessation can besed in KTRs the starting dose of vareniclinehould be decreased in patients with GFR 30Lmin
Obesity
Obesity is an epidemic in the United Statesnd the proportion of obese kidney transplantandidates continues to grow In additioneight gain after transplant is very commonly
bserved Obesity in KTRs is associated with w
ncreased risks of wound complications de-ayed graft function acute rejection and NO-AT resulting in inferior patient and graftutcomes Attention to this potential complica-ion and counseling should be initiated duringhe pretransplant evaluation phase Informa-ion regarding pharmacologic therapies foreight loss in KTRs is not available and we
gree with the KDIGO work group that thera-eutic lifestyle measures should be encour-ged Data regarding steroid therapy with-rawal and weight gain are controversial Aecent double-blind randomized controlled trialxamining early steroid therapy withdrawalid not show a difference in weight gain at 5ears posttransplant compared with the cohortemaining on standard maintenance corticoste-oid therapy62
DIGORecommendations inChapter 17ardiovascularManagement
171 Consider managing CVD at least as intensively inKTRs as in the general population with appropri-ate diagnostic tests and treatments (Not Graded)
172 We suggest using aspirin (65-100 mgd) in allpatients with atherosclerotic CVD unless there arecontraindications (2B)
DOQIRationale andCommentary
Although outcomes are favorable comparedith remaining on the waiting list the risk of
ardiovascular mortality in KTRs is several-foldigher than observed in the general population63
specially in younger age groups and patientsith decreasing allograft function64 CVD is aajor cause of graft loss after the first post-
ransplant year In this context we strongly agreehat CVD should be managed in KTRs at least asntensively as in the general population Ideallyecreasing CVD risk in KTRs requires a multifac-ted and multidisciplinary approach Based onurrent practice models in the United States theransplant and nephrology community has notet been able to achieve these desirable goals65
his clearly deserves more attention becauseontrol of CVD has the potential to contributeore to long-term kidney graft survival than the
iscovery of newer drugs that decrease the ratef allograft rejection Our KDOQI working groupgreed with the use of low-dose aspirin in KTRs
ith evidence of atherosclerosis
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KDOQI Commentary 21
ARTICLE IN PRESS
SUMMARY OF COMMENTARY ONSECTION III CVD
COMMENTARY ON SECTION IV OF KDIGO
TRANSPLANT GUIDELINE MALIGNANCY
DIGORecommendations inChapter 18 Cancerf the Skin andLip
181 We recommend that KTRs especially thosewho have fair skin live in high sun-exposureclimates have occupations requiring sun expo-sure have had significant sun exposure as achild or have a history of skin cancer be toldthat their risk of skin and lip cancer is veryhigh (1C)
182 We recommend that KTRs minimize life-longsun exposure and use appropriate ultravioletlight blocking agents (1D)
183 We suggest that adult KTRs perform skin andlip self-examinations and report new lesions toa health-care provider (2D)
184 For adult KTRs we suggest that a qualified healthprofessional with experience in diagnosing skincancer perform annual skin and lip examinationon KTRs except possibly for KTRs with dark skinpigmentation (2D)
185 We suggest that patients with a history of skin orlip cancer or premalignant lesions be referred to andfollowed by a qualified health professional withexperience in diagnosing and treating skin cancer
With the decrease in acute rejection during the pastdecade in association with improved immunosuppres-sion regimens patient death now rivals chronic graftdysfunction as one of the leading causes of long-termgraft loss Because CVD is the most common cause ofpatient death in KTRs a concerted effort at minimizingrisk factors for heart disease likely will have as great oreven greater impact on optimizing patient and graftoutcomes than the discovery of new antirejection thera-pies CVD risk reduction strategies should include regularscreening for new-onset diabetes (using ADA-based defini-tions) in the posttransplant period in previously nondiabeticpatients good glycemic regulation for diabetic patients accord-ing to current ADA guidelines and lipid management andblood pressure control according to KDOQI recommenda-tions In addition promotion of a healthy lifestyle throughweight control exercise and smoking cessation should be acentral part of posttransplant counseling and care Whenimmunosuppression modification is being considered to miti-gate cardiovascular risk we recommend that this be inconjunction with the transplant center In summary we gener-ally concurred with the suggestions of the work group in thissection but based on current practice standards in the UnitedStateschallengesremainwith implementationof thisguideline
(2D) s
186 We suggest that patients with a history of skincancer be offered treatment with oral acitretin ifthere are no contraindications (2B)
DOQIRationale andCommentary
CounselingandSunscreen
We concur with recommendations 181 and82 because skin cancer is a major source oforbidity and sometimes mortality in KTRsarning patients at risk of the high danger of
kin cancer a 1C recommendation is reinforcedy a recent prospective case-control study ofrgan transplant recipients that showed that regu-ar use of broad-spectrum sunscreens that pro-ide UVA and UVB protection may prevent theevelopment of actinic keratosis invasive squa-ous cell carcinoma and to a lesser extent
asal cell carcinoma66 Most cancer-causing ra-iation is thought to come from the UVB spec-rum and newer broad-spectrum sunscreens pro-ide protection against UVA and UVB radiationounseling about sunscreen and the need for sunvoidance needs to be incorporated into routineffice visits although it may not always beuccessful In a recent study of KTRs in which1 of patients had been informed about theeed for sun protection only 46 used morehan a tube of sunscreen per year67
Dermatology Involvement
There is increased evidence to suggest thatpecialty dermatology clinics for organ trans-lant recipients improve outcome measures in-luding compliance with photoprotection andncreased awareness of skin cancer68 The re-ources required for these specialty clinics makemplementation difficult for community nephrol-gy groups that do not have direct access to aransplant center Transplant patients should bencouraged to have annual visits with their trans-lant center and if dermatology specialty clinicsre available attempt to coordinate a skin cancervaluation annually
UseofRetinoid-likeCompounds
There is a limited scientific basis for KDIGOuggestion recommendation 186 Although reti-oids now are used routinely in KTRs with aigh skin cancer burden our KDOQI work groupelieves that more data are needed before this
uggestion should be accepted as a guideline In
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ARTICLE IN PRESS
ow-immunologic-risk groups and particularlyifficult cases some data suggest that switchingrom CNI to sirolimus therapy may decrease thencidence of skin cancer69 however the riskersus benefit of this maneuver has not been welltudied
DIGORecommendations inChapter 19on-SkinMalignancies
191 Develop an individualized screening plan for eachKTR that takes into account the patientrsquos pastmedical and family history tobacco use compet-ing risks for death and the performance of thescreening methodology (Not Graded)
192 Screen for the following cancers as per localguidelines for the general population (Not Graded)Women cervical breast and colon cancer Menprostate and colon cancer
193 Obtain hepatic ultrasound and alpha feto-proteinevery 12 months in patients with compensatedcirrhosis (Not Graded) [See Recommendations1354 (HCV) and 1365 (HBV)]
DOQIRationale andCommentary
Screening
It is recognized that KTRs have a higher inci-ence of malignancy particularly those associatedith specific viral infections Although cancer
creening may have benefits in this higher riskopulation it should be reinforced that some meth-ds of screening have significant risks which shoulde considered on an individualized basis particu-arly in patients who have projected survival lesshan 5 years
Screening forCancer inPatientsWithHepatitis
Many patients who have underlying cirrhosisn the United States will be followed up by arofessional specializing in liver disease whoay provide additional insight into this cancer
creening recommendation Based on a recentuestionnaire of US gastroenterologists only 50creen patients for hepatocellular carcinoma70
herefore implementation of this guideline byS clinicians is unlikely to be widespread
DIGORecommendations inChapter 20anagingCancerwithReductionof
mmunosuppressiveMedication
201 We suggest consideration be given to reducingimmunosuppressive medications for KTRs with can-
cer (2C)
2011 Important factors for consideration in-clude (Not Graded)bull The stage of cancer at diagnosisbull Whether the cancer is likely to be
exacerbated by immunosuppressionbull The therapies available for the can-
cerbull Whether immunosuppressive medica-
tions interfere with ability to admin-ister the standard chemotherapy
202 For patients with Kaposi sarcoma we suggestusing mTORi along with a reduction in overallimmunosuppression (2C)
DOQIRationale andCommentary
Table 1 (Table 29 in the KDIGO report3 andxcerpted from Grulich et al71) lists cancershat are increased most in immunosuppressedTRs based on standardized incidence ratios
SIRs) which compare the incidence toatched populations Cancers with the highestIRs may be those most likely to respond to aecrease in immunosuppression Except foraposi sarcoma limited evidence is available
or a decrease in immunosuppression in theseettings A strategy to change immunosuppres-ion therapy must occur in consultation withhe transplant center Switching to sirolimusherapy and decreasing immunosuppression inatients who develop Kaposi sarcoma is basedn sound scientific rationale7273
SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
The incidence of cancer posttransplant is 2-20times higher than that in the general population andKDIGO guidelines have been written to outline stepsfor prevention and screening With few exceptions weagree with the recommendations as outlined Skincancer is common in US transplant patients andscreening and prevention are critical However imple-mentation of guidelines for doing so including theKDIGO guidelines is a challenge because of patientpreferences against the routine use of sunscreen aswell as time constraints during office visits Althoughmany posttransplant cancers are viral mediated andrelated to immunosuppression it is less clear how toalter immunosuppression after malignancy has oc-curred We agree that although age-specific screeningfor malignancy should be incorporated into care con-sideration must be given to the risk of screening inpatients with limited life spans (5 years) because of
comorbid conditions
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
ommonPopu
i sarco-Hodgmelanise sm
sophaemia
estima standa10 c
ut esti
0 case
alized t
to guide treatment specifically before the
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
REFERENCES1 McCullough KP Keith DS Meyer KH et al Kidney
nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
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ar
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uap
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sir
ml
gt1
p2
ps2
c2
p2
sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
ation Transpl Rev 200923191-19815 Abbud-Filho M Adams PL Alberuacute J et al A report
f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
cA
nrc
t2
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trN
hUt
Iwa
rl5
mi8
oe1
DA
fsK
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sb2
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It
ar3
tA2
hm2
EA
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Bia et al30
ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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KDOQI Commentary 21
ARTICLE IN PRESS
SUMMARY OF COMMENTARY ONSECTION III CVD
COMMENTARY ON SECTION IV OF KDIGO
TRANSPLANT GUIDELINE MALIGNANCY
DIGORecommendations inChapter 18 Cancerf the Skin andLip
181 We recommend that KTRs especially thosewho have fair skin live in high sun-exposureclimates have occupations requiring sun expo-sure have had significant sun exposure as achild or have a history of skin cancer be toldthat their risk of skin and lip cancer is veryhigh (1C)
182 We recommend that KTRs minimize life-longsun exposure and use appropriate ultravioletlight blocking agents (1D)
183 We suggest that adult KTRs perform skin andlip self-examinations and report new lesions toa health-care provider (2D)
184 For adult KTRs we suggest that a qualified healthprofessional with experience in diagnosing skincancer perform annual skin and lip examinationon KTRs except possibly for KTRs with dark skinpigmentation (2D)
185 We suggest that patients with a history of skin orlip cancer or premalignant lesions be referred to andfollowed by a qualified health professional withexperience in diagnosing and treating skin cancer
With the decrease in acute rejection during the pastdecade in association with improved immunosuppres-sion regimens patient death now rivals chronic graftdysfunction as one of the leading causes of long-termgraft loss Because CVD is the most common cause ofpatient death in KTRs a concerted effort at minimizingrisk factors for heart disease likely will have as great oreven greater impact on optimizing patient and graftoutcomes than the discovery of new antirejection thera-pies CVD risk reduction strategies should include regularscreening for new-onset diabetes (using ADA-based defini-tions) in the posttransplant period in previously nondiabeticpatients good glycemic regulation for diabetic patients accord-ing to current ADA guidelines and lipid management andblood pressure control according to KDOQI recommenda-tions In addition promotion of a healthy lifestyle throughweight control exercise and smoking cessation should be acentral part of posttransplant counseling and care Whenimmunosuppression modification is being considered to miti-gate cardiovascular risk we recommend that this be inconjunction with the transplant center In summary we gener-ally concurred with the suggestions of the work group in thissection but based on current practice standards in the UnitedStateschallengesremainwith implementationof thisguideline
(2D) s
186 We suggest that patients with a history of skincancer be offered treatment with oral acitretin ifthere are no contraindications (2B)
DOQIRationale andCommentary
CounselingandSunscreen
We concur with recommendations 181 and82 because skin cancer is a major source oforbidity and sometimes mortality in KTRsarning patients at risk of the high danger of
kin cancer a 1C recommendation is reinforcedy a recent prospective case-control study ofrgan transplant recipients that showed that regu-ar use of broad-spectrum sunscreens that pro-ide UVA and UVB protection may prevent theevelopment of actinic keratosis invasive squa-ous cell carcinoma and to a lesser extent
asal cell carcinoma66 Most cancer-causing ra-iation is thought to come from the UVB spec-rum and newer broad-spectrum sunscreens pro-ide protection against UVA and UVB radiationounseling about sunscreen and the need for sunvoidance needs to be incorporated into routineffice visits although it may not always beuccessful In a recent study of KTRs in which1 of patients had been informed about theeed for sun protection only 46 used morehan a tube of sunscreen per year67
Dermatology Involvement
There is increased evidence to suggest thatpecialty dermatology clinics for organ trans-lant recipients improve outcome measures in-luding compliance with photoprotection andncreased awareness of skin cancer68 The re-ources required for these specialty clinics makemplementation difficult for community nephrol-gy groups that do not have direct access to aransplant center Transplant patients should bencouraged to have annual visits with their trans-lant center and if dermatology specialty clinicsre available attempt to coordinate a skin cancervaluation annually
UseofRetinoid-likeCompounds
There is a limited scientific basis for KDIGOuggestion recommendation 186 Although reti-oids now are used routinely in KTRs with aigh skin cancer burden our KDOQI work groupelieves that more data are needed before this
uggestion should be accepted as a guideline In
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ow-immunologic-risk groups and particularlyifficult cases some data suggest that switchingrom CNI to sirolimus therapy may decrease thencidence of skin cancer69 however the riskersus benefit of this maneuver has not been welltudied
DIGORecommendations inChapter 19on-SkinMalignancies
191 Develop an individualized screening plan for eachKTR that takes into account the patientrsquos pastmedical and family history tobacco use compet-ing risks for death and the performance of thescreening methodology (Not Graded)
192 Screen for the following cancers as per localguidelines for the general population (Not Graded)Women cervical breast and colon cancer Menprostate and colon cancer
193 Obtain hepatic ultrasound and alpha feto-proteinevery 12 months in patients with compensatedcirrhosis (Not Graded) [See Recommendations1354 (HCV) and 1365 (HBV)]
DOQIRationale andCommentary
Screening
It is recognized that KTRs have a higher inci-ence of malignancy particularly those associatedith specific viral infections Although cancer
creening may have benefits in this higher riskopulation it should be reinforced that some meth-ds of screening have significant risks which shoulde considered on an individualized basis particu-arly in patients who have projected survival lesshan 5 years
Screening forCancer inPatientsWithHepatitis
Many patients who have underlying cirrhosisn the United States will be followed up by arofessional specializing in liver disease whoay provide additional insight into this cancer
creening recommendation Based on a recentuestionnaire of US gastroenterologists only 50creen patients for hepatocellular carcinoma70
herefore implementation of this guideline byS clinicians is unlikely to be widespread
DIGORecommendations inChapter 20anagingCancerwithReductionof
mmunosuppressiveMedication
201 We suggest consideration be given to reducingimmunosuppressive medications for KTRs with can-
cer (2C)
2011 Important factors for consideration in-clude (Not Graded)bull The stage of cancer at diagnosisbull Whether the cancer is likely to be
exacerbated by immunosuppressionbull The therapies available for the can-
cerbull Whether immunosuppressive medica-
tions interfere with ability to admin-ister the standard chemotherapy
202 For patients with Kaposi sarcoma we suggestusing mTORi along with a reduction in overallimmunosuppression (2C)
DOQIRationale andCommentary
Table 1 (Table 29 in the KDIGO report3 andxcerpted from Grulich et al71) lists cancershat are increased most in immunosuppressedTRs based on standardized incidence ratios
SIRs) which compare the incidence toatched populations Cancers with the highestIRs may be those most likely to respond to aecrease in immunosuppression Except foraposi sarcoma limited evidence is available
or a decrease in immunosuppression in theseettings A strategy to change immunosuppres-ion therapy must occur in consultation withhe transplant center Switching to sirolimusherapy and decreasing immunosuppression inatients who develop Kaposi sarcoma is basedn sound scientific rationale7273
SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
The incidence of cancer posttransplant is 2-20times higher than that in the general population andKDIGO guidelines have been written to outline stepsfor prevention and screening With few exceptions weagree with the recommendations as outlined Skincancer is common in US transplant patients andscreening and prevention are critical However imple-mentation of guidelines for doing so including theKDIGO guidelines is a challenge because of patientpreferences against the routine use of sunscreen aswell as time constraints during office visits Althoughmany posttransplant cancers are viral mediated andrelated to immunosuppression it is less clear how toalter immunosuppression after malignancy has oc-curred We agree that although age-specific screeningfor malignancy should be incorporated into care con-sideration must be given to the risk of screening inpatients with limited life spans (5 years) because of
comorbid conditions
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
ommonPopu
i sarco-Hodgmelanise sm
sophaemia
estima standa10 c
ut esti
0 case
alized t
to guide treatment specifically before the
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
REFERENCES1 McCullough KP Keith DS Meyer KH et al Kidney
nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
o2
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dt
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wad6
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wt
tdp
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ar
ti2
mi2
i2
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ba5
ra2
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gt1
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p2
sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
ation Transpl Rev 200923191-19815 Abbud-Filho M Adams PL Alberuacute J et al A report
f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
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ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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ARTICLE IN PRESS
ow-immunologic-risk groups and particularlyifficult cases some data suggest that switchingrom CNI to sirolimus therapy may decrease thencidence of skin cancer69 however the riskersus benefit of this maneuver has not been welltudied
DIGORecommendations inChapter 19on-SkinMalignancies
191 Develop an individualized screening plan for eachKTR that takes into account the patientrsquos pastmedical and family history tobacco use compet-ing risks for death and the performance of thescreening methodology (Not Graded)
192 Screen for the following cancers as per localguidelines for the general population (Not Graded)Women cervical breast and colon cancer Menprostate and colon cancer
193 Obtain hepatic ultrasound and alpha feto-proteinevery 12 months in patients with compensatedcirrhosis (Not Graded) [See Recommendations1354 (HCV) and 1365 (HBV)]
DOQIRationale andCommentary
Screening
It is recognized that KTRs have a higher inci-ence of malignancy particularly those associatedith specific viral infections Although cancer
creening may have benefits in this higher riskopulation it should be reinforced that some meth-ds of screening have significant risks which shoulde considered on an individualized basis particu-arly in patients who have projected survival lesshan 5 years
Screening forCancer inPatientsWithHepatitis
Many patients who have underlying cirrhosisn the United States will be followed up by arofessional specializing in liver disease whoay provide additional insight into this cancer
creening recommendation Based on a recentuestionnaire of US gastroenterologists only 50creen patients for hepatocellular carcinoma70
herefore implementation of this guideline byS clinicians is unlikely to be widespread
DIGORecommendations inChapter 20anagingCancerwithReductionof
mmunosuppressiveMedication
201 We suggest consideration be given to reducingimmunosuppressive medications for KTRs with can-
cer (2C)
2011 Important factors for consideration in-clude (Not Graded)bull The stage of cancer at diagnosisbull Whether the cancer is likely to be
exacerbated by immunosuppressionbull The therapies available for the can-
cerbull Whether immunosuppressive medica-
tions interfere with ability to admin-ister the standard chemotherapy
202 For patients with Kaposi sarcoma we suggestusing mTORi along with a reduction in overallimmunosuppression (2C)
DOQIRationale andCommentary
Table 1 (Table 29 in the KDIGO report3 andxcerpted from Grulich et al71) lists cancershat are increased most in immunosuppressedTRs based on standardized incidence ratios
SIRs) which compare the incidence toatched populations Cancers with the highestIRs may be those most likely to respond to aecrease in immunosuppression Except foraposi sarcoma limited evidence is available
or a decrease in immunosuppression in theseettings A strategy to change immunosuppres-ion therapy must occur in consultation withhe transplant center Switching to sirolimusherapy and decreasing immunosuppression inatients who develop Kaposi sarcoma is basedn sound scientific rationale7273
SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
The incidence of cancer posttransplant is 2-20times higher than that in the general population andKDIGO guidelines have been written to outline stepsfor prevention and screening With few exceptions weagree with the recommendations as outlined Skincancer is common in US transplant patients andscreening and prevention are critical However imple-mentation of guidelines for doing so including theKDIGO guidelines is a challenge because of patientpreferences against the routine use of sunscreen aswell as time constraints during office visits Althoughmany posttransplant cancers are viral mediated andrelated to immunosuppression it is less clear how toalter immunosuppression after malignancy has oc-curred We agree that although age-specific screeningfor malignancy should be incorporated into care con-sideration must be given to the risk of screening inpatients with limited life spans (5 years) because of
comorbid conditions
KT
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
ommonPopu
i sarco-Hodgmelanise sm
sophaemia
estima standa10 c
ut esti
0 case
alized t
to guide treatment specifically before the
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
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nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
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sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
ation Transpl Rev 200923191-19815 Abbud-Filho M Adams PL Alberuacute J et al A report
f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
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trN
hUt
Iwa
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mi8
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DA
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Bia et al30
ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
KT
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KDOQI Commentary 23
ARTICLE IN PRESS
COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHER
COMPLICATIONS
DIGORecommendations inChapter 21ransplant BoneDisease
211 In patients in the immediate post kidney trans-plant period we recommend measuring serumcalcium and phosphorus at least weekly untilstable (1B)
212 In patients after the immediate post kidney trans-plant period it is reasonable to base the frequencyof monitoring serum calcium phosphorus andPTH on the presence and magnitude of abnormali-ties and the rate of progression of CKD (NotGraded)2121 Reasonable monitoring intervals would
be (Not Graded)bull In CKD stages 1ndash3T for serum cal-
cium and phosphorus every 6-12months and PTH once with subse-quent intervals depending on baselinelevel and CKD progression
bull In CKD stage 4T for serum calciumand phosphorus every 3-6 monthsand for PTH every 6-12 months
bull In CKD stage 5T for serum calciumand phosphorus every 1-3 monthsand for PTH every 3-6 months
bull In CKD stages 3ndash5T measurement ofalkaline phosphatases annually ormore frequently in the presence of
Table 1 Cancers Categorized by SIR for K
Common CancersaC
igh SIRd (5) Kaposi sarcoma(with HIV)d
Kaposnonnonpen
oderate SIRd (1 to 5P 005)
Lung colon cervixstomach liver
Oronaleuk
o increased riskshownd
Breast prostaterectume
Note Cancers listed in approximate descending order ofAbbreviations HIV human immunodeficiency virus SIRaIncidence in both general and transplant populations
tandardized rate normalized to world populationbIncidence in general population 10 cases100000 b
opulation incidence) 10 cases100000 peoplecIncidence in both general and transplant populations 1dExcerpted from Table 4 of Grulich et al71
eBased on US incidence89 Age-standardized rate (normAdapted from the KDIGO transplant guideline3 with perm
elevated PTH
2122 In CKD patients receiving treatments forCKDndashMBD or in whom biochemicalabnormalities are identified it is reason-able to increase the frequency of measure-ments to monitor for efficacy and sideeffects (Not Graded)
2123 It is reasonable to manage these abnor-malities as for patients with CKD stages3-5 (Not Graded)
213 In patients with CKD stages 1ndash5T we suggest that25(OH)D (calcidiol) levels might be measuredand repeated testing determined by baseline valuesand interventions (2C)
214 In patients with CKD stages 1ndash5T we suggest thatvitamin D deficiency and insufficiency be cor-rected using treatment strategies recommended forthe general population (2C)
215 In patients with an eGFR greater than approxi-mately 30 mLmin173 m2 we suggest measuringBMD in the first 3 months after kidney transplantif they receive corticosteroids or have risk factorsfor osteoporosis as in the general population (2D)
216 In patients in the first 12 months after kidneytransplant with eGFR greater than approximately30mLmin173 m2 and low BMD we suggest thattreatment with vitamin D calcitriolalfacalcidiolor bisphosphonates be considered (2D)2161 We suggest that treatment choices be
influenced by the presence of CKDndashMBD as indicated by abnormal levels ofcalcium phosphorus PTH alkaline phos-phatases and 25(OH)D (2C)
2162 It is reasonable to consider a bone biopsy
Transplant Patients and Cancer Incidence
Cancers in Transplantlation (estimated)b Rare Cancersc
mae vaginae
kin lymphoma kidneyoma skine lipe thyroidall intestinee
Eye
rynx esophagus bladder Melanoma larynx multiplemyeloma anuse
Hodgkin lymphoma
Ovary uterus pancreasbrain testis
ted frequency (SIR rate in general population)rdized incidence ratio
ases100000 people based on world incidence88 Age-
mated incidence in transplant population (SIR general
s100000 people
o US population)of KDIGO
idney
ommonPopu
i sarco-Hodgmelanise sm
sophaemia
estima standa10 c
ut esti
0 case
alized t
to guide treatment specifically before the
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
REFERENCES1 McCullough KP Keith DS Meyer KH et al Kidney
nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
o2
Tf2
Tfh2
TfcM
CU1
dt
coT
wad6
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wt
tdp
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op
Mpp
apt
pI
ar
ti2
mi2
i2
uap
ba5
ra2
cJ
sir
ml
gt1
p2
ps2
c2
p2
sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
ation Transpl Rev 200923191-19815 Abbud-Filho M Adams PL Alberuacute J et al A report
f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
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ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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ARTICLE IN PRESS
use of bisphosphonates due to the highincidence of adynamic bone disease (NotGraded)
2163 There are insufficient data to guide treat-ment after the first 12 months (NotGraded)
217 In patients with CKD stages 4ndash5T we suggest thatBMD testing not be performed routinely becauseBMD does not predict fracture risk as it does in thegeneral population and BMD does not predict thetype of kidney transplant bone disease (2B)
218 In patients with CKD stages 4ndash5T with a knownlow BMD we suggest management as for patientswith CKD stages 4-5 not on dialysis (2C)
DOQIRationale andCommentary
MeasuringCalciumandPhosphorus
Recommendations for the diagnosis and treat-ent of posttransplant bone disease were derived
rom those created by the CKD-MBD KDIGOork group5 Our KDOQI work group concurredith the high-level recommendation to measure
alcium and phosphorus weekly after transplantecause dramatic changes can occur in these ele-ents with restoration of kidney function Sugges-
ions for intervals of follow-up after the early trans-lant period are reasonable and based on therequency of CKD posttransplant Although theres consensus that parathyroid hormone (PTH) lev-ls should be monitored it is not clear at what levelTH should be maintained in KTRs There also areata to suggest that higher than normal PTH levelsay be required to preserve bone formation inTRs on steroid therapy74
MeasuringandTreatingVitaminDDeficiency
Vitamin D deficiency is extremely common inTRs75 and low vitamin D levels should be
epleted to control secondary hyperparathyroid-sm Although vitamin D repletion can lead to aecrease in PTH levels there are no data formprovement in bone disease with repletion
BoneMineralDensityandPreventionofBoneLossWithVitaminDAnaloguesorBisphosphonates
Although the current KDIGO suggestion rec-mmendation (215) supports previous ASTuidelines to obtain an early bone mineral den-ity (BMD) study in KTRs with GFR 30 mLin there are no data correlating results of BMDeasurements with fracture risk in KTRs Al-
hough bisphosphonate use may result in less
one density loss in the early posttransplanteriod no study has been sufficiently powered tohow fracture prevention using these therapies76
urthermore bisphosphonate use in patients withFR 30 mLmin or those with low bone turn-ver may cause adynamic bone disease77 Allhese limitations have made bisphosphonate useess common in US transplant patients in recentearsSteroid therapy contributes significantly to
ractures and loss of bone mass in the first 6-12onths after transplant a phenomenon ob-
erved less commonly with steroid-avoidancerotocols or after steroid therapy is with-rawn627879 Thus advocating for a steroid-voidance protocol now used in up to 30 ofS transplant centers may be a reasonablelan for patients at high risk of fractures (olderhite diabetic patients and those with previ-us fractures) to prevent further bone lossost-transplantThe KDIGO recommendations in this sec-
ion focus on the bone disease and biochemicalbnormalities that contribute to fractures inTRs similar to KDOQI recommendations
or CKD-MBD However the preponderancef fractures in the feet and in patients withiabetes suggest that other factors such aseuropathy balance and level of activity alsoay be important factors contributing to the
igh risk of fractures in KTRs8081
DIGORecommendations inChapter 22ematologic Complications
221 Perform a complete blood count at least (NotGraded)bull daily for 7 days or until hospital discharge
whichever is earlierbull two to three times per week for weeks 2-4
weekly for months 2-3bull monthly for months 4-12bull then at least annually and after any change in
medication that may cause neutropenia anemiaor thrombocytopenia
222 Assess and treat anemia by removing underlyingcauses whenever possible and using standard mea-sures applicable to CKD (Not Graded)
223 For treatment of neutropenia and thrombocytope-nia include treatment of underlying causes when-ever possible (Not Graded)
224 We recommend using ACE-Is or ARBs for
initial treatment of erythrocytosis (1C)
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
REFERENCES1 McCullough KP Keith DS Meyer KH et al Kidney
nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
o2
Tf2
Tfh2
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c2
p2
sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
ation Transpl Rev 200923191-19815 Abbud-Filho M Adams PL Alberuacute J et al A report
f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
A
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
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Bia et al30
ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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KDOQI Commentary 25
ARTICLE IN PRESS
DOQIRationale andCommentary
Anemia
Anemia is a common problem posttransplantnd often occurs at higher levels of GFR inTRs than in other patients with CKD82 The
uthors base their recommendations for evalua-ion and treatment on KDOQI guidelines fornemia in CKD which are reasonable andtraightforward83 Financial coverage must bexplored when discharging a new KTR on eryth-opoietin replacement therapy because reimburse-ent may be different from when the patient was
n dialysis therapy
Neutropenia
KDIGO suggestion 223 is reasonable Now thatMV prophylaxis with valgancyclovir is routine inS transplant centers and induction with lympho-
yte-depleting agents frequently is used significanteutropenia is observed more frequently in thearly posttransplant months especially in patientssing mycophenolate compounds Rejection riskould be increased if MPA dose is decreased how-ver CMV disease could occur if valgancyclovirherapy is discontinued Some centers use granulo-yte colony-stimulating factor to treat neutropenian the early posttransplant period to avoid discon-inuing valgancyclovir therapy or decreasing MPAose These decisions should always be made byhe transplant center
Erythrocytosis
This phenomenon usually occurs only in pa-ients with good kidney function and is importanto recognize and treat appropriately AST guide-ines for treatment (hemoglobin 17-19 gdLematocrit 51 to 52) should be followedCE inhibitors are the treatment of choice
KDIGO recommendation 224) and low dosesf these agents often are effective
DIGORecommendations inChapter 23yperuricemia andGout
231 We suggest treating hyperuricemia in KTRs whenthere are complications such as gout tophi or uricacid stones (2D)2311 We suggest colchicine for treating acute
gout with appropriate dose reduction forreduced kidney function and concomitantCNI use (2D)
2312 We recommend avoiding allopurinol in
patients receiving azathioprine (1B) a
2313 We suggest avoiding NSAIDs and COX-2inhibitors whenever possible (2D)
DOQIRationale andCommentary
Colchicine can be very effective in treatingout however higher doses than those describedy the authors in the KDIGO guideline often areeeded The occurrence of diarrhea causing pre-enal azotemia and deterioration in kidney func-ion limits the use of colchicine in KTRs to anven greater extent than the occurrence of myop-thy which usually occurs only in patients withery poor kidney function It is critical to avoidhe use of allopurinol in patients on azathioprineherapy (KDIGO guideline 2312) because ofnhibition of azathioprine metabolism by thisrug If long-term suppression of uric acid syn-hesis is needed in a patient on azathioprineherapy one can switch to a mycophenolateompound because these do not depend on xan-hine oxidase for metabolism
DIGORecommendations inChapter 24 GrowthndDevelopment
241 We recommend measuring growth and develop-ment in children (1C)bull at least every 3 months if 3 years old (includ-
ing head circumference) (Not Graded)bull every 6 months in children 3 years until final
adult height (Not Graded)
242 We recommend using rhGH [recombinant humangrowth hormone] 28 IUm2week (or 005 mgkgday) in children with persistent growth failure afterkidney transplantation (1B)
243 We suggest minimizing or avoiding corticosteroiduse in children who still have growth potential (2C)
DOQIRationale andCommentary
Improving growth in children remains one of therimary goals for pediatric KTRs There now haveeen years of experience with the use of recombi-ant human growth hormone and the risks seem toe minimal compared with the benefits84 Thus weoncur with KDIGO recommendations 241 and42 Although it generally is thought to be prefer-ble to avoid steroid therapy in growing childrenvidence in support of this approach is limitedurthermore the risk of rejection in children hasade some US centers reluctant to use steroid-
voidance protocols
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
REFERENCES1 McCullough KP Keith DS Meyer KH et al Kidney
nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
o2
Tf2
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ar
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i2
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c2
p2
sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
ation Transpl Rev 200923191-19815 Abbud-Filho M Adams PL Alberuacute J et al A report
f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
A
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
cA
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trN
hUt
Iwa
rl5
mi8
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DA
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Bia et al30
ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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ARTICLE IN PRESS
DIGORecommendations inChapter 25 Sexualunction andFertility
2511 Evaluate adults for sexual dysfunction afterkidney transplantation (Not Graded)
2512 Include discussion of sexual activity and counsel-ing about contraception and safe sex practices infollow-up of adult KTRs (Not Graded)
2521 We suggest waiting for at least 1 year aftertransplantation before becoming pregnant andonly attempting pregnancy when kidney func-tion is stable with 1 gday proteinuria (2C)
2522 We recommend that MMF be discontinued orreplaced with azathioprine before pregnancyis attempted (1A)
2523 We suggest that mTORi be discontinued orreplaced before pregnancy is attempted (2D)
2524 Counsel female KTRs with child-bearing poten-tial and their partners about fertility and preg-nancy as soon as possible after transplantation(Not Graded)
2525 Counsel pregnant KTRs and their partners aboutthe risks and benefits of breastfeeding (NotGraded)
2526 Refer pregnant patients to an obstetrician withexpertise in managing high-risk pregnancies(Not Graded)
2531 We suggest that male KTRs and their partners beadvised thatbull male fertility may improve after kidney trans-
plantation (2D)bull pregnancies fathered by KTRs appear to have
no more complications than those in thegeneral population (2D)
2532 We recommend that adult male KTRs beinformed of the possible risks of infertilityfrom mTORi (1C)25321 We suggest that adult male KTRs
who wish to maintain fertility shouldconsider avoiding mTORi or bank-ing sperm prior to mTORi use (2C)
DOQIRationale andCommentary
SexualDysfunction
Sexual dysfunction is a topic often over-ooked in clinic visits but one that manyatients want addressed Sexual dysfunctionas been reported in 30-60 of KTRs8586
he use of 5-phosphodiesterase inhibitors tomprove male erectile dysfunction appears toe safe in KTRs Although KDIGO recommen-ations 2511 and 2512 are not graded ourDOQI work group concurred with these rec-
mmendations t
Pregnancyand theEffect of ImmunosuppressiveDrugsonTeratogenicity
Counseling about contraception in the first yearosttransplant a KDIGO guideline supported byASTonsensus guidelines on pregnancy87 is importantecause fertility may return to normal early post-ransplant The effect of transplant immunosuppres-ive drugs on fertility and teratogenicity must benderstood Mycophenolate compounds are rated asategory D by the US Food and DrugAdministration
FDA) and should be discontinued in women contem-lating pregnancy (Guideline 2522) Despite theame FDA rating for azathioprine there have beenears of experience with its use in pregnant KTRslthough it may be prudent to avoid sirolimus therapyuring pregnancy our work group was divided regard-ng KDIGO recommendation suggestion 2523 somef us agreed that mTOR-inhibitor therapy should betopped in pregnancy while others did not think thereas enough evidence to support this recommenda-
ion Until further data emerge regarding the safety ofTOR inhibitors in pregnancy this precaution must
e weighed against the risks and inconvenience ofhanging immunosuppression therapy All pregnantTRs are considered high-risk pregnancies and shoulde followed up by a high-risk obstetric team
Effect of SirolimusonSpermatogenesis
mTOR inhibitors can decrease testosterone levelsnd male fertility and we therefore concur that coun-eling males treated with this agent is importantKDIGO 2532) Implementation of this recommen-ation will require awareness on the part of the physi-ian when patients are switched to this drug because its used infrequently as an initial agent
DIGORecommendations inChapter 26ifestyle
26 We recommend that patients are strongly encour-aged to follow a healthy lifestyle with exerciseproper diet and weight reduction as needed (1C)
DOQIRationale andCommentary
A healthy lifestyle so important in reachingnd maintaining the sense of wellness that weope patients will achieve posttransplant re-uires an interdisciplinary approach Our workroup was in strong support of this recommenda-
ion
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
REFERENCES1 McCullough KP Keith DS Meyer KH et al Kidney
nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
o2
Tf2
Tfh2
TfcM
CU1
dt
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wad6
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wt
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op
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ar
ti2
mi2
i2
uap
ba5
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cJ
sir
ml
gt1
p2
ps2
c2
p2
sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
ation Transpl Rev 200923191-19815 Abbud-Filho M Adams PL Alberuacute J et al A report
f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
A
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
cA
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t2
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trN
hUt
Iwa
rl5
mi8
oe1
DA
fsK
o
rN
sb2
iaT
Bt
It
ar3
tA2
hm2
EA
i2
dCA
s
aiCCSH
Bia et al30
ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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KDOQI Commentary 27
ARTICLE IN PRESS
DIGORecommendations inChapter 27Mentalealth
27 Include direct questioning about depression andanxiety as part of routine follow-up care after kidneytransplantation (Not graded)
DOQIRationale andCommentary
Depression and anxiety in the transplant popu-ation conditions that may affect adherence of-en are overlooked because patients are expectedo be content with their ldquogift of liferdquo Attention tohis area in the short time allotted for patientisits often requires the help of a multidisci-linary team especially social workers to sur-ey patients for signs of these disorders and gethe help they need
SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
RESEARCH
At the end of each section members of the KDIGOork group made several suggestions for areas of
uture research Our KDOQI work group agreed withhe critical importance of research in these areas toreate evidence upon which future recommendationsnd guidelines can be based
CONCLUSION
The new KDIGO guideline for the care ofidney transplant patients are broad in scope and
Metabolic complications are common posttransplantand attention to the prevention and treatment of theseissues many resulting from side effects of immunosup-pressive drugs constitute a large part of posttransplantcare For the most part our KDOQI work group agreedwith KDIGO recommendations for the prevention andtreatment of bone disease except for having less enthusi-asm for the use of bisphosphonates which now are useduncommonly in KTRs in the United States We agreedwith recommendations for managing hematologic prob-lems gout and growth in children We also concur withrecommendations for management of immunosuppres-sive drugs in pregnancy although our group was dividedabout whether mTOR-inhibitor therapy must be discontin-ued in pregnancy We applaud the KDIGO group forincluding sections on mental health and lifestyle becausethese are important areas that require more attention inthe medical care of KTRs
hould serve as guide for all clinicians caring for A
TRs including transplant clinicians nephrolo-ists nurses and fellows in training Our KDOQIork group concurred with many of the KDIGO
ecommendations except in some important ar-as related to immunosuppression Decisionsbout immunosuppression in the United Statesre largely made by transplant centers and areependent in part on the specific patient popula-ion served Emphasis in the KDIGO guideline isade for the need for continued monitoring ofTRs with the use of kidney biopsy to determine
auses of graft dysfunction even after the earlyosttransplant period Because of increasing rec-gnition of entities such as BK nephropathy andntibody-mediated rejection as important causesor graft dysfunction it is important to haveccess to proper processing and interpretation ofhe transplant biopsy specimen by pathologistsith expertise in this area Most but not allDIGO recommendations are relevant to USatients However implementation of many mayemain a major challenge because of issues ofrug cost and limitation in resources needed tossist in the tasks of educating counseling andmplementing and maintaining lifestyle changesowever these KDIGO recommendations offer
n excellent road map to navigate the complexare of kidney transplant patients
ACKNOWLEDGEMENTSGuideline recommendations included in this article origi-
ally were published in the American Journal of Transplan-ation3 and were reproduced with permission from KDIGO
We thank Robert Harland MD for input on the applicabil-ty of the KDIGO guideline for US KTRs Drs Jeffrey Steinnd Oscar Colegio for input on the pediatric and skin cancerecommendations Drs Jeffrey Berns and Michael Rocco forareful review of this manuscript and Anita Viliusis anderry Willis from the National Kidney Foundation for help
oordinating the work of the group and preparing the manu-cript
Financial Disclosure Dr Bloom has received researchupport from Roche and Novartis is also on the Advisoryoard for Bristol Meyers Squibb and CSL Behring and is aonsultant for Novartis Dr Tomlanovich has received grantupport from Astellas Roche and Novartis and is a consul-ant for Novartis Drs Adey Bia Chan and Kulkarni have nonancial relationships with any commercial entity produc-
ng health carendashrelated products andor services
REFERENCES1 McCullough KP Keith DS Meyer KH et al Kidney
nd pancreas transplant in the United States 1998-2007ccess for patients with diabetes and end stage renal disease
m J Transplant 20099894-906
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Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
ation Transpl Rev 200923191-19815 Abbud-Filho M Adams PL Alberuacute J et al A report
f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
A
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KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
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Bia et al30
ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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Tfh2
TfcM
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wt
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t
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Mpp
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ar
ti2
mi2
i2
uap
ba5
ra2
cJ
sir
ml
gt1
p2
ps2
c2
p2
sw
Bia et al28
ARTICLE IN PRESS
2 Eknoyan G Lameire N Barsoum R et al The burdenf kidney disease improving global outcomes Kidney Int004661310-14143 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelinesor the care of kidney transplant recipients Am J Transplant0099(suppl 3)S19-204 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the prevention diagnosis evaluation and treatment ofepatitis C in chronic kidney disease Kidney Int Suppl008109S1-995 Kidney Disease Improving Global Outcomes (KDIGO)
ransplant Work Group KDIGO clinical practice guidelineor the diagnosis evaluation prevention and treatment ofhronic kidney disease-mineral and bone disorder (CKD-BD) Kidney Int Suppl 2009113S1-1136 Andreoni KA Brayman KL Guidinger MK Sommers
M Sung RS Kidney and pancreas transplantation in thenited States 1996-2005 Am J Transplant 200771359-3757 Ekberg H Tedesco-Silva H Demirbas A et al Re-
uced exposure to calcineurin inhibitors in renal transplanta-ion N Engl J Med 20073572562-2575
8 Ekberg H Bernasconi C Tedesco-Silva H et al Cal-ineurin inhibitor minimization in the Symphony Studybservational results 3 years after transplantation Am Jransplant 200991876-18859 Egbuna OI Davis R Chudinski R et al Outcomes
ith conversion from calcineurin inhibitors to sirolimusfter renal transplantation in the context of steroid with-rawal or steroid continuation Transplantation 200988684-9210 Lebranchu Y Thierry A Toupance O et al Efficacy
n renal function of early conversion from cyclosporine toirolimus 3 months after renal transplantation concept studym J Transplant 200951115-112311 Schold JD Kaplan B AZAtacrolimus is associated
ith similar outcomes as MMFtacrolimus among renalransplant recipients Am J Transplant 200992067-2074
12 Gaston RS Kaplan B Shah T et al Fixed or con-rolled-dose mycophenolate mofetil with standard or reduced-ose calcineurin inhibitors the Opticept trial Am J Trans-lant 200991607-161913 Rush D Arlen D Boucher A et al Lack of benefit of
arly protocol biopsies in renal transplant patients receivingAC and MMF a randomized study Am J Transplant00772538-254514 Chang AT Platt JC The role of antibodies in transplan-
ation Transpl Rev 200923191-19815 Abbud-Filho M Adams PL Alberuacute J et al A report
f the Lisbon Conference on the care of the kidney trans-lant recipient Transplantation 200783(8 suppl)S1-22
16 Israni AK Snyder JJ Skeans MA Tuomari AVaclean JR Kasiske BL Who is caring for kidney trans-
lant patients Variation by region transplant center andatient characteristics Am J Nephrol 200930(5)430-43917 Lee PC Zhu L Terasaki P Everly MJ HLA specific
ntibodies developed in the first year posttransplant areredictive of chronic rejection and renal graft loss Transplan-
ation 200988568-574 t
18 Everly MJ Terasaki PI Monitoring and treatingosttransplant human leukocyte antigen antibodies Hummmunol 200970655-659
19 Birnbaum LM Lipman M Paraskevas S et al Man-gement of chronic allograft nephropathy a systematiceview Clin J Am Soc Nephrol 20094860-865
20 Levey AS Eckardt K-U Tsukamoto T et al Defini-ion and classification of Chronic Kidney Disease Improv-ng Global Outcomes (KDIGO) Kidney Int 2005672089-10021 Jimeacutenez Alvaro S Marceacuten R Teruel JL et al Manage-ent of chronic kidney disease after renal transplantation is
t different from nontransplant patients Transplant Proc009412409-241122 Burgos FJ Pascual J Marcen R et al The role of
maging techniques in renal transplantation World J Urol00422399-40423 Hergesell O Felten H Andrassy K et al Safety of
ltrasound guided percutaneous renal biopsymdashretrospectivenalysis of 1090 consecutive cases Nephrol Dial Trans-lant 199813975-97724 Mengel M Chapman JR Cosio FG et al Protocol
iopsies in renal transplantation insights into patient man-gement and pathogenesis Am J Transplant 20077512-1725 Reeve J Einecke G Mangel M et al Diagnosing
ejection in renal transplants a comparison of molecular-nd histolopathology-based approaches Am J Transplant00991802-181026 Bunnag S Einecke G Reeve J et al Molecular
orrelates of renal function in kidney transplant biopsiesAm Soc Nephrol 2009201149-116027 Saint-Mezard P Berthier CC Zhang H et al Analy-
is of independent microarray datasets of renal biopsiesdentifies a robust transcript signature of acute allograftejection Transplant Int 20093293-302
28 Golgert WA Appel GB Hariharan S Recurrent glo-erulonephritis after renal transplantation an unsolved prob-
em Clin J Am Soc Nephrol 20083800-80729 Ghiggeri GM Carraro M Vincenti F Recurrent focal
lomerulosclerosis in the era of genetics of podocyte pro-eins theory and therapy Nephrol Dial Transplant 200419036-104030 Choy BY Chan TM Lai KN Recurrent glomerulone-
hritis after kidney transplantation Am J Transplant 20066535-254231 Little MA Dupont P Campbell E et al Severity of
rimary MPGN rather than MPGN type determines renalurvival and post-transplantation recurrence risk Kidney Int00669504-51132 Fine RN Becker Y De Geest S et al Nonadherence
onsensus conference summary report Am J Transplant009935-4133 Morrissey PE Flynn ML Lin S Medication noncom-
liance and its implications in transplant recipients Drugs007671463-148134 Vlaminck H Maes B Evers G et al Prospective
tudy on late consequences of subclinical non-complianceith immunosuppressive therapy in renal transplant pa-
ients Am J Transplant 200441509-1513
A
SpT
fd3
stN2
cppG
Jdr9
Ptt
nUiM
lc
oc
tp
DS
dwT
rfm
md
sgA
ocn
ot1
oJ
bwt
ti1
StP
ctaN
ieot3
a2
gpCnt
bn2
Vpcs
oA
ra
KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
cA
nrc
t2
dco9
trN
hUt
Iwa
rl5
mi8
oe1
DA
fsK
o
rN
sb2
iaT
Bt
It
ar3
tA2
hm2
EA
i2
dCA
s
aiCCSH
Bia et al30
ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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ra
KDOQI Commentary 29
ARTICLE IN PRESS
35 AST Infectious Diseases Guidelines 2nd Editionm J Transplant 20099(suppl 4)S1-28136 Akalin E Ames S Sehgal V Murphy B Bromberg J
afety of using hepatitis B core antibody or surface antigen-ositive donors in kidney or pancreas transplantation Clinransplant 200519364-36637 Duchini A Goss J Karpen S Pockros P Vaccinations
or adult solid-organ transplant recipients current recommen-ations and protocols Clin Microbiol Rev 200316(3)357-6438 A randomized placebo-controlled dose-escalation
tudy to assess the safety and effect of cidofivir in renalransplant recipients with BK virus nephropathyCT001384424 Clinical TrialsGov Accessed May 1701039 A multicenter randomized double-blind placebo-
ontrolled multiple dose study of the safety tolerability andopulation pharmacokinetics of CMX001 in post-transplantatients with BK virus viuria NCT00793598 ClinicalTrialsov Accessed May 17 201040 Kliem V Fricke L Wollbrink T Burg M Radermacher
Rohde F Improvement in long-term renal graft survivalue to CMV prophylaxis with oral ganciclovir results of aandomized clinical trial Am J Transplant 20088(5)975-8341 Weinberg A Hodges TN Li S et al Comparison of
CR antigenemia assay and rapid blood culture for detec-ion and prevention of cytomegalovirus disease after lungransplantation J Clin Microbiol 200038768-772
42 Zein NN Rakela J Krawitt EL Reddy KR Tomi-aga T Persing DH Hepatitis C virus genotypes in thenited States epidemiology pathogenicity and response to
nterferon therapy Collaborative Study Group Ann Interned 1996125(8)634-63943 Roland ME Barin B Carlson L et al HIV-infected
iver and kidney transplant recipients 1- and 3-year out-omes Am J Transplant 20088355-365
44 Richeldi L Losi M DrsquoAmico R et al Performancef tests for latent tuberculosis in different groups of immuno-ompromised patients Chest 2009136(1)198-204
45 Kobashi Y Mouri K Obase Y et al Clinical evalua-ion of Quantiferon TB-2G test for immunocompromisedatients Eur Respir J 200730945-950
46 Kasiske BL Snyder JJ Gilbertson D Matas AJiabetes mellitus after kidney transplantation in the Unitedtates Am J Transplant 20033178-18547 Woodward RS Schnitzler MA Baty J et al Inci-
ence and cost of new onset diabetes mellitus among USait-listed and transplanted renal allograft recipients Am Jransplant 20033590-59848 Nam JH Mun JI Kim SI et al Beta-cell dysfunction
ather than insulin resistance is the main contributing factoror the development of postrenal transplantation diabetesellitus Transplantation 2001711417-142349 Isomaa B Almgren P Tuomi T et al Cardiovascularorbidity and mortality associated with the metabolic syn-
rome Diabetes Care 200124683-68950 de Vries AP Bakker SJ van Son WJ et al Metabolic
yndrome is associated with impaired long-term renal allo-raft function not all component criteria contribute equally
m J Transplant 200441675-1683 1
51 Cosio FG Kudva Y van der Velde M et al Newnset hyperglycemia and diabetes are associated with in-reased cardiovascular risk after kidney transplantation Kid-ey Int 2005672415-242152 Armstrong KA Prins JB Beller EM et al Should an
ral glucose tolerance test be performed routinely in all renalransplant recipients Clin J Am Soc Nephrol 20061100-0853 Gerstein HC Miller ME Byington RP et al Effects
f intensive glucose lowering in type 2 diabetes N EnglMed 2083582545-255954 Patel A MacMahon S Chalmers J et al Intensive
lood glucose control and vascular outcomes in patientsith type 2 diabetes Effects of intensive glucose lowering in
ype 2 diabetes N Engl J Med 20083582560-257255 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines on Hypertension and Antihypertensive Agentsn Chronic Kidney Disease Am J Kidney Dis 200443(suppl)S1-29056 Chobanian AV Bakris GL Black HR et al The
eventh Report of the Joint National Committee on Preven-ion Detection Evaluation and Treatment of High Bloodressure the JNC 7 report JAMA 20032892560-257257 Heinze G Mitterbauer C Regele H et al Angiotensin-
onverting enzyme inhibitor or angiotensin II type 1 recep-or antagonist therapy is associated with prolonged patientnd graft survival after renal transplantation J Am Socephrol 200617889-89958 Opelz G Zeier M Laux G Morath C Dohler B No
mprovement of patient or graft survival in transplant recipi-nts treated with angiotensin-converting enzyme inhibitorsr angiotensin II type 1 receptor blockers a collaborativeransplant study report J Am Soc Nephrol 2006173257-26259 Arthur JM Shamim S Interaction of cyclosporine
nd FK506 with diuretics in transplant patients Kidney Int00058325-33060 Kasiske B Cosio FG Beto J et al Clinical practice
uidelines for managing dyslipidemias in kidney transplantatients a report from the Managing Dyslipidemias inhronic Kidney Disease Work Group of the National Kid-ey Foundation Kidney Disease Outcomes Quality Initia-ive Am J Transplant 2004413-53
61 Lemahieu WP Hermann M Asberg A et al Com-ined therapy with atorvastatin and calcineurin inhibitorso interactions with tacrolimus Am J Transplant 20055236-224362 Woodle ES First MR Pirsch J Shihab F Gaber AO
an Veldhuisen P A prospective randomized double-blindlacebo-controlled multicenter trial comparing early (7 day)orticosteroid cessation versus long-term low-dose cortico-teroid therapy Ann Surg 2008248564-577
63 Foley RN Parfrey PS Sarnak MJ Clinical epidemi-logy of cardiovascular disease in chronic renal diseasem J Kidney Dis 199832(suppl 3)S112-11964 Meier-Kriesche HU Baliga R Kaplan B Decreased
enal function is a strong risk factor for cardiovascular deathfter renal transplantation Transplantation 2003751291-
295
cA
nrc
t2
dco9
trN
hUt
Iwa
rl5
mi8
oe1
DA
fsK
o
rN
sb2
iaT
Bt
It
ar3
tA2
hm2
EA
i2
dCA
s
aiCCSH
Bia et al30
ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-
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ARTICLE IN PRESS
65 Gaston RS Kasiske BL Fieberg AM et al Use ofardioprotective medications in kidney transplant recipientsm J Transplant 200991811-181566 Ulrich C Jurgensen HS Degen A et al Prevention of
on-melanoma skin cancer in organ transplant patients byegular use of sunscreen a 24 months prospective case-ontrol study Br J Dermatol 2009161(suppl 3)78-84
67 Mahe E Morelon E Fermanian J et al Renal-ransplant recipients and sun protection Transplantation00478741-74468 Ismail F Mitchell D Casabone A et al Specialist
ermatology clinics for organ transplant recipients signifi-antly improve compliance with photo protection and levelsf skin cancer awareness Br J Dermatol 2008155(5)916-2569 Campistol JM Eris J Oberbauer R et al Sirolimus
herapy after early cyclosporine withdrawal reduces theisk for cancer in adult renal transplantation J Am Socephrol 200617581-58970 Chalasani N Said A Ness R et al Screening for
epatocellular carcinoma in patients with cirrhosis in thenited States results of a national survey Am J Gastroen-
erol 1999942224-222971 Grulich AE van Leeuwen MT Falster MO et al
ncidence of cancers in people with HIVAIDS comparedith immunosuppressed transplant recipients a meta-
nalysis Lancet 200737059-6772 Stallone G Infante B Pontrelli P et al ID2-VEGF-
elated pathways in the pathogenesis of Kaposirsquos sarcoma aink disrupted by rapamycin Am J Transplant 20099(3)558-8673 Duman S Toz H Asci G et al Successful treat-ent of post-transplant Kaposirsquos sarcoma by reduction of
mmunosuppression Nephrol Dial Transplant 20021792-89674 Rojas E Carlini R Clesca P et al The pathogenesis
f osteodystrophy after renal transplantation as detected byarly alterations in bone remodeling Kidney Int 200363915-192375 Stavroulopoulos A Cassidy MJD Porter CJ Hosking
J Roe SD Vitamin D status in renal transplant patientsm J Transplant 200772546-255276 Palmer SC Strippoli G McGregor D Interventions
or preventing bone disease in kidney transplant recipients aystematic review of randomized controlled trials Am Jidney Dis 200545638-64977 Coco M Glicklich D Fuagere MC et al Prevention
f bone loss in renal transplant recipients a prospective t
andomized trial of intravenous pamidronate J Am Socephrol 2003142669-267678 Farmer CKT Hampson G Abbs IC Late low-dose
teroid withdrawal in renal transplant recipients increasesone formation and bone mineral density Am J Transplant00662929-293679 van den Ham E Kooman JP van Hoof CMJP The
nfluence of early steroid withdrawal on body compositionnd bone mineral density in renal transplantation patientsransplant Int 20031682-8780 Nisbeth U Lindh E Ljunghall S Backman U Fellstrom
Increased fracture rate in diabetics and females after renalransplantation Transplantation 1999671218-1222
81 Ramsey-Goldman R Dunn JE Dunlop DD et alncreased risk of fracture in patients receiving solid organransplants J Bone Miner Res 199914456-463
82 Chadban SJ Baines L Polkinghorne K et al Anemiafter kidney transplantation is not completely explained byeduced kidney function Am J Kidney Dis 200749301-0983 National Kidney Foundation KDOQI Clinical Prac-
ice Guidelines and Clinical Practice Recommendations fornemia in Chronic Kidney Disease Am J Kidney Dis00647(suppl 3)S1-14684 Vimalachandra D Craig JC Cowell CT et al Growth
ormone treatment in children with chronic renal failure aeta-analysis of randomized controlled trials J Pediatr
00139560-56785 Tsujimura A Matsumiya K Tsuboniwa N et al
ffect of renal transplantation on sexual function Archndrol 200248467-47486 Raiz L Davies EA Ferguson RM Sexual function-
ng following renal transplantation Health Soc Work 20038264-27287 McKay DB Josephson MA Armenti VT et al Repro-
uction and transplantation report on the AST Consensusonference on Reproductive Issues and Transplantationm J Transplant 200551592-159988 GLOBOCAN 2002 In International Agency for Re-
earch on Cancer Cancer Mondial 200289 United States Cancer Statistics 1999-2005 incidence
nd mortality web-based report US Cancer Statistics Work-ng Group US Department of Health and Human Servicesenters for Disease Control and Prevention and Nationalancer Institute In (vol 2009) Atlanta GA US Cancertatistics Working Group US Department of Health anduman Services Centers for Disease Control and Preven-
ion and National Cancer Institute 2009
- KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
-
- KDIGO GUIDELINE PROCESS
- KDOQI PROCESS FOR INTERPRETATION OF THE KDIGO GUIDELINE IN THE CARE OF US TRANSPLANT PATIENTS
- COMMENTARY ON SECTION I OF THE KDIGOTRANSPLANT GUIDELINEIMMUNOSUPPRESSION
-
- KDIGO Recommendations in Chapter 1Induction Therapy
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 2 Initialand Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Initial Immunosuppression
- Steroid Therapy Discontinuation
- Early Use ofmTORInhibitors
-
- KDIGO Recommendations in Chapter 3Long-term Maintenance ImmunosuppressiveMedications
- KDOQI Rationale and Commentary
-
- Decreasing Immunosuppressive Dosage
- Continue or Withdraw CNI Therapy
- Steroid Therapy Withdrawal
-
- KDIGO Recommendations in Chapter 4Strategies to Reduce Drug Costs
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 5Monitoring Immunosuppressive Medications
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 6Treatment of Acute Rejection
- KDOQI Rationale and Commentar
- KDIGO Recommendations in Chapter 7Treatment of Chronic Allograft Injury (CAI)
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION IIMMUNOSUPPRESSION
- COMMENTARY ON SECTION II OF KDIGOTRANSPLANT GUIDELINE GRAFTMONITORING AND INFECTIONS
-
- KDIGO Recommendations in Chapter 8Monitoring Kidney Allograft Function
- KDOQI Rationale and Commentary
-
- Routine Screening Tests and Time and Frequencyof Monitoring
- Serum Creatinine and EstimatedGFR
-
- KDIGO Recommendations in Chapter 9 KidneyAllograft Biopsy
- KDOQI Rationale and Commentary
-
- Biopsy
- Safety and Accuracy
- Molecular Markers
-
- KDIGO Recommendations in Chapter 10Recurrent Disease
- KDOQI Rationale and Commentary
-
- Recurrent Focal Segmental Glomerulosclerosis
- IgA Nephropathy
- Membranoproliferative Glomerulonephritis
- Hemolytic Uremic Syndrome
- Biopsy and Treatment
-
- KDIGO Recommendations in Chapter 11Preventing Detecting and TreatingNonadherence
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 12Vaccination
- KDOQI Rationale and Commentary
-
- HepatitisB
- Live Vaccine and Timing of Vaccine
-
- KDIGO Recommendations in Chapter 13 ViralDiseases
- KDOQI Rationale and Commentary
-
- BKVirus
- Cytomegalovirus
- Epstein-Barr Virus
- Herpes and Varicella
- Hepatitis C
- HepatitisB
- HumanImmunodeficiency Virus
-
- KDIGO Recommendations in Chapter 14 OtherInfections
- KDOQI Rationale and Commentary
-
- Urinary Tract Infection
- Pneumocystic Pneumonia
- Tuberculosis
- Candida Prophylaxis
-
- SUMMARY OF COMMENTARY ON SECTION IIGRAFT MONITORING AND INFECTIONS
- COMMENTARY ON SECTION III OF KDIGOTRANSPLANT GUIDELINE CARDIOVASCULARDISEASE
-
- KDIGO Recommendations in Chapter 15Diabetes Mellitus
- KDOQI Rationale and Commentary
-
- Diabetic Screening
- DiabetesManagement
-
- KDIGO Recommendations in Chapter 16Hypertension Dyslipidemias Tobacco Use andObesity
- KDOQI Rationale and Commentary
-
- Hypertension
- Dyslipidemia
- Tobacco Use
- Obesity
-
- KDIGO Recommendations in Chapter 17Cardiovascular Management
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION III CVD
- COMMENTARY ON SECTION IV OF KDIGOTRANSPLANT GUIDELINE MALIGNANCY
-
- KDIGO Recommendations in Chapter 18 Cancerof the Skin and Lip
- KDOQI Rationale and Commentary
-
- Counseling and Sunscreen
- Dermatology Involvement
- Use of Retinoid-likeCompounds
-
- KDIGO Recommendations in Chapter 19Non-Skin Malignancies
- KDOQI Rationale and Commentary
-
- Screening
- Screening for Cancer in Patients With Hepatitis
-
- KDIGO Recommendations in Chapter 20Managing Cancer with Reduction ofImmunosuppressive Medication
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ONSECTION IV MALIGNANCY
- COMMENTARY ON SECTION V OF KDIGOTRANSPLANT GUIDELINE OTHERCOMPLICATIONS
-
- KDIGO Recommendations in Chapter 21Transplant Bone Disease
- KDOQI Rationale and Commentary
-
- Measuring Calcium and Phosphorus
- Measuring and Treating VitaminDDeficiency
- Bone Mineral Density and Prevention of Bone LossWith VitaminDAnalogues or Bisphosphonates
-
- KDIGO Recommendations in Chapter 22Hematologic Complications
- KDOQI Rationale and Commentary
-
- Anemia
- Neutropenia
- Erythrocytosis
-
- KDIGO Recommendations in Chapter 23Hyperuricemia and Gout
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 24 Growthand Development
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 25 SexualFunction and Fertility
- KDOQI Rationale and Commentary
-
- Sexual Dysfunction
- Pregnancy and the Effect of ImmunosuppressiveDrugs on Teratogenicity
- Effect of Sirolimus on Spermatogenesis
-
- KDIGO Recommendations in Chapter 26Lifestyle
- KDOQI Rationale and Commentary
- KDIGO Recommendations in Chapter 27 MentalHealth
- KDOQI Rationale and Commentary
-
- SUMMARY OF COMMENTARY ON SECTION VOTHER COMPLICATIONS
- RESEARCH
- CONCLUSION
- ACKNOWLEDGEMENTS
- REFERENCES
-