Anemia in Ckd

KDOQI Clinical Practice Guidelines and ClinicalPractice Recommendations for Anemia in Chronic

Kidney DiseaseTables ............................................................................................................................... S1

Figures ............................................................................................................................. S2

Abbreviations and Acronyms ........................................................................................ S4

Work Group Membership ............................................................................................... S7

KDOQI Advisory Board Members.................................................................................. S8

Foreword .......................................................................................................................... S9

I. EXECUTIVE SUMMARY S11

II. CLINICAL PRACTICE GUIDELINES AND CLINICAL PRACTICE RECOMMEN-DATIONS FOR ANEMIA IN CHRONIC KIDNEY DISEASE IN ADULTS S16

1.1. Identifying Patients and Initiating Evaluation .................................................... S17

1.2. Evaluation of Anemia in CKD............................................................................. S28

2.1. Hb Range ............................................................................................................ S33

3.1. Using ESAs ......................................................................................................... S54

3.2. Using Iron Agents............................................................................................... S58

3.3. Using Pharmacological and Nonpharmacological Adjuvants to ESA Treatmentin HD-CKD......................................................................................................... S71

3.4. Transfusion Therapy .......................................................................................... S79

3.5. Evaluating and Correcting Persistent Failure To Reach or Maintain IntendedHb....................................................................................................................... S81

III. CLINICAL PRACTICE RECOMMENDATIONS FOR ANEMIA IN CHRONIC KID-NEY DISEASE IN CHILDREN S86

1.1: Identifying Patients and Initiating Evaluation .................................................... S87

1.2: Evaluation of Anemia in CKD............................................................................. S89

2.1: Hb Range ............................................................................................................ S90

VOL 47, NO 5, SUPPL 3, MAY 2006

AJKD CONTENTSAmerican Journal ofKidney Diseases

3.1: Using ESAs ......................................................................................................... S933.2: Using Iron Agents............................................................................................... S993.3: Using Pharmacological and NonPharmacological Adjuvants to ESA Treatment

in HD-CKD......................................................................................................... S1053.4: Transfusion Therapy .......................................................................................... S1063.5: Evaluating and Correcting Persistent Failure To Reach or Maintain Intended

Hb Level ............................................................................................................. S107

IV. CLINICAL PRACTICE RECOMMENDATIONS FOR ANEMIA IN CHRONIC KID-NEY DISEASE IN TRANSPLANT RECIPIENTS S109

V. APPENDIX 1: METHODS OF EVIDENCE REVIEW AND SYNTHESIS ................... S117

Work Group Biographies............................................................................................. S126

Acknowledgments ....................................................................................................... S131

References.................................................................................................................... S132

KDOQI Disclaimer

SECTION I: USE OF THE CLINICAL PRACTICE GUIDELINES AND CLINICAL PRACTICERECOMMENDATIONS

These Clinical Practice Guidelines (CPGs) and Clinical Practice Recommendations (CPRs) arebased upon the best information available at the time of publication. They are designed to provideinformation and assist decision-making. They are not intended to define a standard of care, andshould not be construed as one. Neither should they be interpreted as prescribing an exclusive courseof management.

Variations in practice will inevitably and appropriately occur when clinicians take into account theneeds of individual patients, available resources, and limitations unique to an institution or type ofpractice. Every health-care professional making use of these CPGs and CPRs is responsible forevaluating the appropriateness of applying them in the setting of any particular clinical situation. Therecommendations for research contained within this document are general and do not imply a specificprotocol.

SECTION II: DEVELOPMENT PROCESS

The National Kidney Foundation makes every effort to avoid any actual or potential conflicts ofinterest that may arise as a result of an outside relationship or a personal, professional or businessinterest of a member of the Work Group.

Specifically, all members of the Work Group are required to complete, submit and sign aDisclosure Questionnaire showing all such relationships that might be perceived as real or potentialconflicts of interest. All affiliations are published in their entirety at the end of this publication in theBiographical Sketch section of the Work Group members.

In citing this document, the following format should be used: National Kidney Foundation. KDOQIClinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic KidneyDisease. Am J Kidney Dis 47:S1-S146, 2006 (suppl 3).

Support for the development of the KDOQI Clinical Practice Guidelines and Clinical PracticeRecommendations for Anemia in Chronic Kidney Disease was provided by Amgen, Inc.

The National Kidney Foundation gratefully acknowledges the support of Amgen, Inc. as thefounding and principal sponsor of KDOQI.

T

TTTTT

TTTTTT

T

T

T

T

T

T

T

TTT

TT

TT

TTT

T

T

TT

A

Tables

able 1. Key Differences Between Current Guidelines (KDOQI Anemia 2006) andPrevious Anemia Guidelines (KDOQI 2000 and EBPG 2004) ...................................... S15

able 2. Relationship Between Hb Level and Kidney Function ................................................. S18able 3. Relationship Between Hct and Kidney Function............................................................ S19able 4. Prevalence of Anemia by Level of Kidney Function...................................................... S20able 5. Difference in Hb and Hct From Reference by Category of CCr...................................... S20able 6. Difference in Hb and Hct From Reference According to Category of BSA

and Normalized eGFR ........................................................................................... S21able 7. Hb for Males by Race/Ethnicity and Age: United States, 1988 to 1994......................... S24able 8. Hb for Females by Race/Ethnicity and Age: United States, 1988 to 1994 ..................... S25able 9. Normal Increase in Hb Levels Related to Long-Term Altitude Exposure ...................... S26able 10. Maximum Hb Cutoff Values for Anemia in Pregnancy.................................................. S27able 11. Adjustment to Hb for Smoking by Number of Packets per Day..................................... S27able 12. RCTs Examining Effects of Distinct Hb Targets/Levels on Key Clinical Outcomes

in the HD-CKD and PD-CKD Populations .................................................................... S34able 13. RCTs Examining Effects of Distinct Hb Targets/Levels on QOL in the HD-CKD

and PD-CKD Populations............................................................................................... S36able 14. Non-CVD/Mortality AE Rates in RCTs Examining Distinct Hb Targets/Levels

in HD-CKD and PD-CKD Populations: ESA versus ESA............................................. S38able 15. Non-CVD/Mortality AE Rates in RCTs Examining Distinct Hb Targets/Levels

in the HD-CKD and PD-CKD Populations: ESA versus Placebo .................................. S40able 16. Effects of Distinct Hb Targets/Levels on Key Clinical Outcomes in the

ND-CKD Population ...................................................................................................... S41able 17. RCTs Examining Effects of Distinct Hb Targets/Levels on QOL in the

ND-CKD Population ...................................................................................................... S42able 18. Non-CVD/Mortality AE Rates in RCTs Examining Distinct Hb Targets/Levels

in the CKD Population .......................................................................................... S43able 19. RCTs Examining Effects of Distinct Hb Targets/Levels on Exercise Capacity

in the HD-CKD and PD-CKD Populations .................................................................... S44able 20. Target Hb Levels in the HD-CKD and PD-CKD Populations........................................ S45able 21. Target Hb Levels in the ND-CKD Population................................................................ S48able 22. Anemia Management Protocol Information for Initial Anemia Management

Used in ESA RCTs ................................................................................................ S56able 23. RCTs for Ferritin and TSAT Targets in the HD-CKD Population .................................. S60able 24. Value of Baseline Ferritin for Assessing Likelihood of Response to IV Iron Therapy

in the HD-CKD Population ............................................................................................ S61able 25. Value of Ferritin in Assessing Iron Storage Excess or Deficiency.................................. S61able 26. Value of Baseline TSAT for Assessing Likelihood of Response to IV Iron Therapy

in the HD-CKD Population ............................................................................................ S62able 27. Value of Baseline CHr for Assessing Likelihood of Response to IV Iron Therapy........ S62able 28. Mean Monthly Dose of Iron in Adult Prevalent HD-CKD Patients on ESA Therapy.... S63able 29A. Comparative RCTs of IV versus PO Iron Administration and Efficacy of

Anemia Management in the HD-CKD and PD-CKD Populations ................................. S65able 29B. Comparative RCTs of IV versus PO Iron Administration and Efficacy of

Anemia Management in the ND-CKD Population ......................................................... S65able 30. Comparative RCTs of PO Iron Administration versus Placebo/Control and

Efficacy of Anemia Management in the HD-CKD and PD-CKD Populations .................... S66able 31. Serious AEs of Iron Agents in Patients Naïve to Tested Iron Agent (N � 100) ............. S66
able 31A. IV versus PO Iron Agents in the HD-CKD and PD-CKD Populations .......................... S67
merican Journal of Kidney Diseases, Vol 47, No 5, Suppl 3 (May), 2006: pp S1-S3 S1

TT

TT

TT

TT

T

T

TTTTTTTTTTTTT

FFFF

FF

FF

F

F

FF

FIGURESS2

able 31B. IV versus PO Iron Agents in the ND-CKD Population .................................................. S67able 32. RCTs Evaluating Effects of Treatment with IV L-Carnitine on Hb Levels and ESA

Doses in the HD-CKD Population.................................................................................. S72able 33. Use of L-Carnitine as an Adjuvant to ESA Treatment in the HD-CKD Population.............. S73able 34. RCTs Evaluating Effects of Treatment With IV Ascorbic Acid on Hb Levels

and ESA Doses in the HD-CKD Population ........................................................................... S74able 35. Use of Ascorbic Acid as an Adjuvant to ESA Treatments in the HD-CKD Population........ S74able 36. RCTs Evaluating Effects of Treatment With IM Androgens on Hb Levels in the

HD-CKD Population ...................................................................................................... S75able 37. Use of Androgens as an Adjuvant to ESA Treatment in the HD-CKD Population......... S76able 38. Published Experience in Patients With Anemia, CKD, and a Preexisting

Hematologic Disorder .................................................................................................... S84able 39. Hb Levels (g/dL) in Children Between 1 and 19 Years for Initiation of

Anemia Workup.............................................................................................................. S88able 40. Hb Levels (g/dL) in Children Between Birth and 24 Months for Initiation

of Anemia Workup.......................................................................................................... S88able 41. Literature Review of Anemia in Transplant CKD: Key Conclusions........................... S110able 42. Prevalance of PTA by Duration of Posttransplantation Period ..................................... S112able 43. Example of a Summary Table....................................................................................... S119able 44. Systematic Review Topics and Screening Criteria ....................................................... S120able 45. Literature Search Yield of Primary Articles for Systematic Review Topics................. S121able 45A. Assessment of Study Applicability ............................................................................... S121able 46. Details of First-Look Topics, Ovid Literature Searches, and Yield by Topic ............... S122able 46A. Grades for Study Quality .............................................................................................. S122able 47. Evaluation of Studies of Prevalence ............................................................................. S123able 48. Format for Guidelines................................................................................................... S123able 49. Balance of Benefit and Harm ................................................................................................. S124able 50. Definitions of Grades for Quality of Overall Evidence ................................................ S124
able 51. Example of an Evidence Profile ................................................................................... S125
Figures

igure 1. Kidney Failure in the United States ................................................................................. S12igure 2. Relationship Between Current and Previous Anemia Guidelines .................................... S14igure 3. Relationship Between Hb Level and eGFR ..................................................................... S21igure 4. Relationship Between eGFR and Prevalence of Anemia as Defined by Differing Hb

Levels for (A) Males and (B) Females............................................................................. S21igure 5. Prevalence of Anemia by CKD Stage .............................................................................. S22igure 6. Relationship Between Level of Renal Function, Reflected by SCr Level or

GFR, and Prevalence of Anemia, Defined at Different Hb Cutoff Levels, AmongPatients under the Care of Physicians .............................................................................. S22

igure 7. Hb Percentiles by GFR in the Canadian Multicentre Longitudinal Cohort Study ........... S22igure 8. Prevalence of Low Hb Level by Category of GFR in the Canadian Multicentre

Longitudinal Cohort Study............................................................................................... S23igure 9. Prevalence of Low Hb Level by eGFR in Patients with Diabetics Compared with the

General Population ..................................................................................................................... S23igure 10. Changes in Hb Levels and eGFR Over 2 years in Adult Patients with CKD Stages 3

and 4 Not Treated with ESA ............................................................................................ S23igure 11. Distribution of Hb Levels in Adult Males and Females by Age Group............................ S26
igure 12. Distribution of Ferritin and TSAT Values by Age Group in Males and Females ............. S30

FFF

F

FF

F

FIGURES S3

igure 13. Distribution of Hb Levels by Ferritin Range in Patients with CKD ................................ S31igure 14. Distribution of Hb Levels by TSAT Range in Patients with CKD................................... S31igure 15. Target and Achieved Hb Levels in 18 RCTs Comparing Higher Against Lower

(or Placebo/Control) Hb Targets for ESA Therapy .......................................................... S50igure 16. Baseline Mean Pretreatment Hb Levels Compared with Achieved Mean Hb

Levels in the Upper and Lower Target..................................................................... S51igure 17. Exposure to Eprex® and Case Counts of PRCA .............................................................. S82igure 18. Mean Epoetin Dose per Patient per Administration by Percentile of Dose (1st, 5th to

95th, and 99th) ................................................................................................................. S82igure 19. Process of Triaging a Topic to a Systematic Review or a Narrative Review ........................ S118

S

Acronyms and Abbreviations� Change1 Increase2 Decrease

ABP Ambulatory blood pressureABPM Ambulatory blood pressure monitoring

ACE Angiotensin-converting enzymeADE Adverse drug event

AE Adverse eventARBs Angiotensin receptor blockersARF Acute renal failureAST Aspartate transaminaseBID Twice dailyBIW Twice weekly

BP Blood pressureBSA Body surface area

CABG Coronary artery bypass graftCBC Complete blood count

CCr Creatinine clearanceCESDS Center for Epidemiologic Studies Depression ScaleCFU-E Erythroid colony-forming units

CHF Congestive heart failureCHOIR Correction of Hemoglobin and Outcomes in Renal Insufficiency

CHr Content of hemoglobin in reticulocytesCI Confidence interval

CKD Chronic kidney diseaseCMV CytomegalovirusCPG Clinical practice guidelineCPR Clinical practice recommendation

CREATE Cardiovascular Risk Reduction by Early Anemia Treatment With Epoetin Beta TrialCRI Corrected reticulocyte indexCV Cardiovascular

CVA Cerebrovascular accidentCVD Cardiovascular diseaseD/C Discontinuation

DBP Diastolic blood pressureDNA Deoxyribonucleic acid

DOQI Dialysis Outcomes Quality InitiativeEBPG European Best Practices GuidelineeGFR Estimated glomerular filtration rate

ERI Erythropoietin resistance indexERT Evidence Review TeamESA Erythropoiesis-stimulating agent

ESRD End-stage renal diseaseFACIT Functional Assessment of Chronic Illness Therapy

FDA Food and Drug AdministrationGFR Glomerular filtration rate

GI GastrointestinalHb HemoglobinHct Hematocrit
HD Hemodialysis
American Journal of Kidney Diseases, Vol 47, No 5, Suppl 3 (May), 2006: pp S4-S64

ACRONYMS AND ABBREVIATIONS S5

HD-CKD Hemodialysis-dependent chronic kidney diseaseHDF HemodiafiltrationHPS Hemophagocytic syndromeHTN Hypertension

HU HydroxyureaHUI Health Utilities IndexHUS Hemolytic uremic syndromeIHD Ischemic heart diseaseIM IntramuscularIU International UnitIV Intravenous

KDIGO Kidney Disease: Improving Global OutcomesKDOQI Kidney Disease Outcomes Quality Initiative

KDQ Kidney Disease QuestionnaireKDQOL Kidney Disease Quality of Life

KEEP Kidney Early Evaluation ProgramKLS Kidney Learning SystemKPS Karnofsky Performance Scale

LV Left ventricularLVD Left ventricular dilation

LVEDd Left ventricular end-diastolic diameterLVH Left ventricular hypertrophy

LVMI Left ventricular mass indexLVVI Left ventricular volume indexMAP Mean arterial blood pressureMCH Mean corpuscular hemoglobin

MCHC Mean corpuscular hemoglobin concentrationMCV Mean corpuscular volume

MDRD4 Modification of Diet in Renal DiseaseMI Myocardial infarction

MR Mitral regurgitationN, n Number of subjectsN/A Not applicable

NAPRTCS North American Pediatric Renal Transplant Cooperative Studynd Not documented

ND-CKD Non–dialysis-dependent chronic kidney diseaseNHANES National Health and Nutrition and Examination Survey

NKF National Kidney FoundationNOS Not otherwise specified

NS Not significantOR Odds ratioPD Peritoneal dialysis

PD-CKD Peritoneal dialysis–dependent chronic kidney diseasePHRBC Percent hypochromic red blood cells

PHRC Percent hypochromic red cellsPO Oral

PRCA Pure red cell aplasiaPt Patient

PTA Posttransplantation anemiaQoAL Quality of American Life
QOL Quality of life

T

ACRONYMS AND ABBREVIATIONSS6

QOW Every other weekRCT Randomized controlled trial

rHuEPO Recombinant human erythropoietinRQoLP Renal Quality of Life Profile

RR Relative riskSAE Severe adverse eventSBP Systolic blood pressure

SC SubcutaneousSCD Sudden cardiac death

SCr Serum creatinineSF-36 36-Item Medical Outcomes Study Short-Form Health Survey

SIP Sickness Impact ProfileSQUID Superconducting quantum interference device

TDS Total daily supplementTID Thrice dailyTIW Thrice weekly

TRESAM Transplant European Survey on Anemia ManagementTSAT Transferrin saturationTTO Time trade-offTTP Thrombotic thrombocytopenic purpura

x-ND-CKD Non–dialysis-dependent kidney transplant recipient populationU Unit

URR Urea reduction ratioUSFDA United States Food and Drug AdministrationUSRDS United States Renal Data System

vs VersusWHO World Health Organization

ZPP Zinc protoporphyrin

Anemia in Chronic Kidney Disease

Work Group Membership

p C
Work Grou
David B. Van Wyck, MDUniversity of Arizona College of Medicine

Tucson, AZ

G

Nashville, TN

Medical Center,

Christina Kwack Yuhan, MD,

Gowri Raman, MD

Andrew S. Levey, MD

o-Chairs

Kai-Uwe Eckardt, MDUniversity of Erlangen-Nuremberg

Erlangen, Germany

Work

John W. Adamson, MDBlood Center of SE Wisconsin

Blood Research InstituteMilwaukee, WI

George R. Bailie, MSc, PharmD, PhDAlbany College of Pharmacy

Albany, NY

Jeffrey S. Berns, MDUniversity of Pennsylvania School of Medicine

Philadelphia, PA

Steven Fishbane, MDWinthrop University Hospital

Mineola, NY

Robert N. Foley, MDNephrology Analytical Services

Minneapolis, MN

Sana Ghaddar, RD, PhDAmerican University of Beirut

Faculty of Agriculture and Food SciencesBeirut, Lebanon

John S. Gill, MD, MSUniversity Of British Columbia

St. Paul’s HospitalVancouver, Canada

Kathy Jabs, MDVanderbilt University Medical Center

roup

Patricia Bargo McCarley, RN, MSN, NPDiablo Nephrology Medical Group

Walnut Creek, CA

Hans H. Messner, MDUniversity Health NetworkPrincess Margaret Hospital

Toronto, Canada

Allen R. Nissenson, MDUCLA Medical Center

Los Angeles, CA

Gregorio T. Obrador, MDUniversidad Panamericana School of Medicine

Mexico City, Mexico

John C. Stivelman, MDNorthwest Kidney Center

Seattle, WA

Colin T. White, MDBritish Columbia Children’s Hospital

Vancouver, Canada

Liaison MemberFrancesco Locatelli, MD

Azienda Ospedaliera DI LeccoLecco, Italy

Iain C. Macdougall, MDKing’s College Hospital

London, England

Evidence Review TeamNational Kidney Foundation Center for Guideline Development and Implementation at Tufts-New England

Boston, MA

Katrin Uhlig, MD, MS, Project Director and Program Director, Nephrology
Assistant Project Director
Amy Earley, BSRebecca Persson, BA

Ashish Mahajan, MD, MPHPriscilla Chew, MPH

In addition, support and supervision was provided by:

Joseph Lau, MD, Program Director, Evidence Based MedicineEthan Balk, MD, MPH, Evidence Review Team Co-Director

, Center Director

GBPAPWALBCGKMCDDLRM

DMR

KDOQI Advisory Board Members

Adeera Levin, MD, FACPKDOQI Chair

Michael Rocco, MD, MSCE
KDOQI Vice-Chair
Garabed Eknoyan, MD
KDOQI Co-Chair Emeritus
aureen Michael, BSN, MBA

WJGRTBNCARNDWS

EJD

NKF-KDOQI Guidelin

ichard Milburn

AK

Nathan Levin, MD, FACP
KDOQI Co-Chair Emeritus
eorge Bailie, PharmD, PhDryan Becker, MDeter G. Blake, MD, FRCPC, MBB.Chllan Collins, MD, FACPeter W. Crooks, MDilliam E. Haley, MDlan R. Hull, MDawrence Hunsicker, MDertrand L. Jaber, MDynda Ann Johnson, MD, MBAeorge A. Kaysen, MD, PhDarren King, MSW, ACSW, LCSWichael Klag, MD, MPHraig B. Langman, MDerrick Latos, MDonna Mapes, DNSc, MSinda McCann, RD, LD, CSRavindra L. Mehta, MD, FACP

illiam Mitch, MDoseph V. Nally, MDregorio Obrador, MD, MPHulan S. Parekh, MD, MShakor G. Patel, MD, MACPrian J.G. Pereira, MD, DMeil R. Powe, MDlaudio Ronco, MDnton C. Schoolwerth, MDaymond Vanholder, MD, PhDanette Kass Wenger, MDavid Wheeler, MD, MRCPinfred W. Williams, Jr., MD

huin-Lin Yang, MD

x-Officioosephine Briggs, MD
avid Warnock, MD
e Development Staff
onna Fingerhutargaret Fiorarancio
nthony Gucciardoerry Willis, PhD

Tmulshgmlsi

tcbTthtghatloptoMeirimaahc

VOL 47, NO 5, SUPPL 3, MAY 2006

AJKD American Journal ofKidney Diseases

A

Foreword

tba

ugrpotpcmwCtdUtEwsfrosdaatistr

his publication of the Clinical PracticeGuidelines and Clinical Practice Recom-

endations for Anemia represents the secondpdate of these guidelines since the first guide-ine on this topic was published in 1997. The firstet of guidelines established the importance ofemoglobin in dialysis patients, and establisheduidelines and targets for the treatment of ane-ia in dialysis patients. The first update, pub-

ished in 2000, described anemia in a widerpectrum of the chronic kidney patients, andncluded those not on dialysis.

A number of important randomized clinicalrials and large observational studies have beenommenced or completed in CKD populationsoth on and off dialysis, over the past 5 years.he key questions that have been addressed in

hese recent studies have been the optimalemoglobin target for CKD patients. To datehere has been little support normalizing hemo-lobin, though a number of important studiesave not been completed or reported (CHOIRnd TREAT), and the community eagerly awaitshem. Nonetheless, the key aspects of the pub-ished data from both controlled trials andbservational studies, support the ongoing im-ortance of hemoglobin levels in risk stratifica-ion of patients with CKD, whether with nativer transplant kidneys, or on dialysis therapies.uch has been learned about the causes of

rythropoietin resistance, and some small stud-es have reported methods of treating ESAesistance. Furthermore, there are multiple newnsights into the optimizing treatment of ane-ia with iron supplementation and ESA. Novel

ctions of ESAs on cognitive function, as wells preservation of kidney and cardiac functionave been described. To date there are no
linical trials to support the use of ESA for
merican Journal of Kidney Diseases, Vol 47, No 5, Suppl 3 (May

hese ‘non anemia’ purposes, but both theasic and clinical science of ESA therapy aredvancing at a rapid pace.This updated set of guidelines on anemia is

nique and different from the previous anemiauidelines. Firstly, the guidelines have been sepa-ated into evidence based guidelines and clinicalractice recommendations, based on the strengthf evidence. The term guideline is reserved forhat which is robust enough to be used, if appro-riate, as a clinical performance measure. Clini-al practice recommendations are those recom-endations based on expert opinion of theorking group, but lacking sufficient hard data;PRs are also susceptible to testing in a clinical

rial. Secondly, these guidelines incorporated in-ividuals from countries outside the US (Europe,K, Middle East, Mexico and Canada) and at-

empted to build on most recently publisheduropean Best Practice guidelines (2004), asell as the previously published KDOQI ver-

ions. Lastly, the working group was clearlyocused on ensuring that this document wasobust and clear for the reader. There was anvert recognition that research recommendationshould be organized and described in sufficientetail to ensure that prior to the next update ofny anemia guideline, there would be new dataddressing gaps in our current knowledge. Thus,here are no concrete research recommendationsn this version; they will be published in aeparate document in the near future. The in-ended effect of this change in how the researchecommendations are presented is to provide a

© 2006 by the National Kidney Foundation, Inc.0272-6386/06/4705-0101$32.00/0
doi:10.1053/j.ajkd.2006.04.023
), 2006: pp S9-S10 S9

gtpp

Ghdgtaaleptlmucpt

Ltms

ichitltaUtd

FOREWORDS10

uidepost for funding agencies and investigatorso target research efforts in those areas that willrovide important information that will benefitatient outcomes.This final version of the Clinical Practice

uidelines and Recommendations for Anemiaas undergone revision in response to commentsuring the public review, an important and inte-ral part of the KDOQI guideline process. None-heless, as with all guideline documents, there isneed for revision in the light of new evidence,

nd more importantly, a concerted effort to trans-ate the guidelines into practice. Considerableffort has gone into their preparation over theast 2 years, and every attention has been paid toheir detail and scientific rigor, no set of guide-ines and clinical practice recommendations, noatter how well developed, achieves its purpose

nless it is implemented and translated into clini-al practice. Implementation is an integral com-onent of the KDOQI process, and accounts for
he success of its past guidelines. The Kidney
earning System (KLS) component of the Na-ional Kidney Foundation is developing imple-entation tools that will be essential to the

uccess of these guidelines.In a voluntary and multidisciplinary undertak-

ng of this magnitude, many individuals makeontributions to the final product now in yourands. It is impossible to acknowledge themndividually here, but to each and every one ofhem we extend our sincerest appreciation. Thisimitation notwithstanding a special debt of grati-ude is due to the members of the Work Group,nd their co-chairs, David Van Wyck and Kai-we Eckardt. It is their commitment and dedica-

ion to the KDOQI process that has made thisocument possible.

Adeera Levin, MDKDOQI Chair

Michael Rocco, MD
KDOQI Vice-Chair

ikdamfi(tt(uueIaTsGCbmtas

A

tocl1fUspeplonp

A

a

A

EXECUTIVE SUMMARY

tmcdtsCtrmcccesotbwd

piwmitsodtrbuevrdvestc

a

INTRODUCTIONAnemia commonly contributes to poor qual-

ty of life (QOL) in patients with chronicidney disease (CKD). Fortunately, among theisorders that may afflict patients with CKD,nemia is perhaps the most responsive to treat-ent. Anemia was the subject of one of therst efforts of the National Kidney FoundationNKF) to improve patient outcomes throughhe development, dissemination, and implemen-ation of Dialysis Outcomes Quality InitiativeDOQI) Clinical Practice Guidelines.1 The firstpdate of these guidelines appeared in 2001nder the newly organized NKF-Kidney Dis-ase Outcomes Quality Initiative (KDOQI).2

n 2004, the NKF-KDOQI Steering Committeeppointed a Work Group and Evidence Revieweam (ERT) to undertake the first comprehen-ive revision of the KDOQI Clinical Practiceuidelines for the Management of Anemia inKD. This Executive Summary provides arief background description of CKD and ane-ia, outlines the scope of the guidelines and

he methods of evidence review and synthesis,nd provides the complete text of the guidelinetatements.

BACKGROUND

bout CKD

CKD is a worldwide public health issue.3 Inhe United States, the incidence and prevalencef kidney failure are increasing (Fig 1), out-omes are poor, and the cost is high.4 The preva-ence of earlier stages of CKD is approximately00 times greater than the prevalence of kidneyailure, affecting almost 11% of adults in thenited States.4,5 There is growing evidence that

ome of the adverse outcomes of CKD can berevented or delayed by preventive measures,arly detection, and treatment. Strategies to im-rove outcomes include Clinical Practice Guide-ines (CPGs) for CKD4 and for the managementf hypertension,3 dyslipidemia,6 bone disease,7

utrition,8 and cardiovascular disease (CVD)9 inatients with CKD.

bout Anemia

Before considering a patient with both anemia
nd CKD, a brief introduction to the processes

hat contribute to anemia may be helpful. Ane-ia is the clinical manifestation of a decrease in

irculating red blood cell mass and usually isetected by low blood hemoglobin (Hb) concen-ration. The cause, treatment, and prognosticignificance of anemic disorders vary widely.auses are distinguished clinically by markers of

he magnitude and appropriateness of a marrowesponse to anemia. Under usual conditions, bonearrow generates approximately 200 billion new

ells per day to match the number of senescentells removed from circulation. The expectedompensatory response to anemia is a height-ned rate of erythropoiesis. Failure to demon-trate a compensatory response signifies slowedr defective erythropoiesis. Thus, hyperprolifera-ive disorders reflect increased destruction of redlood cells with normal marrow response,hereas hypoproliferative and maturation disor-ers reflect impaired red blood cell production.The cellular and molecular biology of erythro-

oiesis has important implications for understand-ng, evaluating, and treating anemia in patientsith CKD. Effective circulating red blood cellass is controlled by specialized interstitial cells

n the kidney cortex that are exquisitely sensitiveo small changes in tissue oxygenation.11 If tis-ue oxygenation decreases because of anemia orther causes, these cells sense hypoxia and pro-uce erythropoietin.12 Within erythroid islands,he autonomous unit of erythropoiesis in mar-ow, receptors on the surface of the earliest redlood cell progenitors, erythroid colony-formingnits (CFU-Es), bind erythropoietin. Binding ofrythropoietin to erythropoietin receptors sal-ages CFU-Es and the subsequent earliest eryth-oblast generations from preprogrammed celleath (apoptosis), thereby permitting cell sur-ival and division and the eventual expansion ofrythropoiesis. If successful, these erythropoietin-timulated events increase the production of re-iculocytes, restore normal circulating red bloodell mass, and correct tissue hypoxia.13

In anemic patients, 1 or more steps in thisutoregulatory sequence may fail. In the pres-

© 2006 by the National Kidney Foundation, Inc.0272-6386/06/4705-0102$32.00/0
doi:10.1053/j.ajkd.2006.03.010
), 2006: pp S11-S15 S11

eteeatuegdirtdaprAraboppesgbsma

p(etnd

tflwt23

acKCAiaannivgotrctcrrs

I

mrgtdtpf

laibUtlsR

EXECUTIVE SUMMARYS12

nce of kidney disease, erythropoietin produc-ion may be impaired, leading to erythropoi-tin deficiency and the apoptotic collapse ofarly erythropoiesis. If folate and vitamin B12

re lacking, deoxyribonucleic acid (DNA) syn-hesis is impaired, and erythroblasts, normallyndergoing rapid division during this period ofrythropoiesis, succumb to apoptosis.13 In on-oing folate or vitamin B12 deficiency, disor-ered DNA synthesis, maturation arrest, andneffective early erythropoiesis lead to a mac-ocytic anemia. Conversely, if iron is lacking,he Hb-building steps that follow rapid cellivision are affected: synthesis of both hemend globin slow, and erythropoiesis is im-aired. Reticulocytes that emerge from mar-ow are few, poorly hemoglobinized, and small.

hypochromic microcytic anemia eventuallyesults. Inflammation, a disorder commonmong patients with CKD, appears to impairoth the early erythropoietin-dependent periodf erythropoiesis and the later iron-dependenteriod. Inflammatory cytokines inhibit erythro-oietin production, directly impair growth ofarly erythroblasts, and—especially in the ab-ence of erythropoietin—promote death by li-and-mediated destruction of immature erythro-lasts.14 In addition, inflammatory cytokinestimulate hepatic release of hepcidin, which si-ultaneously blocks iron absorption in the gut

Fig 1. Kidney failure in the United States. Preva-ence estimates of kidney failure treated by dialysisnd transplantation (end-stage renal disease [ESRD])n the United States. Prevalence refers to the num-er of patients alive on December 31st of the year.pper and lower estimates reflect the effect of poten-

ial changes in ESRD incidence, diabetes preva-ence, ESRD death rate, and underlying age and racetructure of the US population after the year 2000.eprinted with permission.10

nd iron release from resident macrophages, f

rompting a decrease in transferrin saturationTSAT) and thereby promoting iron-deficiencyrythropoiesis.15 Thus, the anemia of inflamma-ion characteristically is hypoproliferative andot infrequently includes features suggesting iron-eficiency erythropoiesis.This synopsis provides an introduction to

he subject and purpose of the following CPGsor patients with both anemia and CKD. Guide-ine 1.1 describes identification of the patientith anemia and CKD. Guideline 1.2 describes

he recommended initial evaluation; Guideline.1, the goal of treatment; and Guidelines 3.1,.2, and 3.3, the use of therapeutic agents.

SCOPE OF THE GUIDELINESNew findings, new agents, and the need for

n expanded scope prompt the need for aomprehensive revision of existing NKF-DOQI CPGs for the Treatment of Anemia inKD. In preparing the current guidelines, thenemia Work Group members broadened our

nquiry to include all stages of CKD, identifyreas of concern to current practitioners, adoptstructured intensive evidence review processot previously used, apply that process to bothewly available literature and literature exam-ned in the development of previous guidelineersions, formulate conclusions that distin-uish evidence-based guidelines from expert-pinion–based clinical practice recommenda-ions (CPRs), and present both guidelines andecommendations in a new format to morelearly describe what is not known. To ensurehat the next update profits from evidence weurrently lack, we identified limitations of cur-ently available evidence and, in a subsequenteport, will identify priorities for needed re-earch.

ntended Reader

Our intended reader is the practitioner whoanages patients with CKD, including neph-

ologists, primary-care providers, cardiolo-ists, nurse practitioners, nurses, and dieti-ians. Clinical pharmacists, quality outcomesirectors, and clinical investigators will findhe document useful. We write primarily forractitioners in North America. Nevertheless,rom the onset, we have coordinated our ef-
orts with guideline development processes

esEmGgK(

S

wo(fetfumotpiwrdlbs

ER

medeetCtpoetaWDCK

mo“rtppctTdbtobtbglabgoa

beCwwfiHeRt[wbicL

fai

R

EXECUTIVE SUMMARY S13

lsewhere, ensured that Work Group member-hip includes experts from Latin America andurope, and planned so that this documentay serve as the last of the KDOQI Anemiauidelines and a foundation for the first trulylobal guideline under the auspices of theidney Disease: Improving Global Outcomes

KDIGO) initiative (www.kdigo.org).

cope

We address the target population of patientsith CKD stages 1 to 5 not on dialysis therapy,n hemodialysis (HD) or peritoneal dialysisPD) therapy, or with a kidney transplant in theull range of practice settings in which they arencountered. However, the evidence continueso derive disproportionately from findings inacility-based HD patients. We have not beennmindful of cost implications. However, netedical benefit to the patient is the foundation

f each of our guidelines and recommenda-ions. Our commitment, in short, is to assistractitioners in the care of patients by describ-ng best practice and the evidence for it. In thisay, individual practitioners who face local

eimbursement constraints may make informedecisions armed with appropriate facts. Simi-arly armed, those responsible for guiding reim-ursement policy may make informed deci-ions consistent with the evidence.

vidence, Opinion, Guidelines, andecommendations

When the quality of evidence is high oroderately high, we present a CPG based on

vidence, rate the quality of that evidence, andistinguish the evidence-based guideline bynclosing it in a text box. When the quality ofvidence is low, very low, or missing, but theopic is important to practitioners, we offer aPR and cite limitations to the current litera-

ure. In a subsequent document, we will pro-ose and prioritize needed research. Through-ut this document, a text box surrounds eachvidence-based guideline, and the strength ofhe guideline is rated as “strong” or “moder-tely strong.” The phrase, “In the opinion ofork Group members” precedes each CPR.istinguishing evidence-based guidelines fromPRs is in keeping with recent advances in
DOQI policy and practice. f
The overall strength of each guideline state-ent was rated by assignment as either strongr moderately strong. A strong rating indicatesit is strongly recommended that cliniciansoutinely follow the guideline for eligible pa-ients. There is high-quality evidence that theractice results in net medical benefit to theatient.” The moderately strong rating indi-ates “it is recommended that clinicians rou-inely follow the guideline for eligible patients.here is at least moderately high-quality evi-ence that the practice results in net medicalenefit to the patient.” Overall, the strength ofhe guidelines and recommendations was basedn the extent to which the Work Group coulde confident that adherence will do more goodhan harm. Strong guidelines require supporty evidence of high quality. Moderately stronguidelines require support by evidence of ateast moderately high quality. Incorporation ofdditional considerations modified the linkageetween quality of evidence and strength ofuidelines, usually resulting in a lower strengthf the recommendation than would be support-ble based on the quality of evidence alone.Our objective is to describe the evidence

ase for key elements in the identification,valuation, and management of patients withKD-associated anemia. For topics on whiche undertook a systematic literature review,e present detailed information, usually in the

orm of summary evidence tables. These topicsnclude Hb thresholds for initiating therapy,b level therapeutic goals, iron status goals, or

fficacy of adjuvants in achieving Hb goals.esults that bear directly on patient lives (mor-

ality, morbidity, QOL, and adverse eventsAEs]) receive particular attention. Topics forhich the evidence base is limited deserverief mention and receive it. Information thatnvolves implementation, application, or proto-ol development, we leave to the NKF Kidneyearning System (KLS) resources.When the quality of evidence is low, we will

ollow acknowledgement of these limitations inseparate publication by encouraging further

nvestigation.

elationship to Previous Guidelines

The lineage of the current document derives
rom both the most recent (2001) version of the

KrtO

la1

EXECUTIVE SUMMARYS14

DOQI Guidelines for Anemia2 and the mostecent (2004) version of the European Best Prac-ices Guidelines (EBPGs) for anemia (Fig 2).16

Fig 2. Relationship between cu

ur intention is to simplify the current guide- m

ines into sections on identification, definition,nd evaluation of anemia (Guideline 1.1 and.2); Hb treatment target (Guideline 2.1); and

and previous anemia guidelines.
rrent
anagement (Guidelines 3.1-4.1), with parallel

otT

teoad

iraH

I

abim

dl

cfiigs

EXECUTIVE SUMMARY S15

rganization for pediatrics. Key differences be-ween current and past guidelines are set out inable 1.

OPERATING DEFINITIONS

Erythropoiesis-stimulating agent (ESA): Theerm ESA applies to all agents that augmentrythropoiesis through direct or indirect actionn the erythropoietin receptor. Currently avail-ble ESAs include epoetin alfa, epoetin beta, andarbepoetin alfa.Therapeutic goal: A therapeutic goal is the

ntended goal of current therapy, not the cur-ent result of previous therapy. This definitionpplies equally to therapeutic goals for both

Table 1. Key Differences between Current Guidelin(KDOQI 200

Topic KDOQI 2000 Anemia

Guideline EBPG 2004 Anaemia

Guideline Definition of Anemia by Hb <12.0 g/dL in males and

postmenopausal females <11.0 g/dL in premenopausal

females and prepubertal patients

<12.0 g/dL males <11.0 g/dL females

tegrat Ld/g 0.11> Ld/g 21-11 bH tegraT>12.0 in CVD not

recommended Hb >14.0 g/dL not desirab

Target Iron Status TSAT (%) lower limit: 20 upper limit: 50

Ferritin (ng/mL) lower limit: 100

TSAT (%) lower limit: 20 target: 30-50

Ferritin (ng/mL) lower limit: 100 target: 200-500

Adjuvants L-Carnitine Not recommended Not recommended for

general use etabrocsA

esu evitceleS snegordnA

b and iron. v

ndicators of Efficacy

Efficacy of anemia management: Efficacy ofnemia management is indicated in a single patienty an Hb level greater than the target threshold, andn a group of patients, by the percentage of patientsaintained at greater than target threshold.ESA efficacy: ESA efficacy is indicated by the

ose of ESA needed to achieve or maintain Hbevels at greater than the target threshold.

Adjuvant efficacy: Adjuvant efficacy is indi-ated by the percentage of patients who success-ully exceed the target Hb threshold or achieve anncrease in Hb level greater than 1 g/dL withoutnitiating ESA therapy or increasing ESA doses toreater than baseline. Among patients with steady-tate Hb levels greater than target threshold, adju-

QI Anemia 2006) and Previous Anemia Guidelines BPG 2004)

OQI 2006 Anemia Guideline Reason KDOQI 2006 Differs from Prior Guidelines

13.5 g/dL males 12.0 g/dL females

KDOQI 2006 uses more recent NHANES data set, defines anemia as any Hb below the 5th percentile for the adult, gender-specific population. Among males, no adjustment is made for age >70 years, to exclude the possibility that pathological conditions

contribute to lower Hb values. Among females, the 5th percentile determination is made only among individuals without evidence of iron deficiency, as defined by TSAT <16% or ferritin <25 ng/mL.

g/dL, caution when ntionally maintaining

Hb >13 g/dL

Current guideline reflects QOL benefits at Hb maintained ≥11.0 g/dL, risks when intentionally maintaining Hb >13.0, and recognition that Hb will often exceed 13 g/dL unintentionally, without evidence

of increased risk, in patients with Hb intent to treat ≥11.0 g/dL. TSAT (%)

lower limit ≥20

Ferritin (ng/mL) r limit: 200 HD-CKD 00 non-HD-CKD 500 not routinely recommended

TSAT:Current guideline reflects unchanged lower bound for iron therapy;

upper limit of TSAT not specified.

Ferritin:Current guideline distinguishes HD- from non–HD-CKD on basis of available evidence. Lower limit sets objective of iron therapy. There is insufficient evidence to assess harm and benefit in maintaining ferritin > 500 ng/mL . In HD-CKD, 200 ng/mL reflects evidence for

substantial efficacy of IV iron at ferritin <200 ng/mL.

Not routinely recommended

Current guideline based on low-quality evidence which shows lack of efficacy

ylenituor toNrecommended

Current guideline reflects combination of safety concerns and low quality evidence of efficacy

rof ecnedivE .snrecnoc ytefas suoires stcelfer enilediug tnerruC dednemmocer toefficacy is low quality,.

es (KDO0 and E

KD

<<

le

≥11inte

lowe1>

N

ant efficacy is indicated by ESA dose reduction.

II. CLINICAL PRACTICE GUIDELINES AND CLINICALPRACTICE RECOMMENDATIONS FOR ANEMIA IN

CHRONIC KIDNEY DISEASE IN ADULTS

Itc

astwcta(tlg

S

wii4Cgki

A

CPR 1.1. IDENTIFYING PATIENTS AND
INITIATING EVALUATION
df

ssfCcad

sCtrict(mscc

asdebc(tHi

eHsallbgt1ib

dentifying anemia is the first step in evaluatinghe prognostic, diagnostic, and therapeutic signifi-ance of anemia in the patient with CKD.

1.1.1 Stage and cause of CKD:In the opinion of the Work Group, Hbtesting should be carried out in allpatients with CKD, regardless of stageor cause.

1.1.2 Frequency of testing for anemia:In the opinion of the Work Group, Hblevels should be measured at leastannually.

1.1.3 Diagnosis of anemia:In the opinion of the Work Group,diagnosis of anemia should be madeand further evaluation should be un-dertaken at the following Hb concen-trations:● <13.5 g/dL in adult males.● <12.0 g/dL in adult females.

BACKGROUNDAnemia develops early in the course of CKD

nd is nearly universal in patients with CKDtage 5.17 The purpose of specifying Hb levelhresholds to define anemia is to identify patientsho are most likely to show pathological pro-

esses contributing to a low Hb level and whoherefore are most likely to benefit from furthernemia evaluation. Thus, the current guidelineGuideline 1.1) identifies Hb level thresholdshat should trigger diagnostic evaluation (Guide-ine 1.2). Conversely, Hb levels that should trig-er ESA therapy are defined in Guideline 2.1.

RATIONALE

tage and Cause of CKD

Hb testing should be carried out in all patientsith CKD, regardless of stage or cause. Anemia

s associated with CKD of any cause,18-22 includ-ng transplant-associated CKD (see Guideline.1). The severity of anemia in patients withKD is related to both the degree of loss oflomerular filtration rate (GFR) and the cause ofidney disease. The lowest Hb levels are found
n anephric patients and those who commence e

ialysis therapy at very low levels of kidneyunction.23,24

The reported prevalence of anemia by CKDtage depends in large part on the size of thetudy; whether study participants are selectedrom the general population, are at high risk forKD, or are patients already under a physician’sare; what level of Hb is defined as constitutingnemia; and whether patients do or do not haveiabetes.Studies reviewed for the purposes of guideline

tatement 1.1.1 include those of patients withKD before dialysis therapy, those with kidney

ransplants, and those on dialysis therapy. Theeviewed literature spans close to 40 years ofnvestigation up to the year 2000 and describeslinical findings of researchers as they explorehe relationships between Hb level or hematocritHct) and kidney function (Table 2 and 3). Theajority of available data were derived from

tudies of small sample size, most of which areross-sectional studies, or baseline data fromlinical trials of variable size and robustness.

In 12 of the 21 studies reviewed, there was anssociation between level of Hb or Hct and theelected measure of kidney function. They alsoemonstrate variability in levels of Hb or Hct atach level of kidney function, whether assessedy using serum creatinine (SCr) concentration,reatinine clearance (CCr), or estimated GFReGFR). However, the consistency of the informa-ion they provide indicates a trend toward lowerb levels at lower levels of GFR and variability

n Hb levels across GFR levels.More recent studies used large databases to

xamine the relationship between Hb level orct and kidney function (Table 4). A cross-

ectional analysis examined 12,055 ambulatorydult patients (�18 years of age) who had ateast 2 SCr measurements 2 years apart and ateast 1 Hct measurement and weight recordedetween 1990 and 1998.25 Results should pro-ressively lower Hct at an estimated CCr lesshan 60 mL/min/1.73 m2 in men and 40 mL/min/.73 m2 in women (Table 5). When GFR normal-zed to body surface area (BSA) was estimatedy using the Modification of Diet in Renal Dis-
ase (MDRD) equation, both men and women
), 2006: pp S17-S27 S17

dHmannaGbh(i

tutdviUNtA

aaaifittila3s

ocIimmor1

ANEMIA IN CHRONIC KIDNEY DISEASE IN ADULTSS18

eveloped a statistically significant decrease inct at the same BSA-normalized GFR, 50 mL/in/1.73 m2. This relationship persisted when

nalyses were restricted to patients who wereormochromic and normocytic, ie, presumablyon–iron deficient. However, the change in age-nd race-adjusted Hct with decreasing levels ofFR was greater in men than women. It shoulde noted that only 10% of men and 6% of womenad an eGFR of 50 mL/min/1.73 m2 or lessMDRD formula), and the indications for measur-ng SCr and Hct were unknown.

Two studies examined the relationship be-ween prevalent Hb concentration and GFR bysing results from the National Health and Nutri-ion and Examination Survey (NHANES) IIIatabase. NHANES III is a cross-sectional sur-ey of nutritional and health status in 15,419ndividuals randomly selected from the generalS population from 1988 to 1994. Results fromHANES III26,27 are consistent with those ob-

ained in ambulatory adult patients (Table 6).25

t an eGFR less than 75 mL/min/1.73 m2 in men c

nd 45 mL/min/1.73 m2 in women, the associ-ted Hb level is lower than that seen at eGFRsbove those thresholds (Fig 3). The relationships observed best in the distribution of the lowestfth percentile of Hb levels. In general, the lower

he eGFR at less than the respective threshold,he lower the associated Hb level, but confidencentervals (CIs) are broad at the lowest eGFRevels because the number of observed individu-ls with a low eGFR is small. For example, only.5% of women and 1.4% of men in the surveyhowed an eGFR of 30 mL/min/1.73 m2 or less.

The relationship between GFR and prevalencef anemia is determined in large part by the Hboncentration used to define anemia. In NHANESII, prevalence of a Hb level less than 13 g/dLncreases at less than a threshold eGFR of 60L/min/1.73 m2 in males and 45 mL/min/1.732 in females (Fig 4). However, the prevalence

f a Hb level less than 11 g/dL is not greater thaneference except at an eGFR less than 30 mL/min/.73 m2 in both males and females. Again, pre-
ise estimates of prevalence are limited by rela-

tG

meCNasdc1

mvlp2pee34

s1pHdtgpv

3tdsdaGw8tSp

ANEMIA IN CHRONIC KIDNEY DISEASE IN ADULTS S19

ively small numbers; in particular, less than aFR of 30 mL/min/1.73 m2 (N � 52).The relationship between prevalence of ane-ia and GFR may be changing as a result of

arlier identification and treatment of anemia.omparing results of NHANES III withHANES IV shows a lower prevalence of

nemia for each CKD stage in the more recenturvey (Fig 5).28 In this analysis, anemia wasefined by World Health Organization (WHO)riteria (Hb level � 12 g/dL in women and �3 g/dL in men).The prevalence of anemia among patients isuch greater than that observed among indi-

iduals randomly surveyed in the general popu-ation. In a cross-sectional study of 5,222 adultatients with CKD who were selected from37 US physician practices (including familyractice, internal medicine, nephrology, andndocrinology), mean Hb levels for an MDRDGFR of 60 or greater (CKD stages 1 and 2),0 to 59 (CKD stage 3), 15 to 29 (CKD stage
), and less than 15 mL/min/1.73 m2 (CKD 3
tage 5) were 12.8 � 1.5, 12.4 � 1.6, 12.0 �.6, and 10.9 � 1.6 g/dL, respectively.29 Therevalence of untreated anemia (defined as ab level � 12, 10 to 12, and � 10 g/dL) forifferent CKD stages (Fig 6) is much greaterhan that reported in NHANES surveys.26,27 Areater disease burden among patients com-ared with randomly selected individuals pro-ides a likely explanation for these findings.Because data points at GFR levels less than

0 mL/min/1.73 m2 were scarce in all excepthe previous cross-sectional study,29 the Cana-ian Multicentre Study30 was used to demon-trate trends in a large cohort of patients beforeialysis therapy (Fig 7). The prevalence ofnemia was greatest at the lowest levels ofFR, but approached 20% among patientsith a GFR of 30 to 44 mL/min/1.73 m2 (Fig). Similarly, in another study of 131,848 pa-ients who began dialysis therapy in the Unitedtates between 1995 and 1997, proportions ofatients with Hcts less than 30% and less than
6% immediately before the initiation of dialy-

st

dspaapp

edwwPma1gb


is therapy were 67.5% and 93%, respec-ively.31

Patients with diabetes are more prone to bothevelop anemia and develop anemia at earliertages of CKD than their nondiabetic counter-arts (Fig 9).32-37 In a cross-sectional clinicaludit of 820 Australian patients with diabetes,nemia was 2 to 3 times more prevalent inatients with diabetes compared with the generalopulation at all levels of GFR (Fig 9). In an

Table 4. Prevalence of Ane

Author, Year N Definition of Anemia Hb (g/dL)

Applicability Le

El-Achkar, 2005 37 5,380 Men & Women >50 yr, Hb <12; Women

≤50 yr, Hb <11

Hsu, 2002 26 15,971 Men Hb 10-12

Women Hb10-12

Astor, 2002 27 15,419 Men Hb <12 b

Women Hb <11

GHsu, 2001 25 8,220 Hb <11

63

McClellan, 2004 29 5,222 Hb <12

Fehr, 2004 85 4,760 Hb <11

Footnotes:a. Data given for age 61-70 and Hb <12 g/dL. b. To focus on clinically significant and potentially treatable anemia, a more stringent definition (Hb <12 for

men and Hb <12 for women) the overall prevalence for men was 3.5% vs. women 10.7%. c. All prevalence rates adjusted for age = 60. This corresponds to approximately 160,000 (SE 44,000) nond. At any given level of CrCl, men had steeper slope of decrease in Hb, as did blacks> Mexican >whites, olde. No statistical pooling between categories of creatinine clearance stages.

Coding of Outcome: statistically significant increase in anemia with decreasing kidney function.

xtension of the same audit, patients with type 2iabetes with a CCr of 60 to 90 mL/min/1.73 m2

ere twice as likely to have anemia than thoseith a CCr greater than 90 mL/min/1.73 m2.atients with diabetes with a CCr less than 60L/min/1.73 m2 were twice as likely to have

nemia as those with a CCr of 60 to 90 mL/min/.73 m2.36 In the Kidney Early Evaluation Pro-ram (KEEP 2.0), a cross-sectional community-ased screening program aimed at detecting CKD

Level of Kidney Function

y Prevalence of Anemia Results Quality

Diabetic Nondiabetic 8.7% 6.9% 7.5% 7%

22.2% 7.9% 52.4% 50%

(Likelihood [%] of Hb level <12 g/dL) a

Men Women 3% 7% 4% 10% 12% 25%

%8.1 %3.1 %2.5

%1.44 c

Men Women 9% (7/77) 5% (18/333) 10% (3/29) 10% (12/116) 0% (0/17) 33% (9/27)

60% (12/20) 52% (11/21)

d

%7.62 41.6% 53.6%

%5.57<1%

%2< %3~ %51~ %83~

1 for women) was used for most analyses. However, in analysis using the WHO definition (Hb <13 for

ed civilians in the US in 1991. er men, and younger vs. older women.

mia by

vel of KidneFunction

GFR ≥89

GFR 60-89 GFR 30-59 GFR <30

CrCl >80 CrCl 41-50 CrCl 21-30 GFR ≥ 09

98-06 RFG 95-03 RFG 92-51 RFG

FR >41-50

GFR 31-40 GFR 20-30 GFR ≤20 GFR ≥ 06

0> GFR ≥300> GFR ≥15

51< RFGCrCl >90 e

CrCl 98-06CrCl 95-04 CrCl 93-02 CrCl 02<

men, Hb <1

institutionalizer vs. young

ahee58[25

fm

2sucbadw(ial

asdp9aaA


mong high-risk patients (those with diabetes,ypertension, or a family history of kidney dis-ase), the prevalence of anemia at each level ofGFR from patients with CKD stages 2 throughwas greater than in patients without diabetes:

.7% versus 6.9% in stage 2 (P � not significantNS]), 7.5% versus 5.0% in stage 3 (P � 0.015),2.2% versus 7.9% in stage 4 (P � 0.001), and2.4% versus 50% in stage 5 (P � 0.88).37

The following conclusions can be drawnrom these studies: (1) the prevalence of ane-ia at higher levels of GFR (CKD stages 1 and

Fig 3. Relationship between Hb levelnd eGFR. Data represent a cross-ectional survey of individuals ran-omly selected from the general USopulation (NHANES III). Median and5% confidence limits around the 95th

nd 5th percentiles are shown for malesnd females at each eGFR interval.dapted with permission.27

) is relatively low in individuals randomlyelected from the general population, but is notncommon in patients with CKD under theare of a physician or identified by virtue ofeing at high risk for CKD; (2) among individu-ls from a general population, mean Hb levelsecrease and anemia develops consistently onlyhen GFR is less than 60 mL/min/1.73 m2

stage 3 CKD); (3) the prevalence of anemiancreases at later stages of CKD (CKD stages 4nd 5); (4) there is significant variability in Hbevels at any given level of kidney function;

Fig 4. Relationship betweeneGFR and prevalence of anemia asdefined by differing Hb levels for(A) males and (B) females. Data
from NHANES III. Reprinted withpermission.27

acml

mr

F

ahimCactCtlt1

scErrtpsavtdptt

D

fcar

dlCN

cfsos


nd (5) anemia among patients with diabetesompared with patients without diabetes isore prevalent, more severe, and occurs ear-

ier in the course of CKD.These observations underscore the need toeasure Hb levels in every patient with CKD,

egardless of stage or cause.

requency of Hb Testing in Patients With CKD

Hb levels should be measured at least annu-lly. Because little is known about the naturalistory of anemia in patients with CKD, precisenformation is unavailable to determine the opti-um frequency of Hb testing in patients withKD. The recommendation that patients be evalu-ted at least annually rests on observations fromlinical trials that (in the absence of ESA therapy)he natural history of anemia in patients withKD is a gradual decline in Hb levels over

ime.38,39 In 1 trial,39 patients assigned to theower Hb target (9.5 to 10.5 g/dL) entered therial with Hb values greater than target (mean,1.8 g/dL) and received ESA only if Hb levels

Fig 5. Prevalence of anemia by CKD stage. Anemia,efined as an Hb level less than 13.0 g/dL in males and

ess than 12.0 g/dL in females, was plotted by stage ofKD in results from NHANES III compared withHANES IV. USRDS 2004.28

ubsequently decreased. During 2 years, a signifi-ant proportion of patients eventually requiredSA therapy. However, among those who did not

equire ESA therapy, mean Hb values remainedelatively stable (Fig 10). This evidence suggestshe need for regular surveillance of Hb levels inatients with CKD without ESA therapy. Thetatement Hb levels should be measured at leastnnually emphasizes that more frequent Hb sur-eillance likely will be needed for selected pa-ients, including those with greater disease bur-en, unstable clinical course, or evidence ofrevious Hb level decline. Frequency of Hbesting in patients already undergoing ESAherapy is addressed in Guideline 3.1.1.

iagnosis of Anemia

Diagnosis of anemia should be made andurther evaluation should be undertaken at Hboncentrations less than 13.5 g/dL in adult malesnd less than 12.0 g/dL in adult females. Theecommended thresholds for defining anemia

Fig 6. Relationship betweenlevel of renal function, reflected bySCr level or GFR, and prevalenceof anemia, defined at different Hbcutoff levels, among patients un-

Fig 7. Hb percentiles by GFR in the Canadian Multi-entre Longitudinal Cohort Study. Patients were re-erred to nephrologists between 1994 and 1997. Re-ults shown exclude patients receiving ESA therapyr with an arteriovenous fistula. Reprinted with permis-ion.4,30

der the care of physicians. Re-printed with permission.29

rt(atgaamfito

rmccmmtead

faawofgotldfwma

GS

lbpcceIr<s


epresent the mean Hb of the lowest fifth percen-ile of the sex-specific general adult populationTable 7 and 8; Fig 11).

40,41

The conclusion thatnemia therefore is defined as a Hb level lesshan 13.5 g/dL in adult males and less than 12/dL in adult females (Fig 3) assumes a lack ofdjustment downward for age in males and andjustment upward for iron deficiency in fe-ales. Although mean Hb level representing thefth percentile decreases among males older

han 60 years, it is clear that a substantial fractionf older males with low Hb levels show concur-

Fig 8. Prevalence of low Hb level by category ofFR in the Canadian Multicentre Longitudinal Cohorttudy. Reprinted with permission.4,30

Fig 9. Prevalence of low Hbevel by eGFR in patients with dia-etes compared with the generalopulation. Open circles (Œ) indi-ate the diabetic population, whilelosed circles (�) represent gen-ral population data from NHANESII. A: Hb <11 g/dL; B: WHO crite-ia (men, Hb <13 g/dL; women, Hb12 g/dL). Reprinted with permis-ion.35

ent evidence of pathological conditions thatay cause or contribute to anemia.32 Because we

annot exclude potential pathological states, weannot assume that lower Hb levels in olderales are normal. Therefore, we make no adjust-ent for age among males. The recommended

hreshold of less than 12.0 g/dL in females reflectsxclusion from the healthy population of individu-ls whose iron status test results suggest that ironeficiency is contributing to a low Hb level.The recommended definition of anemia dif-

ers from previous CPGs. The WHO definesnemia as a Hb level less than 13.0 g/dL indult men and less than 12 g/dL in adultomen.42 Differences between the current rec-mmendation and the WHO definition ariserom differences in the data source for theeneral population: the WHO definition is basedn sparse data obtained prior to 1968, whereashe definition proposed in the current guide-ines is based on more recent NHANES IIIata. The recently published Revised EBPGor the Management of Anaemia in Patientsith Chronic Renal Failure also defines ane-ia as a Hb level less than 13 g/dL in men, but

djust this to less than 12 g/dL for men older

Fig 10. Changes in Hb levels and eGFRover 2 years in adult patients with CKDstages 3 and 4 not treated with ESA. Oraliron supplements and occasional IV irontreatment were administered to maintainTSAT at greater than 20% and ferritin levelsgreater than 100 ng/mL. Data given as mean� SD. Although mean Hb levels showedlittle or no change, the number of studypatients remaining without ESA therapy de-clined. Results courtesy of the authors, fromcontrol group patients previously described.
Reprinted with permission.39

tadwpmufs

cp

aHgso


han 70 years. Because the EBPGs do notdjust for the potential contribution of ironeficiency in women, the EBPG threshold foromen is less than 11.5 g/dL.16 Finally, therevious KDOQI Anemia Guidelines recom-ended less than 12 g/dL for men (reflecting

se of a different data set), less than 11 g/dLor women of reproductive age (different data
et, no attempt to exclude effect of iron defi- a
iency), and less than 12 g/dL for postmeno-ausal women (no change).The importance of identifying patients with

nemia in the presence of CKD is 2-fold. First, ab value in the lowest fifth percentile of theeneral population may signify the presence ofignificant nutritional deficits, systemic illness,r other disorders that warrant attention. Second,
nemia in patients with CKD is a known risk

fonltboet

u

Hbdpet

nc0


actor for a number of significant adverse patientutcomes, including hospitalizations, CVD, cog-itive impairment, and mortality.16,43-50 Regard-ess of whether concurrent disorders, if any, arereatable, awareness of their presence is likely toe helpful to the clinician. Similarly, the benefitsf anemia treatment (see Guideline 2.1) cannotxtend to patients whose anemia remains uniden-ified.

Altitude, age, race, and smoking each contrib-
te to the interpretation of the normal range of 1
b values, in addition to sex, and therefore muste considered in patients with CKD. The currentefinition for anemia reflects results from adultatients older than 18 years, of all races andthnic groups, and living at relatively low alti-ude (�1,000 m or 3,000 ft).

Altitude has a direct impact on red blood cellumber, mass, and volume.51 Generally, Hb con-entration can be expected to increase by about.6 g/dL in women and 0.9 g/dL in men for each
,000 m of altitude above sea level.52 This in-

cpTtu(

afi(aHsianradnaaCnboa

wc

leAtiaogaimattotwgisd

rt


rease in Hb levels seems to be caused at least inart by increased erythropoietin production.53

he threshold Hb level defining anemia in pa-ients living at high altitude should be adjustedpward, in keeping with the degree of elevationTable 9).

In children, mean Hb level and the variabilityround the mean vary highly with age. Thesendings are discussed elsewhere in more detailin CPR for Children 1.1). Among adult males,s previously noted, the lower fifth percentile ofb values declines as age advances (Fig 11). One

tudy reported a mean decrease of 1 to 1.5 g/dLn Hb concentration in males as they increased inge from 50 to 75 years; however, this trend wasot seen in women, in whom Hb concentrationemained stable between 20 and 80 years ofge.54 Although it previously was believed thatecreases in Hb levels might be a consequence oformal aging, evidence has accumulated thatnemia reflects poor health and increased vulner-bility to adverse outcomes in older persons.32

onsequently, the current recommendation makeso adjustment for aging in men. An associationetween an increasing prevalence of anemia andlder age has been reported in most,27,55 but notll,29 studies of patients with CKD, in keeping

Table 9. Normal Increase in Hb Levels

Altitude (meters) 000,1<

000,1 005,1 000,2 005,2 000,3 005,3 000,4 005,4


ith current opinion that anemia is not a normalonsequence of aging.56

Among women of reproductive age, menstrualosses, the potential for iron deficiency, and theffect of pregnancy each deserve consideration.lthough Hb values in women are lower than

hose in men (Table 7 and 8), Hb concentrationsn iron-replete women remain stable between 20nd 80 years of age.54 Regardless of the presencer absence of CKD, the prevalence of anemia isreater in women compared with men.55 Mensesnd pregnancy may each contribute to this find-ng. Menstrual losses of iron average 0.3 to 0.5g/d and may result in mostly iron-deficiency

nemia.42 Among pregnant women, Hb concen-ration decreases during the first and secondrimesters largely because of the dilutional effectf expanding blood volume. In the third trimes-er, Hb concentration remains low in pregnantomen who do not take iron supplements, butradually increases toward prepregnancy levelsn those who take iron supplements.57-59 Table 10hows maximum Hb cutoff values for anemiauring pregnancy.Hb values also vary significantly between

aces, with African-American individuals consis-ently showing Hb concentrations 0.5- to 0.9-

Fig 11. Distribution of Hb levels in adultmales and females by age group. The 5th,50th, and 95th percentiles are shown foreach age group. In females, results reflectonly individuals with serum ferritin greaterthan 25 ng/mL or TSAT greater than 16%because lower values may contribute tolow Hb levels. Dash-dot-dash lines indi-cate recommended cutoff value to defineanemia. (Source: US Renal Data System[USRDS] special data request, NHANES1999-2002 data set).

ted to Long-Term Altitude Exposure

crease in Hb (g/dL) 0

2.0+ 5.0+ 8.0+ 3.1+ 9.1+ 7.2+ 5.3+ 5.4+

Rela

In

gpiddcvawca

cacmtoaCasm

b

1

2

3

4

5

6

mentation


/dL lower than those of Caucasoid or Orientalopulations.60-62 Because the reason for this dispar-ty in Hb level distributions by race has not beenetermined and could reflect increased disease bur-en, this guideline does not provide race-specificutoff values for anemia.41,63,64 Anemia may de-elop at an earlier stage in the course of CKDmong non-Hispanic African Americans comparedith individuals of other races.27 African-Ameri-an patients have a greater prevalence of anemiat every stage of CKD compared with whites.55

Last, smoking is associated with elevatedarboxyhemoglobin levels, which are associ-ted with a compensatory increase in total Hboncentration.65 If the same definition of ane-ia is applied to both smokers and nonsmokers,

he risk for developing anemia is lower in currentr past smokers than nonsmokers.55 Becausepproximately 20% to 40% of patients withKD are current or past smokers,55 consider-tion should be given to the significance of amoking history in interpreting results of Hbeasurement (Table 11).

Table 10. Maximum Hb Cutof

Weeks’ Gestation 21 61 02 42 82 23 63 04

retsemirT tsriF

dnoceS drihT

Maximum cutoff values for anemithird National Health and Nutritionexcluded persons who had a highvalues for anemia during pregnanwomen who had adequate suppleReprinted with permission.41

Table 11. Adjustment to Hb for Sm

puorG srekomsnoN )lla( srekomS

0.5-1 packet/day 1-2 packets/day >2 packets/day
LIMITATIONS

Many studies that examined the relationshipetween Hb level and kidney function:

. Have been cross-sectional and not longitu-dinal in design.

. Described patients entered into clinical trialsor seen by nephrologists, which are not a trulyrepresentative sample of patients with CKD.

. Included small numbers of patients withlower levels of kidney function.

. Used a great variety of methods to assesslevel of kidney function. It therefore isdifficult to determine whether the variabil-ity in Hb at levels of kidney function iscaused by variability in measurements ofkidney function or variability associatedwith CKD itself.

. Used the MDRD4 formula to estimateGFR, the precision of which decreases athigher levels of kidney function.

. Did not describe the cause of the anemia inpatients with CKD.

s for Anemia in Pregnancy

oncentration (g/dL) 0.11 6.01 5.01 5.01 7.01 0.11 4.11 9.11

0.11 5.01 0.11

d on the 5th percentile from the tion Survey (NHANES III), which of iron deficiency. Maximum

sed on values from pregnant .

by Number of Packets per Day

)Ld/g( bH 0

3.0++0.3 +0.5 +0.7

f Value

Hb C

a are base Examina likelihoodcy are ba

oking

cltt

mouctaaiecddt(cmTsor

S

CPR 1.2.: EVALUATION OF ANEMIA IN CKD

I

ifb

iiHdmsrtl

hcbfrressptrr

io

Hvcbma

td

mldP

Anemia in patients with CKD is not alwaysaused by erythropoietin deficiency alone. Initialaboratory evaluation therefore is aimed at iden-ifying other factors that may cause or contributeo anemia or lead to ESA hyporesponsiveness.

1.2.1 In the opinion of the Work Group,initial assessment of anemia shouldinclude the following tests:1.2.1.1 Acomplete blood count (CBC)

including—in addition to theHb concentration—red bloodcell indices (mean corpuscu-lar hemoglobin [MCH], meancorpuscular volume [MCV],mean corpuscular hemoglo-bin concentration [MCHC]),white blood cell count, anddifferential and platelet count.

1.2.1.2 Absolute reticulocyte count.1.2.1.3 Serum ferritin to assess iron

stores.1.2.1.4 Serum TSAT or content of Hb

in reticulocytes (CHr) to as-sess adequacy of iron forerythropoiesis.

BACKGROUND

Although erythropoietin deficiency is com-on among patients with anemia and CKD,

ther potential causes and potentially contrib-ting disorders should be identified or ex-luded. The recommended laboratory evalua-ion provides information regarding the degreend cause of anemia, activity of the erythroidnd nonerythroid marrow, and assessment ofron stores and iron availability for erythropoi-sis. In particular, clinicians should considerauses of anemia other than erythropoietineficiency when: (1) severity of the anemia isisproportionate to the deficit in renal func-ion; (2) there is evidence of iron deficiency, or3) there is evidence of leukopenia or thrombo-ytopenia. An evaluation of the cause of ane-ia should precede initiation of ESA therapy.his guideline provides a framework for under-tanding the tests used in the initial evaluationf anemia and sheds light on the utility of test
esults in evaluating iron status. t
American Journal of Kidney28

RATIONALE

nitial Assessment of Anemia

The CBC provides information about the sever-ty of anemia, adequacy of nutrients (includingolate, vitamin B12, and iron), and adequacy ofone marrow function.Severity of anemia is assessed best by measur-

ng Hb concentration rather than Hct because Hbs a stable analyte that is measured directly. Theb assay is standardized and is not influenced byifferences in instrumentation. Conversely, Hcteasurement is relatively unstable and lacks

tandardization. The Hct result is derived indi-ectly by automated analyzers and is instrumen-ation dependent.16 Analytical advantages of Hbevel over Hct are described next.2

Although blood-sample storage conditionsave no effect on Hb measurement, Hct in-reases with storage temperature and durationecause stored red blood cells swell. The MCVrom which the Hct is calculated (MCV � eryth-ocyte count) increases after 8 hours of storage atoom temperature and after 24 hours when refrig-rated.86 The degree of MCV increase afterample storage may erroneously elevate the re-ulting Hct value by as much as 2 to 4 Hctercentage points.87 Long sample shipping dis-ances and sample transit times, as commonlyequired for US dialysis facilities, increase theisk for introducing error into Hct results.

Hyperglycemia is associated with an increasen MCV (but not Hb level) and therefore spuri-usly elevates the Hct result.88,89

The coefficient of variation for same-samplect is greater than that for Hb, largely because ofariability in the number and size of erythrocytesounted to calculate the Hct.90 Within-run andetween-run coefficients of variation in auto-ated analyzer measurements of Hb are one half

nd one third those for Hct, respectively.91

For these reasons, Hct is an unacceptable testo evaluate anemia, and Hb should be the stan-ard measure for assessing anemia.Hb should be measured on standardized auto-ated blood count analyzers in an accredited

aboratory. In patients with non–dialysis-depen-ent (ND) CKD (ND-CKD) and patients withD-dependent CKD (PD-CKD), the timing of

he blood sample draw is not critical because

Diseases, Vol 47, No 5, Suppl 3 (May), 2006: pp S28-S32

ptdglmaaeiomwtlHwviol(alpovt

iCctplpsftce

CDmimwgtB

Wt(d

mideitadn4ro

R

clmttttrirmpavvprt

R

i


lasma volume in these patients remains rela-ively constant. However, in patients with HD-ependent CKD (HD-CKD), interdialytic weightain contributes to a dilutional decrease in Hbevel, whereas intradialytic ultrafiltration pro-otes a contractional increase in Hb level. Thus,sample obtained immediately before dialysis

nd during volume expansion underestimates theuvolemic Hb level, whereas a sample obtainedmmediately after dialysis overestimates the euv-lemic Hb. In a study of 68 stable HD patients,ean predialysis versus postdialysis Hb levelsere 10.5 � 1.3 and 11.5 � 1.3 g/dL, respec-

ively.92 There was a strong linear inverse corre-ation between percentage of change in Hb andct values and percentage of change in bodyeight, indicating that increments in Hb and Hctalues after dialysis were a direct function of thentradialytic variation in body weight and degreef ultrafiltration. Moreover, the predialysis Hbevel measured after a long interdialytic period3 days) was 0.5 to 0.6 g/dL less than the predi-lysis Hb level measured after a short interdia-ytic period (2 days). Among all pre-HD andost-HD Hb values, levels measured at the endf short intervals were closest to the mean Hbalue of the week, derived from calculation ofhe area under the curve.93

Given the relationship between Hb level andnterdialytic weight gain in patients with HD-KD, midweek predialysis sampling theoreti-ally is optimal. However, information that pa-ient outcomes are affected by sampling day inatients with HD-CKD is lacking. Moreover,ogistical considerations preclude sampling allatients with HD-CKD at midweek. Therefore,ampling for Hb determination should be per-ormed before dialysis without specific referenceo dialysis day. In the interpretation of results,onsideration should be given to the potentialffect of the patient’s volume status.

In addition to Hb, other reported results of theBC may convey important clinical information.eficiency of folate or vitamin B12 may lead toacrocytosis, whereas iron deficiency or inher-

ted disorders of Hb formation (�- or �-thalasse-ia) may produce microcytosis. Macrocytosisith leukopenia or thrombocytopenia suggests aeneralized disorder of hematopoiesis caused byoxins (eg, alcohol), nutritional deficit (vitamin
12 or folate deficiency), or myelodysplasia. p
hen these findings are present, further diagnos-ic evaluation may be indicated. Hypochromialow MCH) likely reflects longstanding iron-eficiency erythropoiesis.In general, the anemia of CKD is normochro-ic and normocytic; that is, morphologically

ndistinguishable from the anemia of chronicisease. It characteristically is hypoproliferative:rythropoietic activity is low, consistent withnsufficient erythropoietin stimulation. Prolifera-ive activity is assessed by determination of thebsolute reticulocyte count, the reticulocyte in-ex, and the reticulocyte production index. Theormal absolute reticulocyte count ranges from0,000 to 50,000 cells/�L of whole blood. Theeticulocyte index is calculated from the ratio ofbserved to normal reticulocyte count. Thus:

eticulocyte index

� �observed absolute reticulocyte count�� normal absolute reticulocyte count�

Conversely, the reticulocyte production indexorrects for the effects of erythropoietin-stimu-ated early release of reticulocytes from the bonearrow. Early release shortens the fraction of

ime reticulocytes mature in marrow and propor-ionally prolongs their maturation time in circula-ion. The result of early release is an increase inotal reticulocyte count. However, that increaseeflects the premature shift to the circulation, notncreased erythroid production.94 Normal matu-ation time in circulation is 1 day. The expectedaturation time, presuming a sufficient erythro-

oietin response to anemia, increases to 1.5 dayst Hb values between 10 and 13 g/dL, 2 days atalues between 7 and 10 g/dL, and 2.5 days atalues between 3 and 7 g/dL. The reticulocyteroduction index is calculated by dividing theeticulocyte index by the expected maturationime. Thus:

eticulocyte production index

� �reticulocyte index�� expected maturation time�

In an anemic patient, a reticulocyte productionndex greater than 3 is evidence of a normal
roliferative response to anemia, whereas a pro-

dltasaapmb

tfis

EW

iearcic(aPpli

mpotbsdbs

ptatisstrbttd

trHiw


uction index of 2 or less is regarded as hypopro-iferative, ie, little or no effective response. Al-hough there is significant between-patient vari-bility in absolute reticulocyte count, the test isufficiently useful to serve its intended purposes a semiquantitative marker of erythropoieticctivity. The specific utility of the reticulocyteroduction index for the diagnosis and manage-ent of anemia in patients with CKD has not

een evaluated.By contrast, erythropoietin levels are not rou-

inely useful in distinguishing erythropoietin de-ciency from other causes of anemia in clinicalettings.18,19,85,95,96

valuating Iron Status in Anemic Patientsith CKD

Iron status test results reflect either the level ofron in tissue stores or the adequacy of iron forrythropoiesis. Serum ferritin level is the onlyvailable blood marker of storage iron. Tests thateflect adequacy of iron for erythropoiesis in-lude TSAT, MCV, and MCH and the relatedndices, percentage of hypochromic red bloodells (PHRC) and content of Hb in reticulocytesCHr). Because long sample transport and stor-ge times spuriously elevate PHRC results, theHRC test is not suitable for routine use in manyatient-care settings. MCV and MCH decrease toess than normal range only after long-standing
ron deficiency. Thus, timely and reliable assess- a
ent of the adequacy of iron supply for erythro-oiesis generally requires results of either TSATr, when available, CHr. We further recommendesting Hb, ferritin, and TSAT or CHr togetherecause the combination provides important in-ight into external iron balance and internal ironistribution. The distribution of ferritin and TSATy age and sex in the general population ishown in Fig 12.

Testing iron status before treating anemia inatients with CKD serves 2 purposes: to assesshe potential contribution of iron deficiency tonemia and determine whether further evalua-ion for sources of gastrointestinal (GI) bleedings needed. Iron status testing is poorly suited toerve a third purpose, the prediction of respon-iveness to iron therapy, because no single ironest or combination of tests discriminates iron-esponsive from iron-unresponsive patients andecause patients respond to intravenous (IV) ironherapy even when iron status results are substan-ially greater than the range associated with evi-ence of iron deficiency (Guideline 3.2).The potential contribution of iron deficiency

o anemia is demonstrated best by examining theelationship between iron status test results andb difference from a reference value. Not surpris-

ngly, the nature of the relationship depends onhether the test measures iron stores or iron

Fig 12. Distribution of ferritin and TSATvalues by age group in males and females.Data are given as 5th, 50th, and 95th per-centiles. Centers for Disease Control andPrevention; National Center for Health Sta-tistics, 2005.40

dequacy for erythropoiesis.

srNr(mmiyUrliC

bcfrwaubtdfc

s

dCtrottlssaiTlrt(2

enfclpClaTt

rmp


The relationship between measures of irontores (serum ferritin) and Hb difference fromeference is shown in Fig 13. In patients withD-CKD, Hb values do not decrease to less than

eference level except at the lowest ferritin levels�25 ng/mL in males and �11 ng/mL in fe-ales). These ferritin results closely approxi-ate the fifth percentile of serum ferritin values

n a randomly selected population (males � 20ears, 33 ng/mL; females � 60 years, 15 ng/mL;S Renal Data System [USRDS] special data

equest, NHANES 1999 to 2002 data set) andikely represent sex-specific thresholds at whichron stores are exhausted in patients with ND-KD.In patients with HD-CKD, the relationship

etween serum ferritin and Hb values is lesslear, probably because the relationship betweenerritin level and iron stores may be disturbed. Inelatively healthy patients with HD-CKD beforeidespread use of IV iron therapy, the finding offerritin level less than 50 ng/mL was not

ncommon97 and was associated with absentone marrow iron in approximately 80% of pa-ients.98 However, in patients with a greaterisease burden, absent iron stores may still beound at ferritin levels approaching or even ex-eeding 200 ng/mL.99

The relationship between adequacy of ironupply for erythropoiesis (from TSAT) and Hb

Fig 13. Distribution of Hb levels by ferritinange in patients with CKD. Results shown asean 95% � CI for parameter estimates. Re-

rinted with permission.26

ifference from reference in patients with ND-KD is shown in Fig 14. The relationship be-

ween TSAT and Hb values is continuous andelatively linear throughout the encountered rangef TSAT values (Fig 14). There is no obvioushreshold or cutoff value of TSAT below whichhe prevalence of anemia is sharply higher or theevel of Hb is sharply lower. Hb values areignificantly lower than reference (ie, Hb resultseen in patients with a TSAT of 20% to 29%)mong both males and females only when TSATs less than 16%. By comparison, analysis ofSAT values in a randomly selected survey popu-

ation showed that the fifth percentile of TSATesults in males 20 years and older is 12.5%, andhat in females 60 years and older is 10.3%USRDS special data request, NHANES 1999 to002 data set).In short, in patients with ND-CKD undergoing

valuation for anemia, ferritin levels less than 25g/mL in males and less than 12 ng/mL inemales suggest that storage-iron depletion isontributing to anemia. Serum ferritin level isess reliable in the evaluation of iron stores inatients with HD-CKD than in those with ND-KD. Iron-deficiency erythropoiesis is most

ikely to contribute to anemia when TSAT resultsre less than 16%. However, the clinical utility ofSAT is impaired by the absence of a diagnostic

hreshold.

Fig 14. Distribution of Hb levels by TSATrange in patients with CKD. Results shown asmean � 95% CI for parameter estimates. Re-printed with permission.26

miidscGctag

mpcoatimcslr

wCwpGdHlhc

atnorawtitcoecaea

dtescat(csC

F

iae


Although iron status tests provide reasonablearkers to detect iron deficits, there is little

nformation to guide what action should be takenn response, particularly in regard to furtheriagnostic GI workup. In the absence of men-trual bleeding, iron depletion and iron defi-iency result from blood loss from the GI tract.I pathological states—including ulcer disease,

olonic polyps, colorectal carcinoma, Helicobac-er pylori positivity, and sprue—are commonmong iron-deficient patients referred for esopha-ogastroduodenoscopy and colonoscopy.100-103

Testing for occult blood in stool is not recom-ended as part of the evaluation of iron-deficient

atients.104,105 As a screening test for colorectalarcinoma or precancerous colonic polyps, stoolccult blood testing commonly is performed, buthigh false-negative result rate renders it rela-

ively unreliable.106 However, in a patient withron deficiency, the test provides no useful infor-ation because a positive stool test result only

onfirms a diagnosis that the blood test resultsignifying iron deficiency have already estab-ished (GI blood loss), while a negative stool testesult can only be falsely reassuring.

In patients with CKD, occult blood in stoolas found in 6% to 7% of patients with HD-KD and PD-CKD and nearly 20% of patientsith ND-CKD.107 Among patients with heme-ositive stools, follow-up endoscopy identifiesI pathological states (predominantly gastric anduodenal) in approximately 60% of patients.owever, because the likelihood of finding GI

esions in patients with CKD with and withouteme-negative stools has not been examined,
ritical information to establish the sensitivity t
nd specificity of occult blood testing in thearget population is lacking. Moreover, there iso information comparing the clinical utility ofccult blood testing with that of endoscopy in theelevant patient population with iron deficiency,nemia, and CKD or in any target populationith iron deficiency. Finally, there is no evidence

hat either endoscopy or other additional GImaging improves patient outcomes when rou-inely conducted for the evaluation of iron defi-iency. Thus, although colonoscopy can be partf an age-appropriate cancer screening andsophagogastroduodenoscopy should be stronglyonsidered if iron deficiency is confirmed in annemic patient with CKD, there is insufficientvidence to recommend their routine use fornemia evaluation.

In conclusion, although epidemiological evi-ence yields a consistent definition of iron deple-ion (ferritin � 25 ng/dL) and iron deficiencyrythropoiesis (TSAT � 16%), in the absence ofufficient evidence that demonstrates therapeuticonsequences based in these threshold valuesnd in the presence of information that therapeu-ic intervention should be guided by other factorssee Guideline 3.2), these definitions lack spe-ific recommendations for action and thereby fallhort of constituting a guideline statement orPR.

urther Evaluation

These tests are recommended only for the thenitial evaluation of anemia. Should initial evalu-tion yield evidence for disorders other thanrythropoietin deficiency or iron deficiency, fur-
her evaluation is warranted.

Tsis

2

Ttrg

Tc

A

CPG AND CPR 2.1. HB RANGE

eooai

H

lrlfspalhcpWwmldawtcepclnmbp

lrds2tdtld

reatment thresholds in anemia management de-cribe the intended goal of current treatment for thendividual patient. The Hb treatment range repre-ents the intended goal of ESA and iron therapy.

2.1.1 Lower limit of Hb:In patients with CKD, Hb should be11.0 g/dL or greater. (MODERATELYSTRONG RECOMMENDATION)

.1.2 Upper limit of Hb:In the opinion of the Work Group, thereis insufficient evidence to recommendroutinely maintaining Hb levels at 13.0g/dL or greater in ESA-treated patients.

BACKGROUNDPrevious (2001) KDOQI Guidelines for the

reatment of the Anemia of CKD2 incorporatedhe following lines of evidence to support aecommended Hb target level of 11.0 to 12.0/dL in patients with CKD:

● Observational evidence showed that mor-tality rates were lower in HD patients withHb values close to this range in compari-son to HD patients with lower Hb levels.

● Observational evidence in patients withHD-CKD and those with ND-CKD showedan association between anemia and leftventricular hypertrophy (LVH).

● A reasonable body of evidence from ran-domized controlled trials (RCTs) compar-ing distinct Hb level targets suggested thatpartial correction of anemia, to levels ofapproximately 11 to 12 g/dL, led to im-proved QOL.

● A limited body of evidence from distinct-target RCTs suggested that partial correctionof anemia, to levels of approximately 11 to12 g/dL, led to partial regression of LVH.

● A single large RCT examining patientswith HD-CKD with patients with overtCVD suggested that Hb level targets of 14g/dL do not improve the primary studyoutcome of death or myocardial infarction(MI) and appear to jeopardize dialysisvascular access compared with Hb levelsof 10 g/dL.

o develop the current guideline, we undertook a
omprehensive reexamination of the available o

vidence that encompassed both the RCTs previ-usly cited and RCTs published since the previ-us analysis. Because each RCT included irongents as an adjunct to ESA, the guidelinencludes references to both.

RATIONALE

b Level Should Be 11.0 g/dL or Greater

Evidence to support a recommended target Hbevel demands the highest order of methodologicigor. To determine the recommended target Hbevel, we confined consideration to results gainedrom RCTs that enrolled patients who are repre-entative of the key CKD populations (anemia inatients with ND-CKD, PD-CKD, and HD-CD),ssigned patients to at least 2 distinct target Hbevel groups (treatment versus placebo/control origher versus lower Hb level), assessed out-omes that are important to patients, and re-orted results of between-group comparisons.e based our conclusions on evidence that,hen taken together, reflected high or at leastoderate overall quality. Such evidence has few

imitations, shows consistency among trials, bearsirect relevance to the anemic CKD population,nd lacks sparseness or substantial bias. We gaveeight to between-group differences (effect sizes)

hat are not only statistically significant, but alsolinically meaningful, particularly when consid-ring QOL. When weighing evidence of im-roved outcomes against the potential for in-reased risk, we sought to determine the Hbevel(s) at which a patient can expect an overallet benefit. Finally, we required that the recom-ended target Hb statement be clear and unam-

iguous and the target Hb level be achievable inractice.Evidence supporting the statement that Hb

evel should be 11.0 g/dL or greater includesesults from 22 RCTs and is presented both inetail for each trial Table 12 through 19) and inummary for each outcome ( Table 20 and Table1). The evidence is confined to results of be-ween-group comparisons generated by trials ran-omizing patients to distinct intent-to-treat Hbargets, using “ESA versus placebo” or “ESAower Hb target versus ESA higher Hb target”esigns (Fig 15). We excluded evidence from
bservational studies. Cohort-based observa-
), 2006: pp S33-S53 S33

Table 12. RCTs Examining Effects of Distinct Hb Targets/Levels on Key Clinical Outcomes in the HD-CKD and PD-CKD Populations

Arm 1 Clinical Outcomes (Arm 1 vs. Arm 2 vs. Arm 3)

Arm 2Author, Year N

CK

D S

tage

Bas

elin

e a

Hb

(g/d

L)

Follo

w-u

p (

mo)

App

licab

ility

Arm 3

Mean Hb (g/dL) Target

(Achieved)

CVDEvents

(%)LVH

Mortality (%)

Hospitali- zation

Dialysis Adequacy

Transfusion(%) QOL b Q

ualit

y

ESA vs. ESA

ESA High 14.0

(12.7-13.3) Besarab, 1998 108 1,233 HD-CKD

10.2 14 ESA Low 10.0 (10.0)

*Nonfatal MI

3.1 vs. 2.3 NS c

—

*29.6 vs.

24.4 NS c

NS∆Kt/V:

–0.03 vs. +0.06 P <0.001

21 vs. 31 P = 0.001

See QOL Table

ESA High 13.5-14.5

(13.3) Parfrey, 2005 109 596

HD-CKD

11.0 24 ESA Low

9.5-11.5 (10.9)

CVA:4 vs. 1

P = 0.045 Other CVD:

NS

*NS NS — ∆URR:

0 vs. +2 % P <0.05

—See QOL

Table

ESA High 13-14 (13) Foley, 2000 110 146

HD-CKD

10.4 11 ESA Low 9.5-10.5 (10.5)

NS *NS NS — Kt/V:NSh —

See QOL Table

ESA High 11.5-13 (11.7)

*High vs. Low: NS

ESA Low 9.5-11 (10.2)

CanEPO, 1990-1991 49, 117 118

HD-CKD

7.0 6

Placebo (7.4)

— — NS — —

3 vs. 3 vs. 72

ESA vs. Placebo: P <0.05 f

ESA vs. Placebo: P = 0.024

ESA High 13.5-16.0

(3.6)Furuland, 2003 118 416

4-5PD-CKD

HD-CKD d

10.9 12 ESA Low

9-12(11.3-11.7)

— — NS NS — — *See QOLTable

ESA High e <11 (8.7) ESA Low (8.2)

Suzuki, 1989 119 179 HD-CKD

6.3 2 Placebo (6.1)

— — — — —

8 vs. 5 vs. 23

ESA vs. Placebo: P <0.05

See QOL Table

ESA High 13.5-16.0

(14.3) Furuland, 2005 120

Substudy of Furuland, 2003

24HD-CKD

11.1 5.5 ESA Low 9-12 (10.9)

— — — — ∆Kt/V:

–0.1 vs. 0 nd

— —

ESA High e 14 (14) McMahon, 1999,2000 121, 122 14

HD-CKD

8.5 1.5 ESA Low 10 (10) --- — — — — — P <0.02

AN

EM

IAIN

CH

RO

NIC

KID

NE

YD

ISE

AS

EIN

AD

ULT

SS

34

Arm 1 Clinical Outcomes (Arm 1 vs. Arm 2 vs. Arm 3)

Arm 2Author, Year N

CK

D S

tage

Bas

elin

e a

Hb

(g/d

L)

Follo

w-u

p (

mo)

App

licab

ility

Arm 3


(Achieved)

CVDEvents

(%)LVH

Mortality (%)

Hospitali- zation

Dialysis Adequacy

Transfusion(%) QOL b Q

ualit

y

ESA vs. Placebo

ESA10.7-12.7

(11.2) Nissenson, 1995 123 152 PD-CKD

8 6-9

Placebo (8.0) — — NS — —

∆U/pt/4 wk –0.21 vs.

+0.42 P <0.05

—

ESA10-11.7

(10.6-10.9)Bahlmann, 1991 124 129HD-CKD

7.7 6 Placebo (7.8)

NS — NS — — 9 vs. 60 P <0.05

—

ESA e 10-11.7 (11.3)

Sikole, 1993 125 38 HD-CKD

6.7 12Control (8.3) g

—

*LVEDd(mm)48 vs.

53P = 0.002

— — — — —

ESA vs. Placebo in Pediatric Patients

ESA10.5-12 (11.2)

Morris, 1993 126 11

PD-CKDHD-CKD

7.3 6 Placebo (7)

— — — — — — *See QOLTable

Footnotes:* Primary Outcome, if clearly indicated. a. All baseline data given for arm 1, unless otherwise specified. b. Global Scores, if documented, are provided here. Refer to Tables 13 and 19 for details of QOL measurements. c. The primary outcome was a composite of nonfatal MI or death. RR 1.3, 95% CI 0.9-1.8, P>0.05. d 294 HD-CKD, 51 PD-CKD, 72 ND-CKD patients. e. Iron cointervention not documented. f. Data at 8 weeks. g. Median. h. LVD subgroup: Kt/V 1.41 vs.1.50, P=0.025

Coding of Outcomes: Mortality: All-cause mortality. CVD Event: Includes CHF exacerbation, MI, arrhythmias, angina, interventional procedure such as CABG or angioplasty, sudden death, CVA. LVH: As identified by echocardiography with minimum of 6 month follow-up.

AN

EM

IAIN

CH

RO

NIC

KID

NE

YD

ISE

AS

EIN

AD

ULT

SS

35

Table 13. RCTs Examining Effects of Distinct Hb Targets/Levels on QOL in the HD-CKD and PD-CKD Populations

) 3 mrA .sv 2 mrA .sv 1 mrA( LOQ 1 mrACKD Stage Arm 2 Author, Year N

Baseline Hb (g/dL)

Follow-up (mo)

Applic-ability

Arm 3


(achieved)

Primary Outcome of Study Scale/Test Global

QOLVitality and Fatigue Other Measures of QOL

Quality

hgiH ASE )DH( 5 13.5-14.5 (13.1) KDQOL

subscales: SF-36 Vitality and Quality of Social

Interaction

SF-36 Vitality: + Social Interaction: NS Parfrey, 2005 109 324

11.0

24 a

ESA Low 9.5-11.5 (10.8)

LV volume index

FACIT Fatigue Scale

SN

Physical: +ESA High 11.5-13 (11.7)

Relationships: +

Depression: +KDQ Fatigue: +

Frustration: NS

5 (HD)

ESA Low 9.5-11 (10.2) Physical: +SIP +

Psychosocial: NS

CanEPO,1990-1991 49, 117

118

7.0

6 b

Placebo (7.4)

QOL and functional capacity c

SN OTT

hgiH ASE )DH( 514.0

(12.7-13.3) Besarab, 1998 108 1,233

10.2

14

ESA Low 10.0 (10.0)

Mortality and nonfatal MI

SF-36 Physical: + d

Physical Symptoms: NS Depression: +

Relationships: +KDQ f Fatigue: +

Frustration: NS

5 (HD)ESA High 13-14 (13)

Physical Function: NSGeneral Health: NS

Bodily Pain: NS Social Functioning: nd

Emotional Role: nd

SF-36 Vitality: NS

Mental Health: nd

Foley, 2000 110

94

10.1

12 e

ESA Low 9.5-10.5 (10.5)

∆LV mass index in individuals with

concentric LVH; ∆cavity volume index in individuals with

LVD

HUI Mean HUI = 0.81(CI: 0.78, 0.85)

Physical: +4-5(PD,HD)

ESA High 13.5-16.0 (13.6) Relationship: NS

Depression: +

Furuland, 2003 118 253

10.9 12

ESA Low 9-12

(11.4)

QOL and safety KDQ Fatigue: NS g

Frustration: NS g

)41( 41 hgiH ASE )DH( 5 Physical: NS McMahon, 1999, 2000 121, 122

148.3

1.5 ESA Low 10 (10)

Several primary outcomes, including QOL and exercise

performance

SIP +Psychosocial: +

AN

EM

IAIN

CH

RO

NIC

KID

NE

YD

ISE

AS

EIN

AD

ULT

SS

36

Footnotes: a. No CVD or LVD. b. All individuals had LVD or LVH at baseline, no CVD. c. Data shown for ESA arms vs. Placebo. All statistical comparisons for ESA High vs. ESA Low were not significant. d. Increased by 0.6 point for each percentage point increase in Hct. e. Free of marked comorbidity. f. Results given are from repeated measures analysis of variance. g. P = 0.05 h. 25-Part Parental Questionnaire, modified from a previously used questionnaire126. Questions covered various aspects of the child’s well-being and behavior, including mood and psychological behavior, social interaction, somatic

complaints and general health, sleep, diet, school functioning, and physical performance.

Coding of Outcomes:Coding of comparison of study arm 1 versus study arm 2: (+) better, (–) worse with reference to benefit for patient.

Key to QOL Measurement Scales/Tests: 36-item Medical Outcomes Study Short-Form Health Survey (SF-36): Evaluates eight health-related aspects: physical function, social function, physical role, emotional role, mental health, energy, pain, and general health perceptions.

Each portion of the test is scored on a scale that ranges from 0 (severe limitation) to 100 (no limitation). Center for Epidemiologic Studies Depression Scale (CESDS): Has been used extensively in epidemiological studies of the general community and chronic disease populations. It is scored from 0 to 60, with higher scores indicating a

greater number of depression symptoms. Functional Assessment of Chronic Illness Therapy (FACIT): Collection of QOL questionnaires targeted to the management of chronic illness Health Utilities Index (HUI): Provides an overall index of health, derived from scores in 7 aspects: sensation, mobility, emotion, cognition, self-care, pain, and fertility. This is an interval scale that can vary in theory between 0 (death) and

1 (perfect health). Karnofsky Performance Scale (KPS): Uses 10 steps with scores ranging from 100 (normal, without any limitation) to 10 (moribund) as an overall indicator of functional ability and self-sufficiency. It is considered an objective quality-of-life

indicator. Kidney Disease Quality of Life (KDQOL): Validated in dialysis patients. The Short Form (SF) version used for assessment of vitality. Kidney Diseases Questionnaire (KDQ): Is validated in dialysis patients. Contains 26 questions divided into 5 sections: patient-specific physical symptoms, fatigue, depression, relationships, and frustration. All questions are scored on a

7-point Likert scale (7 = no problem, 1 = severe problem). Quality of American Life (QoAL): Asks the patient to rate his or her satisfaction with life on a scale from 1 to 7, with higher scores indicating greater satisfaction. Renal Quality of Life Profile (RQoLP): Instrument based on constructs representing renal patient’s own QOL determinants. Sickness Impact Profile (SIP): Is a behavior-related questionnaire that evaluates non–disease-specific, sickness-related behavioral dysfunction. It is widely used for end-stage renal disease patients and in studies evaluating quality-of-

life improvement with ESA treatment for end-stage renal disease-related anemia. The SIP includes 136 items grouped into 12 categories of activity in physical and psychological dimensions. Scores range from 0 (no behavioral dysfunction) to 100 (100% dysfunction in a category or group). Unlike the KPS and the KDQ, lower scores for the SIP indicate better QOL.

Time Trade-off (TTO): Is a unidimensional measure of QOL that gives a value to a patient’s QOL ranging from 1.0 (full health) to 0 (patient is indifferent between life and death). This is a utility measure using the time trade-off hypothesis.

Arm 1 QOL (Arm 1 vs. Arm 2 vs. Arm 3 ) CKD Stage

Arm 2 Author, Year N Baseline Hb (g/dL)

Follow-up (mo)

Applic-ability

Arm 3


(achieved)

Primary Outcome of Study Scale/Test Global

QOLVitality and Fatigue Other Measures of QOL

Quality

Pediatric Patients Sleep: NS 5

(PD,HD)ESA 10.5-12 (11.2)

Diet: NS School Performance: NS

Morris, 1993 126 10

7.0 8

Placebo (6.5)

QOL, diet, exercise tolerance, and PD

efficiency

25-part Parental Questionnaire h

NS

Physical Performance/ General Health (includes school attendance): + Psychosocial: NS

AN

EM

IAIN

CH

RO

NIC

KID

NE

YD

ISE

AS

EIN

AD

ULT

SS

37

Table 14. Non-CVD/Mortality AE Rates in RCTs Examining Distinct Hb Targets/Levels in HD-CKD and PD-CKD Populations: ESA versus ESA

Arm 1 AEs (Arm 1 vs. Arm 2 vs. Arm 3)

Arm 2 BP Change or Hypertension Access Thrombosis (%) Seizures Other Reported AE aAuthor, Year

ND

ialy

sis

Mod

ality

Description of Intervention

Follo

w-u

p (m

o)

Arm 3 Mea

n H

b (g

/dL)

Ta

rget

(a

chie

ved)

Definition Outcome Definition OutcomeDescription and

Results Tota

l D/C

of

Dru

g

618IV or SC ESA

1.5X pretrial dose; adjusted after 2 wk

ESA High 14.0

(12.7-13.3) 0

Besarab, 1998 108

615

HD b

IV or SC ESA adjusted

14

ESA Low 10.0

(10.0)

Mean SBP and DBP during the study c NS

Both AV graft and AV fistulae

39% vs. 29% (P = 0.001)

NS —

0

hgiH ASE 48213.5-14.5

(13.3) Parfrey, 2005 109

281

HD IV or SC ESA for 24 wk

to reach target then maintained for 72 wk

24

ESA Low 9.5-11.5(10.9)

Hypertension not specified

NS

AV fistulae, permanent

catheter, non-site specific embolism

23% vs. 19% (NS)

—

Overall treatment emergent AE in ≥10% of

patients: 96% vs. 94% d

nd

216 SC ESA TIW ESA High 13.5-16.0

(13.4-14.3) 34

Furuland, 2003 118

200

HD PD e

SC ESA TIW or no treatment

12

ESA Low 9-12

(11.3-11.7)

∆ mean DBP from baseline

90 vs. 83 mm Hg

(P = 0.02)

Complication in AV graft, AV

fistulae or catheter during study

5% vs. 2% in HD patients only

(NS) —

Individuals with at least 1 SAE NOS: 51% vs.

38.5% (NS) Thromboembolic:

Event: 56 vs. 47 per arm (NS) f

15

)7.8( 11< hgiH ASE 95

)2.8( woL ASE 85Suzuki, 1989 119

57

HD IV ESA 3,000 IU TIW 2

Placebo (6.1)

Increased dose of anti-HTN meds

5 vs. 4 vs. 1 individuals

— — — No. of AE NOS 6.7% vs. 8.3%

vs. 1.7% per arm gnd h

hgiH ASE 3713-14 (13)

Foley, 2000 110

73

HD

SC ESA ESA high arm had a 24

wk “ramping” phase. 24 wk maintenance was

similar in both arms

11

ESA Low 9.5-10.5(10.5)

Mean SBP, DBP, during between

groups, and use of anti-HTN meds

For LVH: significant SBP and anti-HTN

For LVD: NS

AV access 8% vs. 14%

(NS) i— — nd

39 ESA

200 U/kg (11.6)

40 ESA

100 U/kg (11.0)

Abraham, 1991 127

42

HD IV ESA TIW

after HD session 25, 100 or 200 IU/kg

2.5-4.5

ESA 25 U/kg

(8.8)

% of individuals with increases in DBP ≥10

mm Hg and/or anti-HTN meds

56% vs. 52% vs. 45%

(NS) — — — — nd

AN

EM

IAIN

CH

RO

NIC

KID

NE

YD

ISE

AS

EIN

AD

ULT

SS

38

Arm 1 AEs (Arm 1 vs. Arm 2 vs. Arm 3)

Arm 2 BP Change or Hypertension Access Thrombosis (%) Seizures Other Reported AE aAuthor, Year

ND

ialy

sis

Mod

ality

Description of Intervention

Follo

w-u

p (m

o)

Arm 3 Mea

n H

b (g

/dL)

Ta

rget

(a

chie

ved)

Definition Outcome Definition OutcomeDescription and

Results Tota

l D/C

of

Dru

g

hgiH ASE 8311.5-13 (11.7)

2

woL ASE 049.5-11 (10.2)

2CanEPO 1990 49

40

HD IV ESA

100 IU/kg initial dose; titrated to achieve targets

6

Placebo (7.4)

Severe HTN required withdrawal j

5% vs. 5% vs. 0%

(P = 0.01)

AV graft or AV fistulae clotting

# of Events: 7 vs. 4 vs. 1

(P = 0.01)

0% vs. 5% vs. 2.5% (NS)

Nonspecific AEs: 63 vs. 61 vs. 65 per

arm k

0

)0.41( 41 hgiH ASE 41Berns, 1999 128

14 HD ESA to maintain target 12

ESA Low 10 (10.1)

HTN: SBP >140 mm Hg,

DBP >90 mm Hg; or ∆ anti-HTN meds.

Slightly more prevalent in Low vs. High

(NS)

— — — — nd

hgiH ASE 814

(14.0) 0McMahon,

1999, 2000 (Crossover) 121,

122 6

HD

SC ESA 2x/wk if total dose <20,000 IU/wk;

IV ESA TIW if total dose >20,000

IU/wk

1.5

ESA Low 10

(10)

Mean ABP for peak day and nocturnal

readings taken before and after HD

NS — — — —

0

Footnotes: a. For “Other Reported AE” column, outcomes may be recorded in no. of events per arm, no. of events per patient, or % given heterogeneity in reporting. b. All individuals had evidence of CHF and IHD. c. Prestudy ABP had to be below 160/100 for 4 weeks prior to study. Subgroup analysis129: 31 patients; mean day & nocturnal BP readings for 24 hr were NS at baseline or at follow-up. d. Of these P >0.05 for all comparisons except headache was greater in the ESA High arm and skeletal pain and surgery were greater in ESA Low arm. e. Includes some predialysis patients, Stages 4-5 CKD. f. Thromboembolic events were defined by WHO classification. g. 7 of 10 continued treatment. h. Not documented per arm. 3 individuals receiving ESA discontinued treatment. i. Patients with ongoing access problems were specifically excluded. The event rates were small and study did not have enough statistical power to detect a moderate impact on access thrombosis; the proportion using natural fistulae in the

Besarab study was 23% compared to 76% in this study. j. DBP was increased in patients on ESA compared to placebo. P = 0.001; no statistical difference between High ESA and Low ESA.k. Nonspecific events include: clotting of tubing in dialysis machine, flu-like symptoms, headache, red eye, epistaxis or hemorrhage, pain in chest, abnormal sense of taste, aches in bone and muscle.

Coding of Outcomes: (Variable per Column Description) Hypertension: Includes mean changes in SBP, DBP, MAP, increase in use of anti-HTN medications, difficult to control hypertension. Access Thrombosis: Synthetic grafts and fistulae.

AN

EM

IAIN

CH

RO

NIC

KID

NE

YD

ISE

AS

EIN

AD

ULT

SS

39

Table 17. RCTs Examining Effects of Distinct Hb Targets/Levels on QOL in the ND-CKD Population

CKD Stage

)2 mrA .sv 1 mrA( LOQ 1 mrAAuthor, Year N

Baseline Hb (g/dL)

Follow-up (mo)

Applic-ability

Arm 2


(achieved)

Primary Outcome of

Study Scale/Test Global QOL Vitality and Fatigue Other Measures of QOL

Quality

)1.21( 31-21 hgiH ASE 4-3 Physical Health: NS SF-36 NS Mental Health: NS Roger, 2004 38 155

11.2 24 a

ESA Low 9-10 (10.8) Change in LV

massRQOLP NS

Home Management: NS

Alertness Behavior: NS Selected SIP Scales

Social Interaction: NS )2.11( 7.11 ASE 5-4

Physical Function: +Role Function: NS Selected SF-36 Scales Energy: +

Health Distress: NS QoAL NS

CESDS NS

Revicki, 1995 132

Roth, 1994 81 35

8.9

12

Control (9.0)

Health-related QOLb

Sexual Dysfunction Interview

NS

Footnotes:a. Excluded patients with unstable or poorly controlled angina, severe CHF (grade III-IV), severe chronic respiratory disease, symptomatic peripheral vascular disease, or a created arteriovenous fistula. b. The interview incorporated dimensions of HRQL identified to cover the expected effects of ESA therapy and anemia in predialysis CKD patients based on review of medical literature and discussions with nephrologists and nurses. The

intent was to comprehensively measure broad areas of functioning and well-being.

Key for QOL Scales: 36-item Medical Outcomes Study Short-Form Health Survey (SF-36): Evaluates 8 health-related aspects: physical function, social function, physical role, emotional role, mental health, energy, pain, and general health perceptions. Each

portion of the test is scored on a scale that ranges from 0 (severe limitation) to 100 (no limitation). Renal Quality of Life Profile (RQOLP): Instrument based on constructs representing renal patient’s own QOL determinants. Sickness Impact Profile (SIP): Established generic health status measure of disability associated with chronic illness. Quality of American Life Survey (QoAL): Is a life satisfaction scale from Campbell et al. The Quality of American Life. New York, NY, Russell Sage Foundation, 1976. Center for Epidemiologic Studies Depression Scale (CESDS): Has been used extensively in epidemiological studies of the general community and chronic disease populations. It is scored from 0 to 60, with higher scores indicating a

greater number of depression symptoms.

AN

EM

IAIN

CH

RO

NIC

KID

NE

YD

ISE

AS

EIN

AD

ULT

SS

42

Table 19. RCTs Examining Effects of Distinct Hb Targets/Levels on Exercise Capacity in the HD-CKD and PD-CKD Populations

Footnotes: a. No CVD or LVD. b. All individuals had LVD or LVH at baseline, no CVD. c. Data shown for ESA arms vs. Placebo. All statistical comparisons for ESA High vs. ESA Low were not significant. d. With cycle ergometer. e. Not a significant improvement but did improve over study time. f. Only 3 children completed the treadmill test.

Coding of Outcomes:Coding of comparison of study arm 1 versus study arm 2: (+) better, (–) worse (with reference to benefit for patient).

)3 mrA .sv 2 mrA .sv 1 mrA( LOQ 1mrACKD Stage Arm 2 Author, Year N

Baseline Hb (g/dL)

Follow-up (mo)

Applic-ability

Arm 3


(achieved)

Primary Outcome of Study Scale/Test Description Results

Quality

hgiH ASE )DH( 513.5-14.5

(13.1)Parfrey, 2005 109 324

11.0

24 a

ESA Low 9.5-11.5 (10.8)

LV volume index 6-min Walk Test Patients are asked to cover as much

distance in an enclosed corridor as they can in 6 minutes

NS

)7.11( 31-5.11 hgiH ASE )DH( 5Naughton Stress

Test Treadmill NS

ESA Low 9.5-11 (10.2) CanEPO, 1990-1991 49, 117 118

7.06

b

Placebo (7.4)

QOL and functional capacity c

6-min Walk Test Patients are asked to cover as much

distance in an enclosed corridor as they can in 6 minutes

NS

Peak heart rate NS )41( 41 hgiH ASE )DH( 5

Peak O2 consumption +McMahon, 1999, 2000 121, 122

14

8.3

1.5

ESA Low 10 (10)

Several primary outcomes, including QOL and

exercise performance Exercise Test d

Work done +

Pediatric Patients

5(PD,HD)

SN gniklaw nim-2 )2.11( 21-5.01 ASE e

Morris, 1993 126 10

7.0

8

Placebo (6.5)

QOL, diet, exercise tolerance, and PD

efficiency

Exercise Tolerance Test

Treadmill NS f

AN

EM

IAIN

CH

RO

NIC

KID

NE

YD

ISE

AS

EIN

AD

ULT

SS

44

tmsaacttashabTcodm

gttfh1aTltltiltsstto

tgpaCr(Nps


ional trials and cross-sectional analyses of largeedical databases, such as within-group analy-

es in RCTs, consistently show that higherchieved Hb values (including �12 g/dL) aressociated with improved patient outcomes, in-luding lower mortality, less frequent hospitaliza-ion, and less severe LVH. Conversely, distinct-arget RCTs consistently show that patientsssigned to a Hb value of 13 g /dL or greaterhow no discernable improvement in survival,ospitalization, or LVH compared with patientsssigned to Hb targets less than 13 g/dL and maye prone to excess adverse cardiovascular events.he failure of observational associations to beonfirmed by interventional trials renders use ofbservational evidence unsuitable to support theevelopment of an intervention guideline state-ent.The statement that Hb level should be 11.0

/dL or greater incorporates evidence from Hbargets ranging from 6 to 16 g/dL (Table 12hrough Table 21; Fig 15). RCTs conducted be-ore 1998 are characterized by small study size,igher target Hb levels within the range of 10 to3 g/dL, and a lower target Hb level that reflectsssignment to placebo or no-treatment control.rials conducted thereafter are characterized by

arger study size, higher target Hb levels withinhe range of 12 to 16 g/dL, and lower target Hbevels between 9 and 12 g/dL. The lesser magni-ude of between-group Hb level differences seenn more recent trials is associated with Hb base-ine values that are greater than those of earlyrials and lower target Hb level ranges that areubstantially greater than Hb levels previouslyeen in placebo or untreated controls. In addi-ion, mean Hb levels achieved in more recentrials frequently are at or less than the lower limitf the higher target Hb level range.Patients in the 19 RCTs reviewed to support

he statement that Hb level should be 11.0 g/d orreater clearly are representative of the anemicatients with CKD that the statement intends toddress. Ten RCTs enrolled patients with HD-KD, 1 enrolled patients with PD-CKD, 2 en-

olled patients with both HD and PD-CKDTables 12 to 14), and 9 enrolled patients withD-CKD (Tables 15 and 16). However, thereponderance of evidence (and thus the greatesttrength of evidence) lies in the HD-CKD patient

group. Although sample size and thus power,

Table 21. Target Hb Levels in the ND-CKD Population

Summary of Findings

Outcome

No. of Studies &

Study Design

Total N of

Patients

Methodological Quality of Studies

Consistency across Studies

Directness of the Evidence,

including Applicability

Other Considerations

Quality of Evidence for

Outcome Qualitative Description of Effect Size Importance of Outcome

All-Cause Mortality

5 RCTs 336 Some

limitations a No important

inconsistencies Some

uncertainty b Sparse data c Very low Unable to assess benefit or harm with any certainty High

Nonfatal CV Events

3 RCTs 249 Some

limitations d No important

inconsistencies b Some

uncertainty e Sparse data c Very low Unable to assess benefit or harm with any certainty High

LVH 2 RCTs 307 No limitations No important

inconsistencies No major

uncertainties None High

No statistically significant benefit. Difference between arms is not statistically significant. However, a trend toward LV growth in those maintained at the lower

Hct.

Moderate

QOL 2 RCTs 238 Some

limitations f N/A g

Some uncertainties h

Sparse data Low

Likely some benefit. One study (achieved Hb 12.1 vs. 10.8 g/dL*) showed no improvement in QOL with early ESA intervention. A second study (achieved Hb 10.5 vs. 8.6 g/dL*) showed statistical improvement in the

energy subscale, no overall score was provided.

High

Transfusion Requirement

1 RCT 83 Major

limitations i N/Aj

Some uncertainty k

Sparse data Very low

Unable to assess benefit or harm with any certainty.There were more transfusions in the control

arm (23%) than in the ESA arm (9%) but this difference was not statistically significant.

Moderate

Kidney Disease Progression

9 RCTs 502 Some to major

limitations l Important

inconsistencies m Some

uncertainty n None Low

Unable to assess benefit or harm with any certainty. The larger studies failed to show worsening of the rate

of kidney disease progression in the ESA-treated arms. However, 2 very small studies suggested that

dialysis started earlier in the occasional patient treated with ESA, but no statistics were given. The 2 largest, 1 study showed statistically significant prolonged renal survival in the ESA treated group which was larger in the subgroup without diabetes than in the group with

diabetes.

High

Seizures 3 RCTs 39 Major

limitations o N/A j

Some uncertainty p

Sparse data Very low Likely no harm. 0 vs. 2 individuals* in all studies noting

seizures. Moderate

Blood Pressure Change

7 RCTs 469 Major

limitations q Some

inconsistencies r Some

uncertainty s None Low

Potential harm. Studies either showed no significant change in BP with ESA treatment or there was a

statistically insignificant trend towards patients who received ESA needing more antihypertensive

management.

Moderate

Balance of Benefit and Harm: Net Benefit at Hb ≥ 11 g/dL based on QOL; Uncertain Trade Off with Increasing Hb Levels, QOL Benefit May Be

Offset by Potential for Harm

Quality of Overall Evidence: Low

AN

EM

IAIN

CH

RO

NIC

KID

NE

YD

ISE

AS

EIN

AD

ULT

SS

48

eaweAtlt

tgcilsbdkCGh

ettbepswg(HtHltoa0

ptpHspstaot

note

s:

SA H

igh

vs. E

SA L

ow o

r Tre

atm

ent v

s. P

lace

bo/C

ontro

l

2 G

rade

A, 2

Gra

de B

and

1 G

rade

stu

dies

.

Res

ults

are

pro

babl

y no

t gen

eral

izab

le a

s m

orta

lity

was

not

a p

rimar

y en

dpoi

nt; m

orta

lity

was

not

attr

ibut

ed to

inte

rven

tion

in a

ny o

f th

e st

udie

s.

Lack

of a

dequ

atel

y po

wer

ed s

tudi

es to

eva

luat

e th

e ou

tcom

e.

2

Gra

de A

1 G

rade

B s

tudi

es.

Res

ults

are

pro

babl

y no

t gen

eral

izab

le s

ince

CV

even

ts w

ere

seco

ndar

y en

dpoi

nts;

in n

one

of th

e R

CTs

was

mor

bidi

ty a

ttrib

uted

to

inte

rven

tion.

1

Gra

de A

stu

dy (w

ith a

sta

tistic

ally

sig

nific

ant,

but p

erha

ps n

ot c

linic

ally

rele

vant

, sep

arat

ion

of H

b le

vels

bet

wee

n ar

ms)

and

1

Gra

de B

stu

dy.

D

iffer

ence

sca

les/

test

s us

ed to

ass

es Q

OL

para

met

ers.

QO

L w

as a

prim

ary

endp

oint

of o

nly

1 st

udy.

Tr

igge

r or t

hres

hold

for t

rans

fusi

ons

wer

e no

t def

ined

.

j. U

nabl

e to

ass

ess

due

to 1

of t

he fo

llow

ing:

onl

y 1

stud

y, fe

w s

tudi

es o

f poo

r qua

lity,

stu

dies

with

fe

w s

ubje

cts

or n

o st

udie

s w

ith th

e ou

tcom

e as

certa

ined

as

the

prim

ary

outc

ome.

Ref

er to

Qua

lity

and

Dire

ctne

ss g

rade

s.

k. S

econ

dary

end

poin

t. l.

3 G

rade

A, 2

Gra

de B

and

4 G

rade

C s

tudi

es.

m. I

ncon

sist

ency

in th

e st

atis

tical

sig

nific

ance

of e

ffect

..

n. B

P an

d di

et ti

ghtly

con

trolle

d in

som

e of

the

stud

ies.

o.

2 s

tudi

es o

f low

qua

lity

and

shor

t dur

atio

n to

mea

sure

out

com

e.

p. S

eizu

res

wer

e no

t prim

ary

or s

econ

dary

out

com

es o

f the

stu

dies

. q.

3 G

rade

A, 1

Gra

de B

and

3 G

rade

C s

tudi

es.

r. Th

e im

porta

nce

of th

e in

cons

iste

ncie

s is

diff

icul

t to

asse

ss g

iven

poo

r qua

lity

of re

porti

ng.

s. D

iffer

ent o

utco

me

mea

sure

s us

ed w

ith v

aria

ble

and

unce

rtain

clin

ical

rele

vanc

e, in

cons

iste

nt

repo

rting

on

BP a

s an

out

com

e.


ffect size, and strength of evidence generallyre lower in patients with ND-CKD than patientsith HD-CKD or PD-CKD, the direction of

ffect for key outcomes appears to be the same.ccordingly, the guideline statement is designed

o address all anemic patients with CKD regard-ess of the presence, absence, or mode of dialysisherapy.

Endpoints measured to support the statementhat Target Hb levels should be maintained atreater than 11 g/dL reflect key clinical out-omes important to patients. Measured outcomesnclude all-cause mortality, nonfatal cardiovascu-ar events, LVH, hospitalization, QOL, transfu-ion requirement, access thrombosis, other throm-oembolic events, seizure, blood pressure change,ialysis adequacy in patients with HD-CKD, andidney disease progression in patients with ND-KD (Table 12 and 16). Accordingly, the Workroup rated the importance of these outcomes asigh or moderately high (Table 20 and Table 21).Most distinct-target RCTs clearly have inad-

quate power to compare AE rates between pa-ients in lower and higher Hb target groups forhe key safety outcomes, mortality, MI, and cere-rovascular events (Table 12 and 16). There are 2xceptions. In patients with HD-CKD with CVD,atients assigned to a Hb target level of 14 g/dLhowed increased risk for death or MI comparedith patients assigned to an Hb level of 10/dL,108 a finding that did not reach significancerelative risk [RR], 1.3; 95% CI, 0.9 to 1.9).owever, safety concerns prompted early study

ermination. In a second trial of patients withD-CKD without symptomatic heart disease or

eft ventricular dilation, patients assigned to a Hbarget of 13.5 to 14.5 g/dL showed a greater ratef cerebrovascular events than those assigned ton Hb target range of 9.5 to 11.5 g/dL (P �.045).109

The risk for vascular access thrombosis inatients with HD-CKD likely increases as thearget Hb level increases, over a wide range ofotential Hb level targets. Patients assigned tob targets of either 9.5 to 11 or 11.5 to 13 g/dL

how increased access thrombosis compared withlacebo-treated controls,49 as do patients as-igned to a Hb target of 14 g/dL compared withhose assigned to a target of 10 g/dL.108 Nativerteriovenous fistulae fare no better than arterio-

venous grafts.49,108Fo * E a. b. c.

d. e. f. g. h. i.

iraIlalaeblt(arecsudtb

aHT

fCt

tcptvuufttHsast

vctetd

fl 991 (s1


Substantial blood pressure increases requiringntervention are seen in ESA-treated patientsegardless of Hb target compared with thosessigned to placebo or no-ESA control groups.ncreased antihypertensive use to achieve equiva-ent blood pressure also has been seen in patientsssigned to higher Hb targets compared withower Hb targets.109,110 However, use of placebond no-treatment control groups is confined toarly trials in which patients entered with lowaseline Hb levels and, with treatment, showedarge relative differences between achieved Hbarget (upper or lower) and baseline Hb levelsFig 16). Blood pressure effects between uppernd lower Hb targets appear less prominent inecent trials compared with earlier trials; how-ver, it is unclear whether this difference isaused by relatively high baseline Hb levels,mall differences between baseline and eitherpper and lower target achieved Hb levels, smallifferences between upper and lower achievedarget levels, or differences in patient selectionetween early and more recent trials.Hospitalizations and seizures appear not to be

ffected by target Hb level in patients with eitherD-CKD, PD-CKD, or ND-CKD (Table 20 and

Fig 15. Target and achieved Hb levels in 18 RCTs coor ESA therapy. Whiskers denote the assigned (intent-egend). Not shown is Lim 1989, Berns 1999, Abraham 12 through Table 21.

able 21). Dialysis adequacy is lower and trans- h

usions less frequent among patients with HD-KD in higher-target compared to lower-target

reatment groups (Table 20).In patients with ND-CKD, the effect of Hb

arget on progression of kidney disease is un-lear. Eight RCTs enrolling more than 500 totalatients yielded inconsistent results. Individualrials showed either prolongation of kidney sur-ival, acceleration of progression to kidney fail-re, or no effect, but many of the trials werenderpowered to detect potentially relevant ef-ects in either direction. Because of this limita-ion, the unavoidable use of compound interven-ions (early versus late plus lower versus higherb targets), and the lack of consistency in re-

ults, the Work Group concluded that consider-tions of kidney disease progression currentlyhould not influence the determination of Hbargets in patients with ND-CKD.

QOL outcomes—particularly those reflectingitality, fatigue, and physical function—show aonsistent positive relationship to level of Hbarget that appears to be continuous within thexamined Hb level range of 6 to 16 g/dL. Pa-ients report greater vitality, less fatigue, lessepression, and improved physical symptoms at

g higher against lower (or placebo/control) Hb targetst) Hb target, data points denote achieved Hb level (seeee Tables 12 and 14). For literature citations, see Table

mparinto-trea

igher compared with lower Hb targets. These

rcwdrfeHeWp

bcHtecrcltHggtuHgt

tcCntenb

iaciaatp

rb1nmipl

td

ttlu ture ci


esults appear to be instrument dependent be-ause differences are more readily discernableith testing instruments specific for CKD. Otherimensions of QOL show less consistent resultsegardless of the instrument used. Although ef-ect size of QOL outcomes and the quality ofvidence are lower in ND-CKD compared withD-CKD and PD-CKD trials, the direction of

ffect is similar in all populations tested. Theork Group rated QOL as highly important to

atients (Table 20 and Table 21).In developing the statement Hb level should

e 11.0 g/dL or greater, the Work Group con-luded that—when comparing higher with lowerb targets—QOL is a sufficient and, apparently,

he sole determinant of treatment benefit. How-ver, both the design of the RCTs supporting thatonclusion and the continuous nature of theelationship between QOL and Hb level posehallenges to translating evidence into a guide-ine statement. Hb targets in RCTs are designedo ensure separation of treatment results in higherb target groups compared with lower Hb targetroups to maximize the possibility that between-roup treatment effects will be detected. Theseargets, whether represented as discrete Hb val-es (eg, 10.0 versus 14.0 g/dL108) or a range ofb values (eg, 9.0 to 10.0 versus 12.0 to 13.0/dL38), (1) were not intended to serve as Hb

Fig 16. Baseline mean pretreatment Hb levels comarget. Results for achieved lower target Hb levels arearget groups, n � 14 total), Berns 1999 (n � 24), and Klevel approaches or exceeds the achieved target Hb levpper achieved Hb levels are relatively small. For litera

argets for anemia management in clinical prac- s

ice, (2) are ill suited to the purpose of measuringlinical performance, and (3) if adopted as aPG, would discourage flexibility in meeting theeeds of individual patients. Moreover, becausehe relationship between QOL and Hb level thatmerges from RCT results is continuous, there iso specific threshold Hb value to distinguishetween the presence and absence of benefit.The Work Group considered, but rejected,

dentifying a discrete Hb value (eg, 11.0 g/dL) asHb target. A discrete target Hb level affords

larity and simplicity, but is almost universallympossible to achieve, renders implementations a performance measure difficult, and discour-ges flexibility in using tradeoff decision makingo meet the needs and preferences of individualatients.Similarly, the Work Group considered, but

ejected, identifying a target Hb level boundedy narrow upper and lower values (eg, 11.0 to2.0 g/dL). Such a target affords neither clarityor simplicity, is possible to achieve in only ainority of patients,111-113 discourages flexibil-

ty in managing individual patients, and likelyromotes cycling of Hb results greater than andess than the target.114

The Work Group chose to define a broadherapeutic range of Hb levels bounded by aiscrete lower threshold above which Hb level

with achieved mean Hb levels in the upper and lowerown for placebo/control groups. Data for Lim 1989 (4n 1989 (n � 14) not shown. In recent trials, baseline Hbrly trials, and differences between baseline and target

tations, see Table 20 and Table 21.

parednot sheinmael of ea

hould be maintained and a upper threshold

atnasttnsa(lRet1bp

atrgtvwlcts

imE

sattsgfpttttfasl

tcpde1ocgpntt

icoimrttcre

caaeththpnamekp

ataitiwg


bove which Hb should not be routinely main-ained. This approach makes clear to the practitio-er that no patient should be maintained intention-lly at less than the lower threshold, and patientshould not be routinely maintained at greaterhan the upper threshold. We chose 11.0 g/dL ashe lower Hb level threshold. Hb values at orear 11.0 g/dL comprise an approximate water-hed, defining the upper Hb targets of early RCTsnd the lower targets of more recent trialsFig 15). Thus, evidence to support the lowerimit of Hb statement draws on the full range ofCTs available and the full range of Hb targetsxamined. This evidence supports the conclusionhat patients treated to a Hb target greater than1.0 g/dL likely will experience measurable QOLenefits with little or no increase in AEs com-ared with treatment at lower Hb levels.Hb values greater than 11 g/dL are readily

chievable. Greater than 80% of prevalent pa-ients with HD-CKD in the United States cur-ently demonstrate Hb levels of 11.0 g/dL orreater.28 Among patients with a Hb level lesshan 11.0 g/dL, greater than 99.6% achieve Hbalues of 11.0 g/dL or greater within 6 monthshen prescribed sufficient ESA. Thus, the guide-

ine as stated can be implemented readily inlinical practice and provides a rational founda-ion for developing clinical performance mea-ures for anemia management.

In the opinion of the Work Group, there isnsufficient evidence to recommend routinelyaintaining Hb levels at 13.0 g/dL or greater inSA-treated patients.Evidence reviewed in the foregoing rationale

upports the conclusion that QOL benefits associ-ted with treating to a higher Hb target extendhroughout the full range of Hb targets examinedo date, spanning 6 to 16 g/dL. However, theame evidence suggests that treating to Hb tar-ets greater than 13 g/dL may increase the riskor serious AEs. The only trial that had sufficientower to examine safety assigned patients to aarget Hb level of 14.0 g/dL in the higher-targetreatment arms108 and compared outcomes withhose seen in patients assigned to a lower Hbarget (10.0 g/dL). That trial was discontinuedor safety concerns. In a second trial, patientsssigned to a higher Hb target (13.5 to 14.5 g/dL)howed an increased incidence of cerebrovascu-
ar AEs compared with those assigned to a lower t
arget (9.5 to 11.5 g/dL).109 Two additional trialsompared the efficacy and safety of Hb targets inatients with ND-CKD, Cardiovascular Risk Re-uction by Early Anemia Treatment With Epo-tin Beta Trial (CREATE; Hb level of 10.5 to1.5 versus 13.0 to 15.0 g/dL)115 and Correctionf Hemoglobin and Outcomes in Renal Insuffi-iency (CHOIR; Hb level of 11.3 versus 13.5/dL).115A The CREATE trial has been com-leted, whereas the CHOIR trial has been termi-ated early by decision of the trial safety commit-ee. Results from either trial are not published athe time of this writing.

In short, efforts to gain QOL benefits by treat-ng to Hb targets of 13 g/dL or greater areountered by increased risk for life-threateningr disabling AEs. The statement that There isnsufficient evidence to recommend routinelyaintaining Hb levels at 13.0 g/dL or greater

ecognizes the concern that, for most patients,he known risks outweigh the known benefits ofreating to higher Hb level. The phrase insuffi-ient evidence reflects the finding that publishedesults from comparative trials large enough toxamine safety are relatively limited.

Moreover, the word routinely reflects the cru-ial limitations of currently available evidencend the need for further investigation. For ex-mple, no clinical trial conducted to date hasxamined target Hb safety and efficacy in selec-ive subgroups that may especially benefit fromigher Hb targets, including, for example, pa-ients who live at high altitude, are employed,ave pulmonary disease, have high levels ofhysical performance, or undergo daily or noctur-al HD. In the absence of information in thesend other potential subgroups, medical decisionaking requires weighing known risks and ben-

fits in mixed-study populations against un-nown risks and unknown benefits in individualatients.The statement Routinely maintaining patients

t Hb levels of 13 g/dL or greater makes it clearhat the recommended upper limit of Hb levelpplies only to patients considered for maintain-ng a Hb level at 13 g/dL or greater as areatment target, not patients for whom Hb levels likely to transiently equal or exceed 13 g/dLhile undergoing treatment for a lower Hb tar-et, and not patients who do not require ESA
herapy. Given the biological variation in Hb

ltgsgst

L

qtlittolhf9gbaoHdtw

ttwabtGspfitl

d

chtt

Q

otcQatpmaresf

DA

ttbw

bittamiasepinc


evels in patients with HD-CKD, if the intent ofreatment is to maintain Hb levels at 11.0 g/dL orreater, a sizeable fraction of patients will neces-arily show Hb values transiently at 13 g/dL orreater. Judicious ESA dose adjustments appearufficient to correct Hb values above intendedargets within 3 to 6 months.112

LIMITATIONS

imits of Available RCTs

The strength of an RCT is to study a specificuestion by studying the efficacy of an interven-ion on specific outcomes in a well-defined popu-ation. Findings from RCTs thus are often limitedn their generalizability to diverse populations oro questions related to effectiveness of combina-ions of interventions on combinations of patientutcomes. These latter questions are what guide-ines attempt to address. For example, consider aypothetical study designed to compare the ef-ect of 3 Hb treatment targets: Hb level less thang/dL, Hb level of 9 to 12 g/dL, and Hb level

reater than 12 g/dL. Patient populations shoulde separated into patients with or without CVDnd: (1) ND-CKD, (2) HD-CKD, (3) PD-CKD,r (4) transplant-associated CKD. Each discreetb target, CVD status, and each CKD categoryeserves scrutiny. However, this is unfeasible:he hypothetical RCT would collapse under theeight of a 3 � 2 � 4 (24-group) study design.Imagine instead constructing a 24-cell matrix

o represent all possible combinations of Hbargets, CVD status, and CKD categories that weish to examine. If we added all the results from

ll available RCTs to the specific cells addressedy the available RCTs, we would have to leavehe vast majority of cells empty at this writing.iven the small number of RCTs and the small

ize of most of the available RCTs, and given theotential differences between target populations,lling in empty cells by extending results from

he few completed cells seems unwarranted andikely to involve substantial error.

Another critical limitation of the evidence, as
iscussed, is the lack of information about the e
omparative safety and efficacy of lower versusigher Hb targets in selected subgroups of pa-ients that may especially benefit from higher Hbargets.

OL/QOL Trade-Off

QOL, like quantity of life, is a hard patientutcome. Available evidence confirms that set-ing Hb targets for individual patients requiresonsideration of the potential trade-off betweenOL and survival, MI, cerebrovascular event, or

ccess thrombosis. However, although we knowhat risk assessment varies widely by culture,ersonal values, level of education, and level ofedical literacy, we lack information on how to

ssist patients with CKD to interpret risk, judgeisk-benefit trade-offs, and express informed pref-rences. Nevertheless, in everyday medical deci-ion making, it is important to incorporate in-ormed patient preference.116

ifferences in Treatment Strategies Used Tochieve Defined Hb Targets

The duration of anemia before initiating ESAherapy and the size and rate of Hb level correc-ion each plausibly contributes to risk, benefit, oroth in anemia therapy. Information on eachould be directly helpful to clinicians.Similarly, it is possible that the risks and

enefits associated with a target Hb level dependn part on which therapeutic agents were used inhe treatment arm. All available hard-outcomerials to date have used both ESAs and irongents together in patients assigned to both treat-ent and control arms. No trial using ESA alone,

ron alone, or noniron adjuvants alone has beendequately designed and powered to confirm thatimilar Hb targets afford similar risks and ben-fits regardless of how they are attained. Theossibility that each potential class of agents,ncluding ESAs, oral iron, parenteral iron, andon-iron adjuvants, shows differing patient out-omes for equivalent Hb outcomes has not been
xplored.

Eatet

S

CPR 3.1. USING ESAs

tamEeaqlrEidobttt

D

SAs are critical components in managing thenemia of CKD. Available ESAs are each effec-ive in achieving and maintaining target Hb lev-ls. Aspects of administration may differ be-ween short-acting and long-acting agents.

3.1.1 Frequency of Hb monitoring:3.1.1.1 In the opinion of the Work

Group, the frequency of Hbmonitoring in patients treatedwith ESAs should be at leastmonthly.

3.1.2 ESA dosing:3.1.2.1 In the opinion of the Work

Group, the initial ESA doseand ESA dose adjustmentsshould be determined by thepatient’s Hb level, the targetHb level, the observed rate ofincrease in Hb level, and clini-cal circumstances.

3.1.2.2 In the opinion of the WorkGroup, ESA doses should bedecreased, but not necessarilywithheld, when a downwardadjustment of Hb level isneeded.

3.1.2.3 In the opinion of the WorkGroup, scheduled ESA dosesthat have been missed shouldbe replaced at the earliest pos-sible opportunity.

3.1.2.4 In the opinion of the WorkGroup, ESA administrationin ESA-dependent patientsshould continue during hospi-talization.

3.1.2.5 In the opinion of the WorkGroup, hypertension, vascu-lar access occlusion, inad-equate dialysis, history ofseizures, or compromised nu-tritional status are not contra-indications to ESA therapy.

3.1.3 Route of administration:3.1.3.1 In the opinion of the Work

Group, the route of ESA ad-ministration should be deter-
mined by the CKD stage, treat- m

ment setting, efficacy, safety,and class of ESA used.

3.1.3.2 In the opinion of the WorkGroup, convenience favorssubcutaneous (SC) adminis-tration in non–HD-CKD pa-tients.

3.1.3.3 In the opinion of the WorkGroup, convenience favors in-travenous (IV) administra-tion in HD-CKD patients.

3.1.4 Frequency of administration:3.1.4.1 In the opinion of the Work

Group, frequency of adminis-tration should be determinedby the CKD stage, treatmentsetting, efficacy consider-ations, and class of ESA.

3.1.4.2 In the opinion of the WorkGroup, convenience favors lessfrequent administration, par-ticularly in non–HD-CKDpatients.

BACKGROUNDThe decision to start ESA therapy in a pa-

ient with CKD-associated anemia invokes andditional series of decisions that must beade before the first dose is administered.ach of the following issues must be consid-red before moving forward: choosing an ESA,n initial ESA dose, and the route and fre-uency of ESA administration; planning a Hbevel monitoring schedule; predicting a desiredate of increase in Hb level; and anticipatingSA dose adjustments for Hb results, AEs, or

ntercurrent hospitalizations. Making informedecisions requires understanding the methodf action of ESAs, then selecting those whichest fit the patient, the patient-care setting, andhe constraints of the health care delivery sys-em from the range of choices that are knowno be safe and effective.

RATIONALE

efinitions

The term ESA applies to all agents that aug-
ent erythropoiesis through direct or indirect

aaadmTsce

F

ilsadtoEewEjtcmnEipiEHfHse9tt

ioitlimas

Eapm

E

mli

mlsntHtppClttTid(istai

mratEmHdacv

nmdt


ction on the erythropoietin receptor. Currentlyvailable ESAs include epoetin alfa, epoetin beta,nd darbepoetin. Epoetin alfa and beta have beenesigned to resemble closely the endogenousolecule and have similar pharmacokinetics.hey are considered “short-acting” in compari-on to darbepoetin, a second-generation mole-ule with a prolonged half-life, which is consid-red “long-acting.”

requency of Hb Monitoring

The statement The frequency of Hb monitor-ng in patients treated with ESA should be ateast monthly is intended to provide sufficienturveillance information to assist in achievingnd maintaining target Hb levels safely and expe-itiously during ESA therapy. This recommenda-ion, which fits common practice, follows a chainf reasoning. The minimum interval betweenSA dose adjustments is 2 weeks because theffect of most dose changes will not be seenithin a shorter interval. Consideration of anSA dose adjustment is based on the next pro-

ected Hb level. Because the accuracy of projec-ion (extrapolation) increases with the number ofontributing data points, the frequency of Hbonitoring is likely to be an important determi-

ant of the accuracy of ESA dose adjustment.vidence to support this line of reasoning is

ndirect. Several RCTs have randomized HDatients with target-range Hb levels to a changen frequency of ESA administration, a change inSA class, or both. RCTs that have monitoredb values weekly and adjusted ESA doses as

requently as every 2 weeks have achieved stableb levels early after randomization.136-138 A

ingle RCT that monitored Hb levels and consid-red ESA dose adjustment monthly required 6 tomonths to stabilize Hb levels after randomiza-

ion,139 but mean Hb level remained within thearget range for that trial.

Within the recommended ranges for monitor-ng and dose adjustment, unstable Hb level,ut-of-target Hb level, and HD favor shorterntervals, whereas stable Hb level, within-arget Hb level, PD, ND-CKD, and minimizingaboratory resource utilization favor longerntervals. The frequency of ESA dose adjust-ent is unaffected by length of action: during

n 8-week period, given Hb monitoring weekly,
hort-acting ESA thrice weekly or long-acting t
SA once weekly, and consideration for dosedjustment every 2 weeks, 44% to 49% ofatients will actually require dose adjust-ent.138

SA Dosing

The initial ESA dose and ESA dose adjust-ents should be determined by the patient’s Hb

evel, the target Hb level, the observed rate ofncrease in Hb level, and clinical circumstances.

This statement aims to guide medical decisionaking so that the initial rate of increase in Hb

evels is in keeping with the patient’s currenttatus, the treatment setting, and the patient’seed for anemia treatment. In general, the objec-ive of initial ESA therapy is a rate of increase inb levels of 1 to 2 g/dL per month. Evidence for

he safety of initial ESA therapy derives princi-ally from interventional trials in patients notreviously treated with ESAs. In patients withKD-associated anemia and initial Hb levels

ess than target range, these trials have shownhe mean initial rate of Hb level increase to be inhe range of 0.7 to 2.5 g/dL in the first 4 weeks.he rate of increase varies greatly and depends

n part on the patient population, initial dose,osing frequency, and route of administrationTable 22). Hypertension and seizures were notedn the first 3 months after initiating therapy ineverely anemic patients, but it is unclear whetherhese events occurred within the first 4 weeksnd whether they were related to the rate ofncrease in Hb levels.

In general, ESA dose adjustments were notade in the first 4 weeks of trials for which

esults are available. The frequency of ESA dosedjustment thereafter should be determined byhe rate of increase in Hb levels during initialSA therapy, the stability of Hb levels duringaintenance ESA therapy, and the frequency ofb testing. The minimum interval between ESAose adjustments in the outpatient setting gener-lly is 2 weeks because the effect of most dosehanges will not be seen within a shorter inter-al.ESA doses should be decreased, but not

ecessarily held, when a downward adjust-ent of Hb level is needed. Withholding ESAoses, particularly for long periods, may leado a delayed decrease in Hb levels to less than
arget range. Such a decrease may initiate

pafiaCdtsrrrt

bpmttpwu

loadtlatm

Es

R

mcAatfPHf(bDIao(

artotgHtt


eriodic cycling of Hb levels at greater thannd less than the target Hb range.114 Thisnding is in keeping with the mechanism ofction of ESA in preventing apoptotic death ofFU-Es and early erythroblasts. Should ESAoses be withheld in an ESA-dependent pa-ient, a prolonged loss of erythropoietic precur-ors may result. Accordingly, the Work Groupecommends that ESA doses not be withheldoutinely for Hb levels greater than targetange, hospitalization, poorly controlled hyper-ension, or vascular access occlusion.

The statement Scheduled ESA doses that haveeen missed should be replaced at the earliestossible opportunity reflects the concern thatissed doses of ESA, like held doses, may lead

o a delayed decrease in Hb levels to less thanarget range. This is illustrated most clearly inatients who receive ESA dosing every 2 to 4eeks, but the principle applies to all patientsndergoing ESA therapy.Similarly, the statement Hypertension, vascu-

ar access occlusion, inadequate dialysis, historyf seizures, or compromised nutritional statusre not contraindications to ESA therapy aims toiscourage the practice of withholding ESAherapy in the presence of conditions potentiallyinked to anemia treatment. If these disordersrise in the course of anemia therapy with ESA,hey should be treated appropriately with specific
easures. There is no evidence that withholding r
SA therapy improves patient outcomes in theseettings.

oute of Administration

The route of administration should be deter-ined by the CKD stage, treatment setting, effi-

acy considerations, and the class of ESA used.mong patients with HD-CKD, either SC or IV

dministration is possible. In the outpatient set-ing, SC administration is the only routinelyeasible route of administration for patients withD-CKD and ND-CKD. Among patients withD-CKD, either SC or IV administration is

easible, but the risk for pure red cell aplasiaPRCA) associated with SC administration, al-eit small, recently prompted the US Food andrug Administration (FDA) to recommend the

V route. The relationship between SC ESAdministration and risk for PRCA experiencedutside the United States is discussed elsewhereGuideline 3.5).

Among short-acting ESAs, efficacy of SCdministration in patients with HD-CKD is supe-ior to that of IV administration. Although manyrials have achieved similar results, the findingsf a single large multicenter RCT are sufficiento establish the strength of evidence for thisuideline statement.140 In this trial, patients withD-CKD were eligible for randomization only if

hey were currently receiving epoetin alfa andheir Hct was within the target range. Upon
andomization (from SC or IV to IV or SC), ESA

ddwltAaEtgssasstEdods

ce

F

m

cimciescweir

vtmtatEimt


oses were first decreased to allow Hb levels toecrease to less than target range. Doses thenere titrated upward to again achieve target Hct

evels, then were adjusted to maintain Hct in thearget range during a 26-week maintenance phase.mong patients who completed the trial, those

ssigned to SC administration showed 27% lowerSA doses than those assigned to IV administra-

ion. Mean achieved Hcts did not differ betweenroups. Of the patients who, by assignment,witched from IV to SC administration, 58%howed a decrease in ESA dose and 23% showedn increase; among their counterparts whowitched from SC to IV administration, the corre-ponding proportions were 28% and 49%, respec-ively. In short, SC administration of short-actingSAs is associated with an approximately 30%ecrease in ESA dose for the same target Hbutcome. However, not all patients show a doseecrease after conversion from IV to SC, andome will show a dose increase.

Among long-acting agents, efficacy of SCompared with IV administration appears to bequivalent at examined dosing frequencies.137,141

requency of Administration

Frequency of administration should be deter-
ined by the CKD treatment setting and the a
lass of ESA. Selecting frequency of ESA admin-stration may require a choice between maxi-um efficacy and optimum convenience and

omfort. Maximum efficacy occurs within dos-ng intervals that are ESA class specific. Forxample, in patients with HD-CKD receiving SChort-acting ESA therapy, ESA efficacy de-reases when the dosing is extended from thrice-eekly to once-weekly administration.139 When

very-2-week administration of long-acting ESAss extended to every 4 weeks, efficacy eitheremains stable142 or decreases incrementally.143

LIMITATIONS

In practice, the use of ESAs is subject to wideariability that reflects broad differences in prac-ice setting, patient preference, and reimburse-ent constraints. The definition of best practice

herefore should reflect both available evidencend prevailing conditions, preferences, and priori-ies. The evidence base for CPRs on the use ofSAs requires information generated from qual-

ty improvement programs and anemia manage-ent protocols that examine multiple interven-

ions and explicitly state underlying goals and
ssumptions.

eaaddipa

S

CPG AND CPR 3.2. USING IRON AGENTS

atplfApdltutsotuiadss

Anemia therapy in patients with CKD requiresffective use of iron agents, guided by appropri-te testing of iron status. Efficacy of iron therapyppears not to be limited to patients with evi-ence of iron deficiency. (See Guideline 1.2 foriagnosis of iron deficiency.) Thus, the goals ofron therapy are to avoid storage iron depletion,revent iron-deficient erythropoiesis, and achievend maintain target Hb levels.

3.2.1 Frequency of iron status tests:In the opinion of the Work Group,iron status tests should be performedas follows:3.2.1.1 Every month during initial

ESA treatment.3.2.1.2 At least every 3 months dur-

ing stable ESA treatment or inpatients with HD-CKD nottreated with an ESA.

3.2.2 Interpretation of iron status tests:In the opinion of the Work Group,results of iron status tests, Hb, andESA dose should be interpreted to-gether to guide iron therapy.

3.2.3 Targets of iron therapy:In the opinion of the Work Group,sufficient iron should be administeredto generally maintain the followingindices of iron status during ESAtreatment:3.2.3.1 HD-CKD:

● Serum ferritin >200 ng/mLAND● TSAT >20%, or CHr >29pg/cell.

3.2.3.2 ND-CKD and PD-CKD:● Serum ferritin >100 ng/mLAND● TSAT >20%.

3.2.4 Upper level of ferritin:In the opinion of the Work Group,there is insufficient evidence to recom-mend routine administration of IV ironif serum ferritin level is greater than500 ng/mL. When ferritin level isgreater than 500 ng/mL, decisions re-
garding IV iron administration should N

weigh ESA responsiveness, Hb andTSAT level, and the patient’s clinicalstatus.

3.2.5 Route of administration:

3.2.5.1 The preferred route ofadministration is IV inpatients with HD-CKD.(STRONG RECOMMEN-DATION)

3.2.5.2 In the opinion of the WorkGroup, the route of iron ad-ministration can be either IVor oral in patients with ND-CKD or PD-CKD.

3.2.6 Hypersensitivity reactions:In the opinion of the Work Group,resuscitative medication and person-nel trained to evaluate and resuscitateanaphylaxis should be available when-ever a dose of iron dextran isadministered.

BACKGROUND

The goal of iron therapy in a patient withnemia and CKD is to achieve and maintain aarget-range Hb level. Iron agents may serve asrimary therapy for selected patients (particu-arly those with ND-CKD) or as adjuvant therapyor those also undergoing treatment with an ESA.dministered as adjuvants to ESAs, iron agentsrevent iron deficiency and serve to minimize theose of ESA needed to achieve target-range Hbevels. Designing appropriate iron therapy for pa-ients with CKD-associated anemia requires annderstanding of the interpretation of iron statusest results, the therapeutic significance of irontatus levels, and the therapeutic and safety limitsf iron administration. Selecting a route of adminis-ration, dose, and class of iron agent requires annderstanding of the efficacy, safety, and tolerabil-ty of available iron therapeutics. The stage of CKDnd treatment setting (HD-CKD and PD-CKD)eserve consideration not only for practical rea-ons, but also because the quantity, quality, andtrength of evidence vary among patients with
D-CKD, HD-CKD, and PD-CKD.

FE

eadta

mtttdctilmah

t

IS

tiEmbiiaaoew

Irfltitmtdcmlgbiat

icmstcc

T

uAiiawict

ttiitHitETg


RATIONALE

requency of Iron Status Tests Should Bevery 1 to 3 Months

The purpose of iron status testing is to eithervaluate anemia or guide the use of iron agents tochieve and maintain targets of iron therapyuring anemia management. Use and interpreta-ion of iron status tests in the initial evaluation ofnemia are described in Guideline 1.2.

Frequency of iron status testing during anemiaanagement should be determined by the pa-

ient’s Hb level relative to the target range and byhe likelihood of blood loss. Initiation of ESAherapy, correction of a less-than-target Hb leveluring ongoing ESA therapy, bleeding, and surgi-al procedures each are likely to promote deple-ion of iron stores and thereby may call forncreased frequency of iron status testing. Simi-arly, iron status testing is appropriate after treat-ent with a course of IV iron, to monitor safety

nd adequacy of therapy, and in a patient withyporesponsiveness to ESA.Clinical settings in which more frequent iron

esting may be necessary include the following:

1. Initiation of ESA therapy2. Correction of a less-than-target Hb level

during ongoing ESA therapy3. Recent bleeding4. After surgery5. After hospitalization6. Monitoring response after a course of IV

iron7. Evaluation for ESA hyporesponse.

nterpretation of Iron Status Test Resultshould Incorporate Hb and ESA Dose

In a patient undergoing ESA therapy, interpre-ation of the results of iron status tests shouldncorporate consideration of the Hb level andSA dose. Together, these results provide infor-ation important to medical decision making

ecause they elucidate the status of both externalron balance (net loss or gain of iron) and internalron balance (disposition of iron between storesnd circulating red blood corpuscles). For ex-mple, a decreasing ferritin level in the presencef a stable or decreasing Hb level may signifyxternal iron loss (GI bleeding or, in patients
ith HD-CKD, dialysis-associated blood loss). H
n this case, iron therapy may be indicated toeplace iron deficits. Conversely, a decreasingerritin level in the presence of an increasing Hbevel signifies an internal shift in iron from storeso Hb, as would be expected in a patient respond-ng to ESA therapy. If iron status remains withinhe target range, additional iron administrationay not be required. If the Hb level is greater

han the target range and is being corrected byecreasing the ESA dose, ferritin level may in-rease as the Hb level corrects. Again, no ironay be needed. Finally, an increase in ferritin

evel accompanied by a decrease in TSAT sug-ests inflammation-mediated reticuloendotheliallockade and may be accompanied by a decreasen Hb level and increase in ESA dose. Whethernd to what extent iron administration is effec-ive and safe in this setting remains unresolved.

In short, medical decision making in usingron agents—including initiation of iron therapy,hoice of route of iron administration, and deter-ination of dose and duration of iron therapy—

hould be guided by results of iron status testsaken together with Hb levels and ESA dose,ombined with a trend analysis of how each hashanged over time.

argets of Iron Therapy

In this section, we distinguish the therapeuticse of iron status tests from their diagnostic use.s diagnostic indices, iron status tests are helpful

n determining the likelihood that iron deficiencys contributing to a low Hb level in patients withnemia and CKD (Guideline 1.2). In all patientsith CKD, as in non-CKD patients, evidence of

ron depletion and iron deficiency should promptonsideration of blood loss, and further evalua-ion may be needed (Guideline 1.2).

By contrast the statement Targets of ironherapy refers to results of iron status tests asreatment targets for the safe and effective use ofron agents. In patients receiving ESA therapy,ron status treatment targets serve to minimizehe ESA doses required to maintain target-rangeb levels. In patients not receiving ESA therapy,

ron status treatment targets serve to maximizehe Hb level and minimize the need to initiateSA therapy to achieve target-range Hb levels.argets of iron therapy reflect the treat-to-targetoals for the use of iron agents in patients with
D-CKD, ND-CKD, and PD-CKD with anemia.

I

idilao(NpGbs

mont(ranTmscedltspf4oPfil

hlebaaApiTdpsgwraHp1

gl2stfnmog2es

tp


ron Targets in Patients With HD-CKDEvidence to support the development of an

ron target guideline in patients with HD-CKD israwn from tissue iron studies (semiquantitativeron in bone marrow and quantitative iron iniver), iron challenge tests (response to IV irondministration), nonrandomized trials (efficacyf single-target IV iron intervention), and RCTscomparing efficacy of 2 different iron targets).o iron intervention trial has been sufficientlyowered to assess safety. Therefore, the Workroup sought to recommend iron targets thatalance efficacy with assumptions regardingafety.

Serum ferritin level greater than 200 ng/L. Earlier versions of KDOQI guidelines rec-mmended a target ferritin level greater than 100g/mL. Two RCTs provide comparative informa-ion on iron status targets for IV iron therapyTable 23). In 1 RCT, patients with HD-CKDandomized to maintain TSAT at 20% to 30%chieved a mean serum ferritin level of 297g/mL compared with those randomized to aSAT of 30% to 50%, who achieved 730 ng/L.148 Patients in the higher TSAT target group

howed a mean 40% reduction in ESA doseompared with those in the lower group. How-ver, the trial was small; iron status targets wereefined by TSAT, not ferritin level; and ferritinevel in the high-target TSAT group increasedhroughout the trial and had not reached a steadytate by the end of study. In the second trial,atients with HD-CKD assigned to a 200-ng/mLerritin target compared with those assigned to a00-ng/mL target achieved mean ferritin levelsf 299 compared with 469 ng/mL, respectively.atients in the higher serum ferritin group hadnal ESA doses 28% lower than those in the

Table 23. RCTs for Ferritin

cseD enilesaB

Author, Year

NFo

llow

-up

(m

o)

App

licab

ility

Hb

(g/d

L)

ESA

Dos

e

Ferr

itin

(ng/

mL)

TSA

T (%

)

Co-intervention

23 10.6 3,625 IU

TIW iH 6.42 582

Besarab, 2000 148

19

6

10.5 3,782 IU

TIW 287 23.9

ESA adjusted to maintain baseline Hb

Lo

19 9.8 312

IU/kg/wk hgiH dn 661

DeVita2003 149

175

10.2 250

IU/kg/wk 204 nd

ESA adjusted to maintain Hb of 10.8-

12 g/dL L

Footnotes: a. Range of mean TSAT for months 4-6. b. Arm 1: 52% vs. Arm 2: 21% had at least a 20% reduction in ESA dose (P <0.05).

ower ferritin group.149 R

Other available evidence reflects the likeli-ood of responsiveness to IV iron, but affordsittle information on the comparative safety andfficacy of iron status targets. Patients with highaseline ferritin levels (mean, 930 ng/mL) weredministered IV iron if TSAT was less than 50%nd ferritin level was less than 1,000 ng/mL.fter receiving an average IV iron dose of 38 mger week for 12 months, patients showed anncrease in ferritin (mean, 1,383 ng/mL) andSAT (from 27% to 36%) values and a 25% ESAose decrease.150 Bone marrow examination inatients with HD-CKD may reveal little or notainable iron in patients with ferritin levelsreater than 100 ng/mL,98 particularly in patientsith evidence of inflammation.99 It has been

eported that IV iron challenge is associated withpositive response (an increase in reticulocyte orb values or a decrease in ESA dose) in manyatients with serum ferritin levels greater than00 ng/mL (Table 24).151-156

Taken together, the evidence suggests thatreater efficacy may be achieved if the lowerimit of the ferritin target were greater than the00 ng/mL threshold. However, given the ab-ence of reliable safety information in clinicalrials, uncertainty about the relevance of resultsrom uncontrolled trials, bone marrow iron exami-ation, IV iron challenge studies to iron treat-ent targets, and the concern for the risk for iron

verload, the statement that serum ferritin levelsenerally should be maintained at greater than00 ng/mL reflects acceptable—if not maximal—fficacy and a cautious consideration for patientafety.

TSAT greater than 20%. The recommendedreatment target of TSAT is 20%, similar torevious KDOQI recommendations. In a single

T Targets in the HD-CKD Population

2 mrA .sv 1 mrA emoctuO s

Intervention Target

(Achieved) Definition Result

P-va

lue

Qua

lity

IV iron dextran 100 mg for 4-6 HD sessions

followed by 25-150 mg/wk

30-50(30.9-34.9) a

Weekly doses of IV iron dextran

25-150 mg/wk

20-30(24.5-27.6)

ESA dose

Arm 1 approximately 40% less than

arm 2 at months 4-6 b

0.004

)L400

(469) IV iron dextran if below target

100 mg for 10 HD sessions 200(299)

Mean decrease in ESA dose

154 vs. 31 IU/kg/wk

<0.001

and TSA

mrA fo noitpir

Arm 1

Arm 2

)%( TAST hg

w TSAT (%)

m/gn( nitirreF

ow Ferritin (ng/mL)

CT comparing higher to lower TSAT targets,

p5ctsaTtlm

aAmc(dg(2s


atients randomized to a target TSAT of 30% to0% demonstrated a 40% reduction in ESA doseompared with those assigned to a target of 20%o 30% (Table 23).148 As is the situation forerum ferritin level, other sources of evidencere indirect and of uncertain value in settingSAT targets. In an uncontrolled prospective

rial described previously, patients with high base-ine ferritin levels (mean, 930 ng/mL) were ad-inistered IV iron if TSAT was less than 50%

of nitirreF enilesaB fo eulaV .42 elbaT hilekiL gnissessA r

egnellahC

esoD egarevA N raeY ,rohtuA

egnaR fo )naem( enilesaB

nitirreF )Lm/gn(

)naem( egnaR enilesaB fo

tnegA )%( TASTesoD evitalumuC

nitirreF

gm 001 ,enabhsiF

6991 251 74006<

141( d) 1.22( d nartxed nori VI )

gm 000,1

gm 04 1002 ,niL 161 23

005-001 )011 ± 012(

6.54-3.21 )8.01 ± 9.72(

edixo cirref VI gm 069

,namttiM7991 551 77

006<931( d)

05< 6.32( d)

gm 005 nartxed nori VI

gm 04 ,ikiustiM3002 951 72

002-01 f

48( d)54-01 f

7.72( d)

nitiordnohc VI nori-etaflus

diolloc gm 023

secidnI lanoitiddA + nitirreF

gm 26 ro 13 ,erotisseT

1002 451 102( 521 d 3.22( ) d)

muidos VI cirref

etanoculg xelpmoc

gm 077,1-286

gm 001 ,gnauhC

3002 351 56005<

032( d) 1.83( d)

nori VI etarahccas

gm 002,2

:setontooF .egnellahc nori ot roirp puorgbus fo nitirref mures naeM .a

tuo eht htiw slaudividni( fo oitar eht ot srefer ytivitisneS .b lohserht tset eht evah ohw emoc a( yb dedivid )d ll eht tuohtiw slaudividni( fo oitar eht ot srefer yticificepS .c divid )dlohserht tset eht evah ton od ohw emoctuo

.detaluclaC .d .04 yb dedivid tcH eht yb deilpitlum tnuoc etycoluciter = IRC .e

.hparg morf detamitsE .f setycorhtyre cimorhcopyH .g

Table 25. Value of Ferritin in A

Author, Year N CKD Stage

Range (mean) of

Concurrent TSAT (%)

Range (mean) of Concurrent

Ferritin (ng/mL)

Test Organ

Iron Determination

Iron Excess

Canavese, 2004 163 40 HD-CKD

7-86 (33 ± 15)

14-886 (361 ± 224) Liver

SQUID (quantitative hepatic iron)

Iron Deficiency

Fernandez-Rodriguez, 1999 98

63 HD-CKDPD-CKD

(18.1 ± 16.3) (273.1 ± 357) Bonemarrow

Stainable ironin aspirate (qualitative)

Kalantar-Zadeh, 1995 99

25

HD-CKDPD-CKD ND-CKD

Tx-ND-CKD

4-50 19-1,840 Bone

marrow

Stainable ironin aspirate (qualitative)

Footnotes: a. Sensitivity refers to patients with the Test Threshold Ferritin who havethe Outcome Definition / (patients with Test Tb. Specificity refers to patients without the Test Threshold Ferritin who do not have the Outcome Definition / (patients

Outcome Definition). c. Estimated from graph.

nd ferritin level was less than 1,000 ng/mL.fter receiving an average IV iron dose of 38g/wk for 12 months, patients showed an in-

rease in ferritin (mean, 1,383 ng/mL) and TSATfrom 27% to 36%) values and a 25% ESA doseecrease.150 Patients with a TSAT of 20% orreater may still show absent bone marrow ironTable 25) or respond to IV iron challenge (Table6).98,99,151-156 The statement that TSAT generallyhould be maintained at greater than 20% therefore

noitalupoP DKC-DH eht ni yparehT norI VI ot esnopse

srednopsernoN srednopseR

noi

emoctuO noitinifeD(

fo)esnopseR

tnemtaerterP )Lm/gn( nitirreF a

tnemtaerterP )Lm/gn( nitirreF a

Ferr

itin

Th

resh

old

(n

g/m

L)

Sens

itivi

ty b

Spec

ifici

ty c

%0 %001 005< %81 %09 003< %43 %66 %73 %77 002< %96 %17 051< %57 %84 001<

D sno

tcH ≥ ro %5 esod ASE

≥ %01 om 2 nI 121 ± 281 611 ± 021

%57 %73 05< %71 %69 004<

%91 %18 %81 %48 003< D

sno bH ≥ Ld/g 1

kw 8 ni %33 %05 002< 821 ± 291 701 ± 412

%21 %88 D noi

IRC e ≥ %1 kw 2 ni 361 ± 141 001 ± 521

%35 %83 001<

%73 %36 rof y k

bH ≥ Ld/g 1 kw 8 ni 47 ± 39 36 ± 87

%06 %56 001<

dna 05<

opyH g %6> %98 %28

%95 %14 dna 001<

%02< TAST %16 %96

%87 %53 001<

DH noi kw

bH ≥ %51 kw 91-6 ni

721 ± 522 511 ± 561 %59 %02 05< %75 %38 003<

%53 %56 dna 003< gp 82< rHC

%39 %36 4 ro

ne kw 2

om

tcH ≥ ro %3 ASE ≥ %03

om 6 ni 131 ± 392 731 ± 591

dna 003> gp 82> rHC

%89 %25

i .yduts hcae yb denifed sa esnopser a ot srefer emoctuO .)emoctuo eht hti .yduts hcae yb denifed sa esnopser a ot srefer emoctuO .)emoctuo eht tuohtiw slaudiv

g Iron Storage Excess or Deficiency

Outcome Definition

Most Recent Iron Therapy

Ferr

itin

Thre

shol

d

(ng/

mL)

Sens

itivi

ty

Spec

ifici

ty

Patient Population

>340 57% 75% >450 46%c 82% >500 39%c 92%

Iron excess: >400 µg/g hepatic iron

None for 6 mo (n = 10)

None for 2 mo (n = 30) >600 25%c 100%

Relatively unselected, mean Hb 11.4 g/dL,

mean albumin 3.6 g/dL

<600 98% 14% <300 92% 36% <200 86% 55% <150 81% 65% <100 72% 80%

Iron deficiency: 0 stainable

iron

No IV iron for 3 mo

<50 50% 95%

Relatively unselected, mean Hb 10.6 g/dL,

mean albumin 3.9 g/dL

Iron deficiency:

0 to +1 stainable iron

None for 13-30 d

<200 50% 87%

Selected for unexplained Hb <11 g/dL; mean

albumin 2.8 g/dL, only 4 patients with albumin

>3.4 g/dL

ritin who have the Outcome Definition plus those with Test Threshold who do not have the Outcome Definition). st Threshold Ferritin who do not havethe Outcome Definition plus those with the Test Threshold who do not have the

R fo doo

taruD

H 01isses

H 42isses

H 1sses

lkeeWw 8

hcaEsses 91-6

f WITht kw yreve 5 rof

w slaudividnidni lla( yb de

ssessin

TestResultScale

µg/g wet

weight

0 to +3

0 to +5

hreshold Ferwithout the Te

rc

s2atAlnbplttw

Itntsbssl(btA

iz


eflects acceptable, if not maximal, efficacy and aautious consideration for patient safety.

CHr greater than 29 pg/cell. Evidence toupport a treatment target for CHr is drawn fromRCTs comparing the use of CHr with TSAT as

n iron target. In the first, patients were assignedo receive IV iron for a CHr less than 29 pg/cell.

control group received IV iron for either TSATess than 20% or ferritin level less than 100g/mL. Ferritin and TSAT were followed up inoth groups, and IV iron was withheld in anyatient with a TSAT greater than 50% or ferritinevel greater than 800 ng/mL. Patients assignedo CHr targets showed a lower cost of anemiareatment and a decrease in IV iron use comparedith those assigned to TSAT/ferritin targets.157

ohilekiL gnissessA rof TAST enilesaB fo eulaV .62 elbaT

egnellahC

esoD egarevA N raeY ,rohtuA

egnaR fo )naem( enilesaB )%( TAST


nitirreF )Lm/gn(

tnegA esoD evitalumuC

gm 001 ,enabhsiF

6991 251 1.22( 74 d nartxed nori VI 006< )

gm 000,1

gm 04 1002 ,niL 161 23

6.54-3.21 )8.01 ± 9.72(

005-001 )901 ± 902(

edixo cirref VI gm 069

,namttiM7991 551 97

05< 6.32( d)

006<931( d)


gm 04 ,ikiustiM3002 951 72

54-01 f

7.72( c)022-01 f

48( d)


diolloc gm 023


1002 451 3.22( 521 d 102( ) d)

muidos VI cirref

etanoculg xelpmoc

gm 077,1-286

:setontooF .egnellahc nori ot roirp puorgbus fo TAST naeM .a

tuo eht htiw slaudividni( fo oitar eht ot srefer ytivitisneS .b lohserht tset eht evah ohw emoc a( yb dedivid )d ll eht tuohtiw slaudividni( fo oitar eht ot srefer yticificepS .c divid )dlohserht tset eht evah ton od ohw emoctuo

enilesab egareva dethgiew detaluclaC .d .srednopsernon dna srednopser fo seulav .04 yb dedivid tcH eht yb deilpitlum tnuoc etycoluciter = IRC .e

.hparg morf detamitsE .f

essA rof rHC enilesaB fo eulaV .72 elbaT

egnellahC

esoD egarevA N raeY ,rohtuA )naem( egnaR

enilesaB fo )gp( rHC


nitirreF )Lm/gn(

tnegAsoD evitalumuC

,namttiM7991 551 1.92( 77 d)

006<931( d )


gm 04 ,ikiustiM3002 951 72

43-62 e

2.13( d)022-01 e


diolloc gm 023


1002 451 5.03( 521 d 102( ) d) cirref muidos

etanoculg xelpmoc gm 077,1-286

gm 001 ,gnauhC3002 351 0.82( 56 d 005< )

nori VI etarahccas gm 002,2

,enabhsiF7991 151 0.72( 23 d gm 000,1 nartxed nori VI 006< )

:setontooF .egnellahc nori ot roirp puorgbus fo rHC naeM .a

TAST tseT eht htiw srednopseR norI ot srefer ytivitisneS .b iw srednopseR norI( / dlohserhT T tseT eht ht TAST tseT eht tuohtiw srednopsernoN ot srefer yticificepS .c t tuohtiw srednopsernoN( / dlohserhT eT eh

.detaluclaC .d .hparg morf detamitsE .e

n the second RCT, patients assigned to a CHrreatment target of 32.5 pg/cell or greater showedo change in ESA dose, whereas those assignedo a TSAT treatment target of 20% or greaterhowed a 38% decrease in ESA dose. However,etween-group ESA differences did not achieveignificance.158 Functional iron studies havehown that the clinical utility of CHr as a base-ine index of response to IV iron challenge variesTable 27).151,153-155,159 Results of CHr also maye instrument dependent. The current recommenda-ion of CHr greater than 29 pg/cell is based on thedvia 120 instrument (Bayer Diagnostics Inc).Other iron status tests have been studied, includ-

ng percentage of hypochromic red blood cells,inc protoporphyrin, and soluble transferrin recep-

noitalupoP DKC-DH eht ni yparehT norI VI ot esnopse


emoctuO fo noitinifeD(

)esnopseR tnemtaerterP )%( TAST a

tnemtaerterP )%( TAST a

TSA

TTh

resh

old

(%

)

Sens

itivi

ty b

Spec

ifici

ty c

%11 %69 03< %22 %29 72< %43 %66 %44 %88 42< %36 %18 12< %57 %85 81<

tcH ≥ ro %5 esod ASE

≥ om 2 ni %01 4.91 ± 4.72 8.11 ± 4.91

%88 %61 51< %0 %77 53<

%91 %18 %71 %26 03< %05 %64 52<

bH ≥ Ld/g 1 kw 8 ni

1.5 ± 1.52 7.11 ± 5.82 %88 %13 02<

%68 %11 IRC e ≥ %1 kw 2 ni 01 ± 42 21 ± 12

%06 %05 02<

%07 %28 03< %73 %36 r bH ≥ Ld/g 1 kw 8 ni %001 %53 02< 8.7 ± 5.43 4.6 ± 7.32

%95 %14

bH ≥ %51 kw 91-6 ni 4.8 ± 4.52 6.6 ± 7.71

%87 %95 91<

i .yduts hcae yb denifed sa esnopser a ot srefer emoctuO .)emoctuo eht hti .yduts hcae yb denifed sa esnopser a ot srefer emoctuO .)emoctuo eht tuohtiw slaudiv

yparehT norI VI ot esnopseR fo doohileki


noitar

fo noitinifeD tnemtaerterP esnopseR

)gp( rHC a

tnemtaerterP)gp( rHC a C

Hr (

pg)

Thre

shol

d

Sens

itivi

tyb

Spec

ifici

tyc

%17 %87 82< %88 %21 %28 %76 72< noisses

%1> IRC kw 2 ni

%88 %44 62< 5.92 4.62 %73 %36 rof ylk

kw %3> tcH kw 8 ni 7.0 ± 6.23 5.1 ± 3.03

%09 %001 23<

≤ %87 %96 03 %95 %14

≤ %39 %75 92≤ %79 %73 82

DH h noiss kw 9

bH ≥ %51 skeew 91-6 ni

0.2 ± 6.13 6.2 ± 0.92≤ %001 %01 62

%53 %56 kw 4 rof 2 yreve om 5 r

ro %3 yb tcH %03 yb ASE

om 6 ni 7.1 ± 6.92 6.1 ± 2.72 %78 %87 82<

%87 %22 noisses

IRC ≥ ni %1 kw 2 9.72 7.32

%08 %001 62<

dlo .)dlohserht TAST tseT teem ton od ohw srednopseR norI sulpoN sulp dlohse tseT eht htiw srednopsern .)dlohserht TAST

fo do R

noitaruD

DH 01snoisses

DH 42snoisses

DH 1 noisses

of ylkeeW kw 8

DH hcaE noisses kw 91-6

w slaudividni dni lla( yb de

iss L gn

euD

DH 1

eeW8

caEes1-6

WIT nehtof kw

DH 1

hserhT TASrhT TAST ts

ti

wtoctcsmRscIeafooll

IP

pTtlCNtgc

U

rfthtasfsbfsatgt

trpntngbt

lbDi

5-%03 neewt


ors. Evidence to support these tests as targets forron treatment is poor or unavailable.

Treat-to-target approaches. There are 2idely used and effective approaches to IV iron

reatment: (1) periodic iron repletion, consistingf a series of IV iron doses administered episodi-ally to replenish iron stores whenever iron sta-us tests decrease to less than target range; or (2)ontinuous maintenance treatment, consisting ofmaller doses administered at regular intervals toaintain iron status tests stable within target. NoCTs are available to compare the efficacy and

afety of these 2 approaches; however, the totalumulative dose may not differ between them.160

n studies that achieved steady-state ferritin lev-ls and reported iron doses administered, theverage IV iron dose needed to maintain a stableerritin level (signifying achievement of the goalf neutral iron balance) appears to be in the rangef 22 to 65 mg/wk (Table 28). Higher doses mayead to progressive increases in serum ferritinevels in some patients.148,156

ron Targets in Patients With ND-CKD andD-CKDEvidence to support an iron treatment target in

atients with ND-CKD and PD-CKD is lacking.here are no RCTs comparing iron targets in

hese patient populations. Dialysis-related bloodoss renders evidence from patients with HD-KD unsuitable for application to patients withD-CKD or PD-CKD. Thus, in these patients,

he Work Group recommends iron treatment tar-ets that reflect a conservative estimate of effi-

udA ni norI fo esoD ylhtnoM naeM .28 elbaT

raeY ,rohtuA ngiseD ydutS Na pu-wolloF

)om(I 1 mrA noitnevretnI

3002 ,elbmirB 381

TCR761 c 8

erac tnemeganam aimena dezilocotorP maet yduts yb

Ld/g 5.21-11 :bH tegraT

erac lausU

aT

5002 ,namloT 931

TCR 9 261

-niteopebrad CS kw/x1 Ld/g 21-11 :bH tegraT T

1002 ,enabhsiF 751

TCR 6 831

,%02< TAST ro Lm/gn 001< nitirref fI 01 no gm 001 ,nartxed nori VI

snoisses DH evitucesnocori VInoc

5002 ,illevreC 481

TCR revossorC6 42 e -niteopebrad CS kw/x1

Ld/g 31-11 :bH tegraTVIT

9991 ,baraseB 061

TCR-noN 81 42

nori )suounitnoc( ecnanetniaM %05-%03 :TAST tegraT

Ld/g 11-01 :bH tegraT f

n-sAt norI

aT :setontooF

.noitelpmoc ta N .aVI fo esod ylhtnom egareva eht stcelfeR .b .)skeew 4 = htnom enO( .deretsinimda nori

shtnom 5> dellorne stneitaP .c hparg morf detamitsE .d

tangised erew doirep yduts htnom-6 hcae fo shtnom 4 tsrif ehT .e tnom 2 lanif eht ,sesahp noitartit esod sa degm 001-52 yb dewollof ,%03> TAST ot gm 000,5-003 nartxed nori VI .f eb TAST niatniam ot skeew 2-1 yreve

.Lm/gn 002< level nitirref ro %02< TAST nehw snoisses DH evitucesnoc 01 no gm 001 nartxed nori VI .g

acy and a cautious approach to patient safety. p

pper Level of Ferritin

The statement There is insufficient evidence toecommend routine administration of IV iron iferritin level if greater than 500 ng/mL reflectshe findings of the Work Group that: (1) no RCTsave compared the safety and efficacy of ferritinargets greater than 500 ng/mL with the safetynd efficacy of lower ferritin targets, (2) fewtudies have examined the efficacy of IV iron aterritin levels greater than 500 ng/mL, (3) notudy has examined either efficacy or safetyeyond surrogate outcomes, (4) no informationrom interventional trials is available about theafety of ferritin targets greater than 500 ng/mL,nd (5) sufficient evidence exists to suggest thatissue iron stores in patients with ferritin levelsreater than 500 ng/mL are normal to greaterhan normal.

No evidence is available to compare ferritinargets greater than 500 ng/mL with lower fer-itin targets. That is, no RCTs have assignedatients to a ferritin target greater than 500g/mL and compared results with those in pa-ients assigned to a ferritin target less than 500g/mL. In the absence of comparisons betweenroups in intention to treat, no conclusions cane drawn to assess RRs and benefits of IV ironherapy at the higher ferritin level.

The efficacy of IV iron in patients with base-ine ferritin levels greater than 500 ng/mL haseen examined in a single uncontrolled study.150

escribed previously, this trial administered IVron to patients for 12 months, withheld iron for

yparehT ASE no stneitaP DKC-DH tne

fo epyT neviG norI emoctuO 2 mrA

esoD naeM b

)om/gm(

gnirud nitirreF naeMetatS ydaetS

)Lm/gn(

esorcus norI dna tsigolorhpe naic

Ld/g 5.2

yramirP htiw stneitap fo noitroporP : egnar tegrat ni seulav bH 251 .sv 841

022 .sv 002

esorcus norI kw/x1

Ld/g 21:yramirP om 9 ta esod ASE 042-041 d

)egnar(

394 2 mrA rof naidem(

)9-3 skeew

nartxed norI ,gp 01 no gm 0

snoisses

:yramirP tnemeganam norI esod nori ,esod ASE ,tcH(

,TAST ,nitirref mures ,tnemeriuqer)rHC 021.sv 062

082 .sv 013

esotlamylop norI- kw/x1 Ld/g 31

esod dna esod niteopebraD ytilibairav 88 .sv 841

395 .sv 507

nartxed norI nori )tnetti ro %02< T

Lm/gn Ld/g 1 g

yramirP esod ASE : 061.sv 802

213 .sv 546 51 keew :1mrA(

;retal dna )skeew lla :2 mrA

detang sdoirep noitaulave sa .ycneiciffe gnisod rofm mumixaM .%0 nitirref fi nevig nori oN .gm 004 esod ylhtno ≥ .Lm/gn 008

l laverP t

noitnevretn

n yramirp yb inilc esrun1-11 :bH tegr

-niteope CS-11 :bH tegra

92< rHC fI01 ,nartxed n

DH evituces

niteopebrad -11 :bH tegramretnI( dedeeAST fi ypareh 002< nitirref1-01 :bH tegr

ised erew sh

atients with a ferritin level greater than 1,000

nmbdcdabsdsvtahtl

tasnbMaiicbvf

sroinwa

wafspivt5fg

putsaitwcmnss

pfcciptTpc

slrpnegi5irfwAiml

wpctiai


g/mL or TSAT greater than 50%, and found thatean ferritin level increased from 930 ng/mL at

aseline to 1,383 ng/mL at 12 months and ESAose decreased by 25%. However, the lack of aontrol group renders conclusions about the ESAose change uncertain. Analysis of uncontrollednemia interventional trials is subject to targetias. That is, patients who are most likely tourvive and complete the trial likely bear a lowisease burden and are, in turn, most likely tohow higher Hb and lower ESA doses. Con-ersely, patients who are least likely to completehe trial bear a high disease burden and thereforere most likely to show worsening anemia andigher ESA doses. Successful trial completionherefore is associated with higher Hb levels andower ESA doses, regardless of intervention.

Other efficacy trials have examined the func-ional relationship between baseline ferritin levelnd likelihood of a surrogate hematologic re-ponse to IV iron challenge (Table 24). However,one of these studies examined patients withaseline ferritin values greater than 500 ng/mL.oreover, because efficacy of IV iron in the

vailable interventional and functional iron stud-es is limited to surrogate outcomes (reticulocytencrease, Hb level increase, or ESA dose de-rease),152-155,161,162 evidence of direct patientenefit (including improved QOL, health, or sur-ival) of IV iron administration in patients aterritin values greater than 500 ng/mL is lacking.

Information on potential harm to patientsimilarly is lacking. Again, evidence to permiteliable assessment of risks and benefits cannly come from RCTs assigning patients tontent-to-treat ferritin targets greater than 500g/mL compared with less than 500 ng/mL,ith adequate power to assess both efficacy

nd safety.Evidence that tissue iron stores in patients

ith ferritin levels greater than 500 ng/mL aredequate to greater than normal includes resultsrom surveys in the general US population andtudies of bone marrow iron or liver iron inatients with CKD. Among randomly selectedndividuals in the general US population, ferritinalues greater than 500 ng/mL lie at or greaterhan the 95th percentile among males aged 15 to9 years and far exceed the 95th percentile amongemales of all ages.163 However, findings in the
eneral population do not necessarily apply to l
atients with CKD. Among patients with CKDndergoing bone marrow examination, no pa-ient with a ferritin level greater than 500 ng/mLhowed absent marrow iron stores.98,99 Finally,mong patients with HD-CKD undergoing tissueron determination by means of magnetic suscep-ometry, ferritin levels greater than 500 ng/mLere associated with hepatic non–heme-iron con-entrations greater than the upper limit of nor-al.163 In short, ferritin values exceeding 500

g/mL likely represent supraphysiological re-ults in the general population and tissue ironufficiency or excess in patients with HD-CKD.

Thus, no current evidence is available to sup-ort routine treatment of patients with serumerritin levels greater than 500 ng/mL. Rather,linicians should judge the individual patient’slinical status and ESA responsiveness and baseron treatment decisions on this assessment. Inarticular, when serum ferritin level is greaterhan 500 ng/mL while the concurrently measuredSAT is less than 20%, iron deficiency may beresent and a course of iron treatment may beonsidered.

In short, no current evidence is available toupport treating most patients with serum ferritinevels greater than 500 ng/mL. A therapeuticesponse to a 1,000-mg IV iron challenge in aatient with a ferritin level greater than 500g/mL is unlikely. Because iron stores are ad-quate or elevated in patients with ferritin valuesreater than 500 ng/mL, the long-term safety ofron therapy at target ferritin values exceeding00 ng/mL is untested, and efficacy results of IVron therapy are limited to surrogate outcomesather than direct patient benefits, the Work Groupavors limiting routine iron treatment to patientsith serum ferritin values less than 500 ng/mL.ccordingly, the conclusion of the Work Group

s that there is insufficient evidence to recom-end routine administration of IV iron if ferritin

evel is greater than 500 ng/mL.The finding of a TSAT less than 20% coupledith a ferritin level greater than 500 ng/mLoses a particularly difficult problem for clini-ians.157 This situation may be caused by ironest variability,157 falsely low TSAT results,nflammation, or reticuloendothelial iron block-de. Evidence on the risks and benefits of IVron therapy in these patients is almost entirely
acking. However, the statement that There is

imtacw

Ttgnrapmiqbm

R

ftRtiaaootslataa

F1

F1

M1


nsufficient evidence to recommend routine ad-inistration of IV iron if ferritin level is greater

han 500 ng/mL does not preclude IV irondministration in selected patients when, in thelinician’s judgment, a trial of iron therapy isarranted.It is important to reiterate that the statement

here is insufficient evidence to recommend rou-ine administration of IV iron if ferritin level isreater than 500 ng/mL refers to ferritin targets,ot to achieved or acquired ferritin levels. Fer-itin levels exceeding 500 ng/mL are oftenchieved as a result of iron therapy given toatients with lower baseline ferritin levels oray be acquired in the course of infection,

nflammation, or other illness. Achieved or ac-uired ferritin levels are described elsewhere,164

ut are not the subject of this guideline state-ent.165

Table 29A. Comparative RCTs of IV versus PO Iron Administrat

Baseline

IV Agent Author, Year

N

CK

D S

tage

Mea

n Fo

llow

-up

(m

o)

App

licab

ility

Hb

(g/d

L)

ESA

Dos

e

TSA

T ( %

)

Ferr

itin

(n

g/m

L)

PO Agent

10.87,100

IU* 23 191 Iron dextran

ishbane, 995 156 52 HD-CKD 4

10.66,750

IU* 21 179

Ferrous sulfate (N = 21)

Iron polysaccharide(N = 11)

7.8 0 21 c 204Iron sodium

gluconate complex udin, 998 167 30 HD-CKD 26

6.8 0 20 c 268 Ferrous sulfate

7.3 0 26 345 Iron dextran acdougall, 996 166 25

HD-CKDPD-CKD

47.2 0 27 309 Ferrous sulfate

* Per treatment. Footnotes: a. Primary outcomes of study given unless otherwise noted. b. Adjusted to target Hct 30%-34%. c. Estimated from graph. d. ESA dose kept stable for at least 8 weeks. Dose decreased if Hb >12 g/dL or dose doubled if Hb had not increased

Coding of Outcomes: + Statistically significant benefit seen for comparison of arm 1 vs. arm 2, unless otherwise noted

noitartsinimdA norI OP .sv VI fo sTCR evitarapmoC .B92 elbaT E dna

enilesaB

tnegA VI ,rohtuA raeY

N

CK

D S

tage

Mea

n Fo

llow

-up

(m

o)

App

licab

ility

Hb

(g/d

L)

ESA

Dos

e

TSA

T ( %

)

Ferr

itin

(n

g/m

L)

tnegA OP

esorcus norI 39 61 dn 2.01 ,kcyW naV5002 961 2 5-3 161

etaflus suorreF 401 71 dn 1.01

esorcus norI 521 71 0 8.9

,natyrahC5002 271 4-3 69 b 5.1

etaflus suorreF 301 61 0 7.9

0 9.9 esorcus norI 001 dn ,sevotS1002 171 4-3 54 d 2.5

etaflus suorreF 47 dn 0 7.9 e

nartxed norI 181 46 0 8.5 ,lawraggA3002 071 5-4 04 f 3

etaflus suorreF 091 06 0 3.6 :setontooF

yduts fo semoctuo yramirP .a .deton esiwrehto sselnu nevigm/Lm 04< ecnaraelc eninitaerC .b .sisylaid gniriuqer ton ,ni

.sesylana htob rof 00.0 = P .cS htiw slaudividnI .d rC ton ,Ld/gm 48.2> .sisylaid gniriuqer

fo esod tnelaviuqe na deviecer stneitap eht ,ylevitanretlA .e rp nori evitanretla na tarelot ylsuoiverp neeb dah taht noitarapeinitaerc naem neewteb secnereffid tnacifingis yllacitsitatS .f .6( puorg nori VI fo ecnaraelc en puorg nori OP dna )nim/Lm 74

:semoctuO fo gnidoC+ rapmoc rof nees tifeneb tnacifingis yllacitsitatS deton esiwrehto sselnu ,2 mra .sv 1 mra fo nosi


Evidence to support the statement The pre-erred route of iron administration is IV in pa-ients with HD-CKD consists of results from 3CTs comparing IV iron with oral iron adminis-

ration (Table 29A–Table 31A), including 2 thatncorporated a placebo or nontreatment controlrm (Table 30). A fourth RCT compared oral irondministration to no-iron control (Table 30). In 2f these 4 RCTs, patients were assigned to IV orral iron treatment while undergoing ESAherapy.159,166 By study completion, those as-igned to IV iron showed a greater Hb level,ower ESA dose, or both compared with thosessigned to oral iron (Table 29A, Table 31A). Inhe third RCT, patients not receiving ESAshowedn increase in Hb levels from 7.8 to 11.0 g/dLfter IV iron, but no change in Hb levels was

fficacy of Anemia Management in the HD-CKD and PD-CKD Populations

ESA Co-

Intervention Clinical Outcome a Result

e Frequency Description Definition Actual Value

IV vs. PO

Statistical Signifi-cance

Qua

lity

g min

2x/wk Mean Hb

(g/dL)11.5 vs. 10.6 +

g

g

TID

BID

IV ESA adjusted b Mean ESA dose

(IU/treatment) 4,050 vs. 7,563 +

mg Each HD session

mg Daily None

Mean Hb (g/dL)

11.0 vs. 6.5 c nd

50 mg) 30 min

Every 2 wk Mean Hb

(g/dL) 11.9 vs. 10.2 +

mg TID

SC ESA adjusted d Mean ESA dose

(IU/kg/16 wk) 1,202 vs. 1,294 NS

eks.

eganaM aimenA f noitalupoP DKC-DN eht ni tnem

-oC ASE noitnevretni emoctuO lacinilC a stluseR

noitinifeD noitpircseD ycneuqerF eulaV lautcA OP .sv VI

lacitsitatS-ifingiS

ecnac

Qua

lity

g

g

x5 ro x2 d 41 revo

htiw stneitap % bH ≥ Ld/g 1

%0.82 .sv %0.44 +

DIT g

stneitap 23 = N ASE no

detsujdanu naeM bH )Ld/g( 24 yad yb

4.0 .sv 7.0 +

naeM ylkeew g SN 7.0 .sv 0.1 )Ld/g( bH

DIT g

ASE CS detsujdanu

htiw stneitap % bH ≥ dna Ld/g 8.0 reF ≥ Lm/gn 061

dna( )%5> TAST

%0 .sv %0.56 )%0 .sv %0.44( + c

g rh

ylhtnom

SDT g

ASE CS ot detsujda bH eveihca

Ld/g 21

esoD ASE naideM)kw/gk/UI(

SN 5.33 .sv 6.14

om/x2 )gm DIT g

detsujdanu ASE bH naeM

)Ld/g( 9.8 .sv 0.01 +

.)50.0<p( enilesab ta )

ion and E

Intervention

Dos

100 mover 2

325 m

150 m

62.5

160 5 mL (~2over 25–

200

by 1 g/dL at 8 we

o ycaciff

noitnevretnI

esoD

m 005 ro

m 002

m 523

m 002

m 523

m 003 2 revo

m 002

001( Lm 2m 002

e .d21( nim/Lm 20.

sg4odompipt

sRmp

pdttfmcipo

oiooC

0 mmol/mL henth period wito


een in patients assigned to oral iron. Between-roup comparisons were not reported.167 Of theavailable RCTs, 3 included a placebo-treatmentr no-iron-treatment arm. Results showed noifference in final Hb level or ESA dose betweenral iron treatment and placebo/control. In sum-ary, evidence in patients with HD-CKD sup-

orts 2 conclusions: (1) oral iron administrations not demonstrably more effective than eitherlacebo or no treatment; and (2) IV iron adminis-ration is superior to oral iron administration.

A newer form of oral iron that has not beentudied widely is heme iron polypeptide. A singleCT of patients with HD-CKD compared treat-ent with IV iron with treatment with heme iron

olypeptide.168 Uncertainty in the randomization

Table 30. Comparative RCTs of PO Iron Administration versPD

Baseline

PO AgAuthor, Year CKD Stage Fo

llow

-up

(m

o)

N

Hb

(g/d

L)

ESA

Dos

e(IU

)

TSA

T ( %

)

Ferr

itin

(n

g/m

L)

Placebo/C

6.8 0 20d 204 Ferrous sFudin, 1998 167 HD-CKD 12-26c 24

6.3 0 16d 190 Contr

7.2 0 27 309 Ferrous sMacdougall, 1996 166

HD-CKDPD-CKD ND-CKD

4 25 7.3 0 23 458 Contr

10.1 5,714 26.5 40 Iron polysac

compl24 iron-deficient patientsf 10.4 4,850 42.6 39 Placeb

11.2 4750 36.4 221 Iron polysac

compl

Markowitz, 1997 185 HD-CKD 3

25 iron-replete

patientsf 10.7 4,692 35.4 228 PlacebFootnotes: a. Primary outcomes of study given unless otherwise noted. b. Outcomes reported at final follow-up, unless otherwise noted. c. 12-month follow-up for control group; 26-month follow-up for oral iron group. d. Estimated from graph. e. ESA dose kept stable for at least 8 weeks. Dose decreased if Hb >12g/dL or dose doubled if Hb had not increaf. Iron Deficient: Ferritin <100 µg/L; ZPP <90 mmol/mL heme; Hb >10g/dL. Iron Replete: Ferritin <100 µg/L; ZPP >9g. Primary outcome was change in serum ferritin and ZPP. Results reported at 3-month follow-up before final 2-mo

Table 31. Serious AEs of Iron Agen

Author, Year Study Design N Population Dose Size

(mg) IV

(m

Iron Dextran McCarthy, 2000 186

Retrospective, database review

254 HD 300

Walters, 2005 176 Retrospective, database review

20,213 c HD and PD —

Ferric Gluconate

Michael, 2002 175 RCT,crossover

2,534 HD d 125

Iron Sucrose e

Aronoff, 2004 187 Prospective, cohort

665 f HD 100

Blaustein, 2003 188 Prospective, cohort

107Stage 3-5

(1 PD, 2 HD patients) 500

Charytan, 2004 189 Prospective, cohort

130 f HD d 100-200 5

Footnotes: a. Modified for K/DOQI use from reference190. See Methods for selection criteria. b. Majority of ADEs occurred during this/these dose(s). c. Incident subpopulation of 48,509 patient study. d. <10% of patient with iron dextran allergic history. e. Included patients with previous intolerance to either iron dextran or ferric gluconate.
f. All patients with previous intolerance to iron dextran and/or ferric gluconate. g. Median cumulative dose: 1,000 mg; range: 100-5,000 mg.
rocedure, disproportionately high baseline ESAoses in the oral iron treatment group, a substan-ial dropout fraction confined to the oral ironreatment group, a significant decrease in serumerritin levels during 6 months of oral iron treat-ent, and an undefined IV iron treatment proto-

ol render the results of this trial difficult tonterpret. Further studies will be required torovide a basis for recommendations on the usef this agent.Evidence to support the statement The route

f iron administration can be either IV or oraln patients with ND-CKD or PD-CKD consistsf results from 4 RCTs comparing IV iron withral iron administration in patients with ND-KD (Table 29B, Table 31A). The Work Group

bo/Control and Efficacy of Anemia Management in the HD-CKD andpulations

Intervention Results

Dose Frequency ESA

Cointervention Clinical Outcome

Definitiona,b

Actual Value Arm 1 vs.

Arm 2

Statistical Signifi-cance

160 mg Daily

— — None

Mean Hb at 12 mo

(g/dL) 6.5 vs. 6.0d nd

200 mg TID Mean Hb

(g/dL) 10.2 vs. 9.9d NS

— —

SC ESA adjustede Mean ESA dose

(IU/kg/16 wk) 1,294 vs. 1,475 NS

)Ld/g( bH naeM DIB gm 051 g 10.7 vs. 10.5 NS

150 mg BID

ESAadjusted

Mean ESA dose (IU)g 6,142 vs. 4,650 nd

)Ld/g( bH naeM DIB gm 051 g 7.3 vs. 8.5 NS

150 mg BID

ESAadjusted

Mean ESA dose (IU)g 4,417 vs. 4,615 nd

at8 weeks. me; Hb >8.3. hut treatment.

ients Naïve to Tested Iron Agent (N > 100)a

Serious ADE Rate (%) Doses (n)

[Doses/pt] Per Patient [Dose] b

Definition of Serious AE

3,578 [nd]

0.8 [1st course]

Suspected anaphylactic reaction comprised of wheezing/dyspnea

20,213 [1]

0.035 [Test or 1st ]

Requiring parenteral administration of epinephrine, corticosteroids, or antihistamines on the same dialysis day

2,514 [1]

0.6 [1st]

Drug intolerance, which included anaphlyactoid reaction, hypotension, chills, back pain, nausea, dyspnea/chest pain, facial flushing, rash and cutaneous symptoms of porphyria, and 1 life-

threatening event requiring parenteral antihistamine, hydrocortisone, and epinephrine.

8,583 [nd]

0[NA]

Any event that is fatal or life-threatening, results in or prolongs hospitalization, results in significant disability or incapacity, is

unusual, or in opinion of the investigator, presents a significant hazard to the patient.

266[2]

0Not specified. No adverse reactions requiring parenteral

medications or hospitalizations ND

[nd] g0

[NA]Hypotension, wheezing, respiratory stridor, shortness of breath,

hypertension, anaphlyaxis, chest tightness

us Place-CKD Po

ent

ontrol

ulfate

ol

ulfate

ol

charide ex o charide ex o

sed by 1 g/dL

ts in Pat

Rate g/min)

5-10

—

12.5

50

3.2

0-100

rmttT

sEtwptaHaEn

f

Ti2m

tftt

i4iaaTatm


ated the evidence from these trials as strong oroderately strong. There are no RCTs in pa-

ients with ND-CKD comparing oral ironherapy with placebo or no iron treatment.here are no RCTs in patients with PD-CKD.The 4 available in ND-CKD RCTs differ sub-

tantially in the use, timing, and adjustment ofSA therapy (Table 31B). Three initiated ESA

herapy in all study patients at randomization,hereas 1 continued ESA therapy in patientsreviously treated, but did not initiate ESAherapy in previously untreated patients. Onedjusted ESA during the trial to achieve a targetb level, whereas 3 permitted no ESA dose

djustment or required removal from the trial ifSA therapy initiation or ESA dose increase waseeded.The 4 available RCTs also differ in the dosing,

requency, and duration of IV iron administered.

he 4 dosing regimens included 1,000 mg admin-stered in 2 or 5 divided doses over 2 weeks,169

00 mg monthly,170 300 mg monthly,171 or 1,000g in 5 doses over 5 weeks.172

Finally, the 4 available RCTs differ substan-ially in severity of anemia at baseline, rangingrom a mean Hb level of 5.8 to 6.3 g/dL in 1rial170 to 9.7 to 10.2 g/dL in the remaining 3rials.

Between-group differences showing superior-ty of IV iron over oral iron were seen in 2 of theavailable RCTs (Table 31B). The 2 studies that

nitiated ESA therapy in patients with moderatenemia found no difference between patientsssigned to IV iron compared with oral iron.171,172

he 2 trials that showed differences either initi-ted ESA therapy simultaneously with ironherapy in patients with severe anemia170 oraintained prior ESA status without adjustment

ititg

RQetiskfttaaim

tIvtpaaimssvHtIC

iWPCfbCappCi

H

wgmsormcaopifdrioi

dtspaotfitsf

tttfas

mbt

iibp


n patients with moderate baseline anemia.169 Inhe latter study, superiority of IV iron over oralron was greatest among patients with ESAherapy and baseline Hb level less than 9.0/dL.169

Other outcomes compared in the 4 availableCTs included rate of decline in kidney function,OL, adverse GI effects, dietary protein andnergy intake, and adherence to prescribedherapy. Compared with patients assigned to oralron therapy, those assigned to IV iron treatmenthowed no difference in rate of decrease inidney function,169-171 no difference in QOL,169

ewer GI symptoms,169-172 no difference in pro-ein and energy intake,171 and better adherenceo prescribed therapy.169 Five patients in 2 trials,ll women with low body mass, experienceddverse reactions to administration of IV iron,ncluding hypotension, cramping, arthralgia, andyalgia.169,171

Given the variability in trial design, inconsis-ency of results, potential for adverse effects ofV iron, lack of information on potential ad-erse effects of oral iron, surrogate nature ofested outcomes in iron intervention trials,aucity of information on patient preferencend adherence to treatment recommendations,nd lack of information on the efficacy of oralron compared with placebo or no-iron treat-ent, the Work Group concluded that the

trength of available evidence is insufficient toupport a guideline statement on the use of IVersus oral iron in patients with ND-CKD.owever, in the opinion of the Work Group,

he route of iron administration can be eitherV or oral in patients with ND-CKD or PD-KD.Because no RCTs are available to compare IV

ron with oral iron in patients with PD-CKD, theork Group considered whether to regard the

D-CKD patient population as similar to ND-KD, similar to HD-CKD, or too dissimilar

rom either to justify a recommendation. On theasis of the assumption that patients with PD-KD do not experience ongoing dialysis-associ-ted blood loss, the Work Group reasoned thatatients with PD-CKD resemble the ND-CKDopulation and differ from patients with HD-KD. Thus, patients with PD-CKD are included

n the current opinion-based CPR. s

ypersensitivity Reactions

There currently are 3 forms of IV iron that areidely available: iron dextran, sodium ferricluconate, and iron sucrose. All forms of IV ironay be associated with acute AEs, occasionally

evere, comprised of hypotension with or with-ut other symptoms and signs. The cause of theeactions is incompletely understood. Immuneechanisms (including mast cell–mediated pro-

esses leading to a clinical syndrome resemblingnaphylaxis) may have a role in some cases. Inthers, the iron agent may release bioactive,artially unbound iron into the circulation, result-ng in oxidative stress and hypotension (labile orree iron reactions). The pathogenesis may differepending on the type of IV iron. Anaphylactoideactions appear to occur more frequently withron dextran,173 and labile or free iron reactionsccur more frequently with nondextran forms ofron.174

The reported frequency of acute drug AEsepends in large part on the structure and rigor ofhe experimental design used. Direct patient ob-ervation after administration of an IV iron agentermits the most reliable assessment. For ex-mple, in a double-blind placebo-controlled trialf sodium ferric gluconate in 2,534 HD pa-ients,175 investigators directly observed patientsor evidence of reactions after blinded IV admin-stration of drug or placebo. If, in the opinion ofhe investigator, a reaction was demonstrated,erum tryptase levels were measured to evaluateor mast cell–mediated hypersensitivity.

Prospective single-arm clinical trials also con-ribute information on drug-related AEs in thearget population (Table 31). In reports of theserials, observation for drug-related AEs was per-ormed by the study nurse or a staff nurse or,lternatively, the method of observation was notpecified.

Retrospective study designs use review ofedical records or large-scale electronic data-

ases to identify potential drug-related AEs afterhe fact.176,177

Finally, pharmacovigilance surveillance stud-es use national voluntary reporting data sources,ncluding the Freedom of Information Act data-ase administered by the FDA, to evaluate AErofiles of IV iron agents. Pharmacovigilance
tudies yield unreliable information about abso-

loiaipd

rrnclAdtiptApvbrnostpapcswoqusrsr

rai0lnt

1

eCfiicdwtpdi

biltoofislwrompfi0s

iibas3oUwdtddfnptrn


ute AE rates and are susceptible to uncontrolledbserver bias, but afford the advantage of detect-ng rare events, shedding light on common char-cteristics of low-frequency events, and suggest-ng relative rates of AEs. However, they do notermit statistical comparison of AE rates forifferent IV iron agents.The frequently nonspecific nature of IV iron–

elatedAEs, the substantial overlap between drug-elated AEs and dialysis-related AEs (eg, dizzi-ess, dyspnea, cramps, pruritus, nausea,onstipation, diarrhea, and hypotension), and theow anticipated event rate for the most seriousEs pose significant challenges for each studyesign described. The single greatest problem ishe absence of generally accepted criteria todentify IV iron–related AEs and distinguish hy-ersensitivity from nonhypersensitivity reac-ions. The absence of criteria for IV iron–relatedEs introduces potential observer bias into bothrospective and retrospective trials. Pharmaco-igilance studies also are subject to observer biasecause only AEs thought to be drug related areeported. As long as neither descriptive criteriaor objective markers are available, designationf an AE as drug related likely will remainomewhat subjective. Although blinding the in-ervention so that neither the investigator nor theatient is aware of the identity of the agentdministered improves the objectivity of AE re-orting, event rates are sufficiently low to pre-lude comparative trials that are logistically fea-ible. For example, to conduct an RCT thatould be adequately powered to compare seri-us AE rates between 2 iron agents would re-uire enrolling more than 10,000 patients, annlikely prospect. Accordingly, comparative as-essment of safety is likely to continue to rely onetrospective chart review, analysis of large-cale medical databases, and pharmacovigilanceeports.

Evidence is available from 2 retrospectiveeports, including 1 in patients with CKD. Bothnalyses concluded that the rate of life-threaten-ng reactions to iron dextran administration is.6% to 0.7%.178,179 Two additional studies usedarge medical databases to further identify theature and consequences of life-threatening reac-ions after IV iron dextran.

Fletes et al 2001.177 This study identified
65 suspected drug-related AEs after 841,252 p
xposures to iron dextran in patients with HD-KD (rate per exposure, 0.02%). There was 1

atal event. Although many AEs followed admin-stration of a test dose or first dose, this studydentified serious AEs in patients who had suc-essfully received previous test or treatmentoses. The majority of the non-naïve patientsho experienced AEs after iron dextran adminis-

ration did so at the time of the first dose of alanned series, suggesting that the risk for first-ose AE may recur in prevalent patients after annterval free from iron dextran exposure.177

Walters and Van Wyck 2005.176 The data-ase of a large dialysis provider was examined todentify episodes of iron dextran–induced anaphy-axis sufficiently severe to require use of resusci-ative medications. They found 7 events in a totalf 48,509 patients treated. However, all 7 eventsccurred in previously unexposed patients afterrst or second exposure to the drug, yielding alightly greater true incidence of 0.035%. Theower figure reported in this study comparedith the 2 studies using chart review probably

eflects the decision to study only the incidencef AE requiring in-center use of resuscitativeedication.176 Of interest, the prevalence of sus-

ected hypersensitivity in that study matched thendings of the previous retrospective reviews:.69% of prevalent patients were recorded asensitive to iron dextran.

Pharmacovigilance surveillance studies yieldnformation on deaths potentially related to IVron. Deaths thought to be IV iron–related haveeen reported to the FDA for each of the IV irongents available in the United States. In an analy-is of US and European surveillance databases,1 deaths occurring in association with 196 casesf iron dextran anaphylaxis were recorded in thenited States between 1976 and 1996 comparedith none with similar exposure rates with so-ium ferric gluconate.180 Another group studiedhe FDA Freedom of Information surveillanceatabase to compare severe AE rates for IV ironrugs.181 They confirmed higher anaphylaxis andatality event rates for iron dextran than for theondextran irons. These results should be inter-reted with caution given that AEs for drugs inhe marketing phase probably are grossly under-eported for all agents; definitions for AEs areot generally accepted, as we have noted; and the
rimary intention of the database is to generate

sdbfd

goadtct

T

tdetumpcrRtstlvtrlowIpifllaidbss

ifvHo

U

sc

R

siildimmbtiMcirftabb

O

1

2

3

aAt


ignals of unexpected AEs, not to comparerugs.182 Nonetheless, these results add to theody of evidence indicating a trend toward morerequent and more severe reactions with ironextran.Taking the pharmacovigilance information to-

ether with evidence that iron dextran AEs mayccur in patients who have successfully receivedprevious test dose or series of therapeutic

oses, we recommend that resuscitative medica-ion and personnel trained to evaluate and resus-itate anaphylaxis accompany each administra-ion of iron dextran.

LIMITATIONS


There are a number of serious limitations tohe evidence supporting iron status targets. ESAose and Hb level response as surrogates for ironfficacy are universal among iron interventionrials (IV iron challenge studies), RCTs, andncontrolled prospective trials. No iron treat-ent trials have been designed or are sufficiently

owered to yield information on outcomes, in-luding the crucial issue of safety, that are di-ectly important to patients. Of the 2 availableCTs comparing iron status targets, 1 used TSAT

argets,108 1 used ferritin targets,149 both weremall, neither examined safety, and the TSATrial showed increasing non–steady-state ferritinevels in the higher TSAT target arm. Con-ersely, IV iron challenge studies yield informa-ion that is limited to the acute hematologicesponse to a dose of IV iron—results that bearittle relevance to optimum treatment targets forngoing iron administration. Moreover, evenhen limited to predicting the acute response to

V iron challenge, available iron status testserform poorly, yielding relatively low sensitiv-ty and specificity over a range of cutoff values,at receiver-operator characteristic curves, and

ow area under the curve. Finally, although stain-ble bone marrow iron may yield importantnformation on the likelihood of storage ironepletion or iron excess or on the relationshipetween iron stores and results of serum irontatus tests, the relevance of this information to
etting optimum treatment targets for iron status f
s uncertain. In short, iron status targets as goalsor treatment require treat-to-target RCTs to pro-ide comparative evidence of efficacy and safety.owever, available evidence is of limited qualityr is altogether lacking.


The limitations of available evidence, de-cribed previously, provide the rationale for theautious use of IV iron at high ferritin levels.


In patients with HD-CKD, available RCTs aremall, thereby limiting their potential applicabil-ty to unselected HD-CKD target populations. Asn all IV iron studies to date, outcomes areimited to the surrogate Hb levels and ESAoses. Although these outcomes have financialmplications for the total cost of anemia manage-ent, the comparative cost of anemia manage-ent using IV versus oral iron treatment has not

een examined, and the relationship, if any, be-ween surrogate outcomes and outcomes that aremportant to patients has not been determined.

oreover, although managing anemia requireshronic and ongoing care, most clinical trialsnvolving therapeutic iron intervention are ofelatively short duration; thus, the long-term ef-ects of iron therapy remain unknown. Resolu-ion of these issues, particularly in the ND-CKDnd PD-CKD patient population, clearly is neededefore a conclusive assessment of net benefit cane made.

ther Limitations

. Absence of generally accepted criteria foridentifying IV iron–related AEs.

. Absence of a distinction in the literaturebetween reactions caused by labile iron andthose caused by hypersensitivity.

. No adequately-powered trials directly com-paring different IV iron agents.

CLINICAL IMPLICATIONSAEs thought to be related to labile iron require

decrease in the dose or rate of infusion or both.Es thought to be related to hypersensitivity to

he agent require stopping the agent and preclude
urther administration.

mtaani

wtermtipsEsE

L

fiLttum

A

CPG AND CPR 3.3. USING PHARMACOLOGICAL ANDNONPHARMACOLOGICAL ADJUVANTS TO

ESA TREATMENT IN HD-CKD

fotsptcwcalscaigmrdbphrli

Wccrc3E3p

Lbh�mrhHdtc

Several pharmacological agents and nonphar-acological manipulations of the HD prescrip-

ion have been examined for potential efficacy asdjuvants to ESA treatment. Studies are not avail-ble to address the use of pharmacological oronpharmacological adjuvants to ESA treatmentn patients with ND-CKD and PD-CKD.

3.3.1 L-Carnitine: In the opinion of theWork Group, there is insufficient evi-dence to recommend the use of L-carnitine in the management of ane-mia in patients with CKD.

3.3.2 Vitamin C: In the opinion of theWork Group, there is insufficient evi-dence to recommend the use of vita-min C (ascorbate) in the managementof anemia in patients with CKD.

3.3.3 Androgens: Androgens should not beused as an adjuvant to ESAtreatmentin anemic patients with CKD.(STRONG RECOMMENDATION)

BACKGROUNDFor the purposes of these recommendations,

e consider adjuvants to ESA therapy to beherapeutic agents or approaches that aim tonhance responsiveness to ESA therapy in iron-eplete patients. The target patient populationay include both ESA-hyporesponsive and rela-

ively responsive patients, although the focus ofnterest often is the hyporesponsive patient. Aositive response to an adjuvant treatment con-ists of either an increase in Hb level at a givenSA dose or the attainment and maintenance of apecific Hb level at a lower ESA dose (seexecutive Summary).

RATIONALE

-Carnitine

In the opinion of the Work Group, there is insuf-cient evidence of efficacy to recommend use of-carnitine in the management of anemia in pa-

ients with CKD. The role of carnitine deficiency inhe pathogenesis of the anemia of CKD, if any, isnclear. Levocarnitine (L-carnitine) is a carrier
olecule involved in the transport of long-chain t

atty acids into the mitochondria, where they arexidized to produce energy. L-carnitine is alsohought to be involved in the metabolic conver-ion of acyl coenzyme A, which accumulates inatients with renal failure and is toxic to cells, tohe less toxic acyl carnitine.191 Deficiency ofarnitine in patients on maintenance HD therapyas demonstrated nearly 30 years ago.192 L-arnitine, which has been studied primarily whendministered IV to HD patients, has been postu-ated to have beneficial effects on ESA-hypore-ponsive anemia, HD-related hypotension, myo-ardial dysfunction, impaired exercise tolerancend performance status, muscle symptoms, andmpaired nutritional status. However, no patho-enic mechanism by which carnitine deficiencyight contribute to anemia or provoke ESA hypo-

esponsiveness has been conclusively eluci-ated. Furthermore, the therapeutic mechanismy which L-carnitine administration might im-rove anemia or enhance ESA responsivenessas not been determined. Finally, no consistentelationship between baseline plasma carnitineevels, anemia, and response to L-carnitine admin-stration has been demonstrated.193,194

In considering L-carnitine administration, theork Group confined evaluation of efficacy out-

omes to RCTs in which the effect of IV L-arnitine on Hb level and ESA dosing had beeneported in patients with CKD. Thus, Work Grouponclusions and the resulting guideline statement.3.1 address the limited use of L-carnitine as anSA adjuvant in patients with CKD. Guideline.3.1 does not address use of L-carnitine forotential nonhematologic indications.In the United States, Medicare coverage for

-carnitine is available for patients who haveeen on dialysis therapy for at least 3 months,ave a plasma free carnitine level less than 40mol/L, and have “erythropoietin-resistant ane-ia . . . that has not responded to standard eryth-

opoietin dosage . . . and for which other causesave been investigated and adequately treated.”195

yporesponsiveness to ESAs is not specificallyefined other than having a persistent Hct lesshan 30% despite erythropoietin dosage that “isonsidered clinically appropriate to treat the par-
icular patient.”
), 2006: pp S71-S78 S71

rmpLpiAojwcttdsBjwott

qtrr(rspmhieIsstui

fa


The statement There is insufficient evidence toecommend use of L-carnitine in the manage-ent of anemia in patients with CKD is sup-orted by results from 6 available RCTs of IV-carnitine administration to ESA-treated HDatients (Table 32).196-200 No RCTs are availablen patients with PD-CKD or ND-CKD (Table 32).nemia was the primary study outcome in only 3f these studies.196-198 No available RCTs wereudged to be of high quality. Five of the 6 RCTsere judged to be of low quality. The RCTs were

haracterized by small numbers of enrolled pa-ients, short duration of observation, concomi-ant use of IV and oral iron, adjustments in ESAosage, high dropout rates, and uncertainty aboutpecific ESA and/or iron dosing during the study.etween-group comparison, the result least sub-

ect to bias, was available in only 2 studies; thereas no difference in either Hb level or ESA doseutcomes in 1 of these studies, and in the other,he comparison was only of erythropoietin resis-
ance index (ERI). Serious limitations in method t
uality, important inconsistencies, major uncer-ainty about the directness and applicability ofesults, imprecise data, and a probability of biasendered the overall quality of evidence very lowTable 33). None of the studies specifically en-olled patients with anemia and ESAhyporespon-iveness or identified a specific subset of patientsarticularly likely to respond to L-carnitine ad-inistration. Therefore, whether L-carnitine en-

ances the effect of ESA therapy in such patientss not known. The Work Group found no specificvidence of adverse drug effects associated withV L-carnitine in patients with CKD. The ab-ence of high-quality evidence for efficacy andafety supports the opinion of the Work Grouphat there is insufficient evidence to recommendse of L-carnitine in the management of anemian patients with CKD.

The conclusion of the Work Group differsrom those of selected previous reports. A meta-nalysis concluded that L-carnitine administra-
ion was associated with higher Hb levels and

lHcWipCthta

iecsmoNClC

sahp

V

imipaita

rsiemv

risc5sasa

ptfpfpRlpsvg

tatwnn


ower ESA doses in ESA-treated patients withD-CKD.201 However, the meta-analysis in-

luded only 3 of the 6 RCTs examined by theork Group and incorporated results from stud-

es outlined in 3 abstracts, but that were neverublished in peer-reviewed journals. An NKFarnitine Consensus Conference recommended

he use of IV L-carnitine in selected ESA-yporesponsive dialysis patients.202 However,he consensus conference lacked systematic databstraction and analysis of method quality.

Previous guideline development processes us-ng systematic evidence review and rigorousvaluation for method quality have reached con-lusions consistent with the current guidelinetatement, there is insufficient evidence to recom-end the use of L-carnitine in the managementf anemia in patients with CKD. These includeKF-KDOQI Guidelines for Nutrition inKD,203 previous NKF-KDOQI anemia guide-

ines,2 and the Revised EBPGs for Anemia inKD.16

Finally, although oral L-carnitine has also beentudied as an ESA adjuvant, no RCTs are avail-ble. Direct comparison of IV to oral L-carnitineas not been reported in HD or other CKDatients.

itamin C (Ascorbate)

In the opinion of the Work Group, there isnsufficient evidence to recommend use of vita-in C (ascorbate) in the management of anemia

n patients with CKD. Vitamin C has been re-orted to increase the release of iron from ferritinnd the reticuloendothelial system and increaseron utilization during heme synthesis.204,205 Al-hough many HD patients may have plasma

Table 33. Use of L-Carnitine as an Adjuvant

OutcomeNo. of Studies

& Study Design Total

N

Methodological Quality of Studiesa Consistency

DirectnesEvidencincludin

Applicab

Hb/Hct Level/ ESA Dose

6 RCTs 171 Serious

limitationsbImportant

inconsistenciescMajor

uncertain

AEsCKD population:

6 RCTs 171

Balance of Benefit and Harm: No Net Benefit

Footnotes: a. Theoretically, adjusting the ESA dose will make any subsequent change in Hb irrelevant since Hb change is b. Quality varied from Grade B to C. c. N/A given between-group comparison was available in only 2 of 6 and only 1 showed statistically significant d. The RCTs were characterized by small numbers of enrolled patients, short duration of observation, concomi

or ESA dose.e. At least 3 studies sponsored by pharmaceutical companies (1 unstated).

scorbic acid levels less than the normal m

ange,206,207 whether this reflects a clinicallyignificant deficiency is uncertain; in other stud-es, ascorbic acid levels have been normal orlevated.208 It has been suggested that 150 to 200g of vitamin C daily is needed to normalize

itamin C levels in most HD patients.206

Several anecdotal reports, small case se-ies,194,209 and nonrandomized studies (primar-ly in HD patients with iron overload, elevatederum ferritin levels, and functional iron defi-iency) using IV vitamin C in doses of 100 to00 mg 3 times weekly have suggested a pos-ible beneficial effect.210-213 Plasma levels ofscorbic acid were not measured in most of thetudies in which vitamin C was administered asn adjuvant to ESA therapy.

Four RCTs of vitamin C in ESA-treated HDatients have been reported (Table 34). Althoughhe uncontrolled studies mentioned tended toocus on a possible role of IV vitamin C inatients with HD-CKD with iron overload andunctional iron deficiency, only 1 RCT includedatients with functional iron deficiency.214 OneCT included patients with iatrogenic iron over-

oad.215 None of the studies specifically includedatients with ESA hyporesponsiveness. Thesetudies have not shown consistent benefit of IVitamin C in either within-group or between-roup comparisons.Oral vitamin C, which can augment absorp-

ion of iron from the GI tract, has been evaluateds an adjunct to ESA therapy in small uncon-rolled studies.216-218 Oral and IV vitamin Cere compared in 1 recent RCT in a smallumber of HD patients for 8 weeks; in a largerumber of patients, oral vitamin C or no treat-

reatment in the HD-CKD Population

Summary of Findings

Othernsiderations


OutcomeQualitative Description of

Effect Size Importance of Outcome

precise data bability of biase Very low

Uncertain benefit due to limited evidence. 1 study with between-arm comparison with partial evidence of

reduced ESA dose.

Moderate

hgiH detroper sEA tnacifingi

Quality of Overall Evidence: Very Low for Benefit

nse to an adjustment in ESA.

SA dose. and oral iron, and adjustments in ESA dosage; 2 studies have primary outcomes other than Hb/Hct

to ESA T

s of e, g

ility Co

tyd

ImPro

s oN

a likely respo

reduction in Etant use of IV

ent were compared for 3 months.219 There was

ni

Hotuoitpfi

hir

sstAsmtc(


o significant difference within or between groupsn Hb levels or ESA doses in either comparison.

The long-term safety of IV ascorbic acid inD patients remains undefined, with secondaryxalosis being the primary concern,220,221 al-hough this was not described with short-termse in any of the studies described. Plasmaxalate levels increase with IV vitamin C admin-stration. A risk for calcium oxalate supersatura-ion in plasma recently was reported in HDatients administered IV vitamin C.222 Asiderom the potential for systemic oxalosis, concerns also warranted because a pro-oxidant effect of

Table 35. Use of Ascorbic Acid as an Adjuvant t

Outcome No. of Studies &

Study Design Total

N

Methodological Quality of Studies a Consistency

DireEin

Ap

Hb/Hct Level/ ESA Dose

4 RCTs 154 Serious

limitationsb Important

inconsistenciesc

AEs

CKD population: 4 RCTs

General population: observational data

154+ None described in RCTs. Theoretical con

systemic oxalosis, retinal oxalosis, calcium intermittent IV doses a


Footnotes: a. Theoretically, adjusting the ESA dose will make any subsequent change in Hb irrelevant since Hb change is a likb. 1 Grade B and 3 Grade C studies.
c. Inconsistencies with regard to the direction of the results for treatment and placebo/control groups. d. References for statistical comparisons varied between studies (within arm or between arms).
igh-dose vitamin C, either directly or throughts effects on mobilization of iron, has beeneported.223,224

In summary, the Work Group concluded thaterious method limitations and important incon-istencies render the quality of available informa-ion on vitamin C efficacy very low (Table 35).t the same time, information on the potential

erious adverse effects (oxalosis) of chronic vita-in C administration is altogether lacking. Thus,

he Work Group concluded that there is insuffi-ient evidence to recommend use of vitamin Cascorbate) in the management of anemia in

reatment in the HD-CKD Population

Summary of Findings

Other Considerations


Outcome Qualitative Description of Effect Size Importance of Outcome

Imprecise datad


No consistent benefit. 2 of 4 reports (both crossover studies) showed benefit

for Hb/Hct; 1 of 4 showed benefit for ESA.

Moderate

olated rare reports of toxicity in patients with ARF or CKD, including secondary pathy, myocardial calcium oxalate deposition. Toxicity in general population with

D-CKD studies is not known nor is applicability to HD-CKD. High


to an adjustment in ESA.

o ESA T

ctness of vidence cluding

plicability

Direct

cern given isoxalate arthos used in H

ely response

pp1chl

ectdwEoatusab

fAcrm

A

tBg

aiAdlpcree

gpsndpmEwpectowtt

c


atients with CKD. None of the RCTs enrolledatients with ESA hyporesponsiveness, and onlyenrolled patients with functional iron defi-

iency214; therefore, whether IV vitamin C en-ances the effect of ESA therapy or iron metabo-ism in such patients is not known.

In addition to the lack of definitive evidence offficacy and safety, there is no evidence thatlinical outcomes—such as reduced hospitaliza-ions, improved cardiovascular status, and re-uced mortality—are improved in patients forhom IV vitamin C treatment is initiated as anSA adjuvant. Whereas the putative mechanismf action of IV vitamin C as an ESA adjuvant isn increase in the release of iron from ferritin andhe reticuloendothelial system and increased irontilization during heme synthesis, none of thetudies reviewed showed reduced utilization ofdministered iron therapy. IV vitamin C has noteen evaluated in patients with PD-CKD.Therefore, given the low quality of evidence

or efficacy and unresolved concerns for seriousEs of chronic administration, the Work Group

oncluded that there is insufficient evidence toecommend use of vitamin C (ascorbate) in theanagement of anemia in patients with CKD.

ndrogens

Androgens should not be used as an adjuvanto ESA treatment in anemic patients with CKD.efore the availability of epoetin therapy, andro-

Table 36. RCTs Evaluating Effects of T

Baseline Cointervention Interve

ArmAuthor, Year

NFo

llow

-up

(m

o)

App

licab

ility

Hb

(g/d

L)

TSA

T (%

)

Ferr

itin

(n

g/m

L)

Description of Cointervention

Arm

16 7.5 34 403 Nandrolone

50 mg IMSheashaa, 2005 259

166

7.3 35 394

SC ESAb

1,000 IU TIW; IV iron

protocol nd Con

9 8.4 41 364 Nandrolone

100 mg IM

Gaughan, 1997 260

106

8.3 32 301

IV ESA1,500 IU TIW d;

Oral and/or IV iron adjusted e Con

6 7.8 nd 1,322 Nandrolone

2 mg/kg IMBerns, 1992 261

64

7.8 nd 776

IV ESAb

40 IU/kg TIW; Oral and/or IV iron

adjusted e Con

Footnotes: a. Primary outcome of study unless otherwise noted. b. All ESA administered per study protocol at start; none with prior ESA treatment. c. Subsequent improvement in symptoms after discontinuation of drug. d. Per study protocol at start; washout until Hb 8.7g/dL in those previously on ESA. e. Iron adjusted to maintain ferritin ≥100 mg/dL and TSAT ≥20%. f. Pat ients randomized to nandrolone decanoate received nandrolone for 2 months before starting ESA.

Coding of Outcomes: Statistically significant benefit for arm 1 vs. arm 2 (with reference to benefit to patient) Statistically significant increase from baseline

ens were used regularly in the treatment of t

nemia in dialysis patients despite the need forntramuscular (IM) injection and a variety ofEs, including acne, virilization, priapism, liverysfunction, injection-site pain, and risk for pe-iosis hepatis and hepatocellular carcinoma. Pro-osed mechanisms of action of these drugs in-lude increased erythropoietin production fromenal or nonrenal sites, increased sensitivity ofrythroid progenitors to the effects of erythropoi-tin, and increased red blood cell survival.

Three RCTs explored a possible role for andro-ens in combination with ESA therapy in HDatients (Table 36). All were small short-termtudies, currently recommended Hb levels wereot achieved, and in 2 of the studies, the ESAoses used were lower than those used in mostatients with HD-CKD on chronic ESA treat-ent. The studies did not enroll patients withSA hyporesponsiveness, so it is not knownhat effect, if any, androgens would have in suchatients. It is unclear whether any enhancedrythropoietic effect caused by androgens wouldonfer clinical benefits that outweigh the poten-ially significant AEs of androgens or the effectsf simply allowing patients to remain at some-hat lower Hb levels without androgens. Short-

erm and long-term toxicity of androgens limitheir use, especially in women.

In short, evidence for efficacy of androgens isharacterized by serious method limitations, impor-

t With IM Androgens on Hb Levels in the HD-CKD Population

Outcomesa

Result/ Metric Comparison AEs

Definition of Clinical

Outcomes Hb (g/dL)

With

in A

rm

vs. B

asel

ine

Bet

wee

n

Arm

s

Description of Event

D/C

of D

rug

or

Red

uctio

n

in D

ose

Qua

lity

10.4 4cMean Hb at 6 mo

10.0 NS

Transient flu-like symptoms, distressing hirsutism, and/or elevated liver function tests 0

11.0 0

Mean Hb at 26 wk

9.4 +

Mild side effects attributed to nandrolone decanoate:

Acne N = 1, injection site pain N = 2, and

injection site hematoma N = 1. Significant in serum glutamic oxaloacetic transaminase from

baseline in androgen group

0

0.12/wk 0 dnRate of increase in Hb

0.11/wk nd NS Unacceptable acne

2

reatmen

ntion

1

2

decanoate 2x/wk

trol

decanoate- weekly

trol

decanoate weeklyf

trol

ant inconsistencies, and sparse data (Table 37).

TqGtidatt(

Oi

S

tlccscaurbstiaa

P

prtv

ttr

V

laavaeEp

S

rvwcwwsbGd

MA

pthat


he Work Group, as a result, considered theuality of evidence to be very low. The Workroup judged mild to severe drug-related AEs in

he target and general population as being highlymportant. Given the very low quality of evi-ence for efficacy and demonstrated AEs ofndrogen therapy, the Work Group concludedhat androgens should not be used as an adjuvanto ESA treatment in anemic patients with CKD.Strong Recommendation)

ther Pharmacological Agents Not Addressedn Guideline Statements

tatinsA growing body of literature indicates that

here may be clinically important, non–lipid-owering effects of the hydroxymethylglutaryloenzyme A reductase inhibitors, or statins, in-luding antiproliferative, anticoagulant, immuno-uppressive, anti-inflammatory, antioxidant, andytoprotective effects. Because a component ofnemia in patients with CKD may be related tonderlying inflammatory processes, a potentialole for statins in enhancing epoetin therapy maye plausible. Only a single small retrospectivetudy addressed statins as adjuvants to ESAherapy.225 Given the nature of this study, furthernvestigation of the effects of statins as ESAdjuvants may be warranted, but their utility, ifny, remains to be determined.

entoxifyllineOne small uncontrolled open-label study of 16

atients with CKD (HD, PD, and transplantecipients) with ESA-resistant anemia evaluatedhe effect of pentoxifylline as an ESA adju-

Table 37. Use of Androgens as an A

OutcomeNo. of Studies &

Study Design Total

N

Methodological Quality of Studies Consistency

DirectEvidincl

Appli

Hb/Hct Level/ ESA dose

3 RCTs 63 Serious

limitationsaImportant

inconsistenciesb Dir

AEs


General population: trials, case reports, narrative reviews

63+Mild to severe AEs noted in RCTs included s

from androgens in non-CKD populations whichcarcinoma. Mechanism of action and pr


Footnotes: a. 1 Grade B and 2 Grade C studies. b. Statistically significant effect with only 1 of 3 studies. c. The studies used different ESA and iron protocols and had different definitions for the Hb/Hct outcome. d. The studies used different ESA and iron protocols and had different definitions for the Hb/Hct outcome.

ant.226 Further studies may be warranted, but t

he utility, if any, of pentoxifylline as an adjuvanto ESA treatment in patients with HD-CKDemains to be determined.

itamin Supplements Other Than Vitamin CAlthough deficiencies of vitamin B12 and fo-

ate are recognized causes of anemia and rarelyre the basis for ESA hyporesponsiveness, therere no RCTs showing that supplementation withitamin B12, folate, or other vitamins (in thebsence of documented vitamin deficiency) is anffective adjuvant to ESA therapy. One RCT ofSA-treated HD patients did not find a benefit ofyridoxine (vitamin B6) as an ESA adjuvant.227

ummary

There was insufficient evidence for efficacy toecommend use of statins, pentoxifylline, anditamin B12 and folate supplements (other thanhen used to correct documented vitamin defi-

iency) as adjuvants to ESA therapy in patientsith CKD. Because these therapies are not inidespread use as ESA adjuvants, they are pre-

ented here primarily for general information,ut were not considered by the Anemia Workroup for inclusion in Guidelines or CPRs ad-ressing ESA adjuvants.

odifications of Dialysis Treatments Notddressed in Guideline Statements

The effects of modifications of the HD dialysisrescription and various components of the HDreatment on anemia in patients with HD-CKDave been studied. Unlike the pharmacologicalgents discussed, it is not likely that these dialysisreatment modifications would be undertaken for

to ESA Treatment in the HD-CKD Population

Summary of Findings

OtherConsiderations


Outcome Qualitative Description of Effect Size Importance of

Outcome


No consistent benefit. Only 1 of 3 papers showing significant between-arm

comparison in Hb/Hct (difference in Hb of 1.6 g/dL).c

Moderate

elevated AST, discomfort at injection site. This is consistent with reported AEs ization, priapism, peliosis hepatis, liver enzyme abnormalities, and hepatocellular of androgens are believed to be similar in non-CKD and CKD populations.

High


djuvant

ness of ence

uding cability

ectc,d

evere acne, include virilofile of AEs

he primary purpose of enhancing ESA responsive-

nAC

comcKTitNao

HO

btipUdsmopmtstIRh1t

wfdfidKooHU(

dstE3

V

aamwbEltEscoaosrpmc

U

fduHtaad(IrECtdlpcst


ess, and they therefore were not considered by thenemia Work Group for inclusion in Guidelines orPRs addressing ESA adjuvants.Distinguishing between the effects of in-

reased HD dose (ie, urea reduction ratio [URR]r Kt/V) from effects of concomitant changes inembrane on response to ESA therapy is diffi-

ult because most studies compared differentt/V levels using membranes of different types.he effects of dialysate composition, primarily

n comparisons of standard bicarbonate dialysateo ultrapure dialysate, also have been evaluated.o RCTs have been reported that compared HD

nd PD (or different doses of PD) on anemiautcomes or ESA dose in ESA-treated patients.

D Intensity (“dose”), Membrane Type, andther Dialysis ModificationsA few studies have examined the relationship

etween dialysis dose and dialysis membraneype and anemia outcomes,228-236 with conflict-ng results. Because in most of these studies,atients in the higher versus lower Kt/V (orRR) groups were dialyzed with membranes ofifferent composition and flux, the role of dialy-is dose cannot be separated from the effects ofembrane permeability or biocompatibility. One

f these studies, which was not an RCT, com-ared different levels of Kt/V with the sameembranes236 and observed an inverse correla-

ion between ESA dose and Kt/V, but no relation-hip between Kt/V and Hb level, in HD patientsreated with unsubstituted cellulose membranes.n a subsequent report, which also was not anCT,235 it was suggested that this relationshipolds only for patients with a Kt/V less than.33, and above this level, there was no correla-ion between Kt/V and ESA dose.

Three RCTs were performed in HD patients inhich anemia-related outcomes were compared

or high-flux and low-flux dialyzers.229-231 Noifference in Hct or ESA responsiveness wasound between groups. Assessment of these stud-es is complicated by the use of membranes ofifferent composition, attainment of differentt/V levels, short study duration, and inclusionf patients not on ESA therapy. In another RCTf HD patients who were unable to reach a targetb level of 11 g/dL or greater with at least 200/kg/wk of recombinant human erythropoietin

rHuEPO), low-flux and high-flux polysulfone u

ialyzers were compared.228 Kt/V values wereimilar in the 2 groups at baseline and the end ofhe 6-month study. Hb levels were higher andSA doses were lower in the high-flux group bymonths and remained so to the end of the study.

itamin EVitamin E has been considered as a potential

djuvant to ESA therapy based on the consider-tion that antioxidant properties of vitamin Eay prolong red blood cell life span in patientsith CKD and anemia. Oral vitamin E has noteen studied in prospective controlled trials ofSA-treated patients. Vitamin E–bonded dia-

yzers were studied in a single RCT in whichhe primary focus was the effects of a vitamin–bonded hemodialyzer on carotid artery athero-clerosis and rheological properties of red bloodells.237 Mean ESA dose decreased after 1 yearn the vitamin E–bonded dialyzers, but Hb levelsnd other important parameters, such as amountf iron administered, were not reported. Theafety of vitamin E also must be considered: aecent meta-analysis in the non–kidney-diseaseopulation suggested that doses of 400 U/d orore of vitamin E were associated with an in-

rease in all-cause mortality.238

ltrapure DialysateInflammatory cytokines are proposed to inter-

ere with the erythropoietic effect of ESAs bothirectly and through impaired mobilization andtilization of iron. An inflammatory stimulus inD patients may be endotoxin or bacterial con-

amination of dialysate. Standards for bacterialnd endotoxin content of water used for dialysisnd for dialysate vary around the world. Forialysate, recently revised voluntary standardsAssociation for the Advancement of Medicalnstrumentation) include an upper limit for bacte-ia of 200 CFU/mL, and for endotoxin, of 2U/mL.239 In some countries, limits of 100FU/mL and 0.25 EU/mL for bacteria and endo-

oxin have been applied, respectively. Ultrapureialysate has 0.1 CFU/mL or less of bacteria andess than 0.03 EU/mL of endotoxin.239,240 Ultra-ure dialysate is produced by generation of mi-robiologically purer water than used fortandard dialysate, minimizing potentially con-aminating biofilm, and use of ultrafilters. Some
ncontrolled observations suggest that the re-

suRpmwuaktr

H

pratlHlsbhoptc

D

oHIiatHtntKddIdwwowo

ctn

P

tEcHo

S

rfdrupdHH

lpaatttaagmdcpFaasafiabdp


ponse to ESA treatment may be enhanced by these of ultrapure dialysate solutions.241 ThreeCTs examined the effects of using online-roduced or filtered ultrapure dialysate on ane-ia outcomes in HD patients.242-244 ESA dosesere significantly decreased by up to 33%. These of ultrapure dialysate typically was associ-ted with lower C-reactive protein and interleu-in 6 levels compared with standard dialysate,hought to be indicative of reduced inflammatoryesponses.

emodiafiltrationHemodiafiltration (HDF) has been evaluated

rospectively in a few RCTs with conflictingesults. A small randomized study that comparedcetate-free biofiltration and low-flux HD in ESA-reated patients suggested that ESA doses wereower with HDF.245 In a comparison of onlineDF with high-flux HD, no differences in Hb

evels or ESA dose were observed.246 Anothertudy, in which only about 40% of patients wereeing treated with an ESA, compared HDF andigh-flux HD. It found no difference in Hb levelsr ESA doses.247 HDF with online production ofyrogen-free solutions also may have an advan-age in terms or anemia outcomes compared withonventional solutions.248

aily and Nocturnal HDThere are no RCTs comparing either daily HD

r nocturnal HD with conventional intermittentD for effects on anemia or ESA requirements.

n the most recent report from a small nonrandom-zed comparison of short daily, long nocturnal,nd conventional HD, only nocturnal HD pa-ients had a statistically significant increase inb levels during 18 months; ESA doses also

ended to increase, although the difference wasot statistically significant.249 In 1 study, conven-ional HD patients with a baseline single-poolt/V of at least 1.3 were changed to short-dailyialysis 6 times per week with the same weeklyialysis time.250 Weekly Kt/V increased by 31%.n the patients studied for 12 months, mean ESAose decreased 45% compared with baseline,ith stable or increased Hb levels. Doses of ESAere trending upward between 6 and 12 monthsf observation. Other studies, none of whichere RCTs, reported variable results.251-254 To
ur knowledge, it has not been studied whether w
hanging from conventional HD to daily or noc-urnal HD specifically enhances ESA responsive-ess in ESA-hyporesponsive patients.

eritoneal DialysisAlthough observational data have suggested

hat patients treated with PD may have lowerSA requirements than HD patients,255,256 noontrolled trials have been reported comparingD and PD or different doses of PD on anemiautcomes or ESA dose in ESA-treated patients.

ummary

Whereas the Anemia Work Group does notecommend changing patients with HD-CKDrom standard bicarbonate dialysate to ultrapureialysate for the purpose of enhancing ESAesponsiveness, studies suggest that the use ofltrapure dialysate results in lower ESA doses inatients with HD-CKD. There is insufficient evi-ence at this time that other modifications in theD prescription or various components of theD treatment enhance ESA therapy.

LIMITATIONSWe acknowledge the limitations of these guide-

ines. For lack of evidence, we do not address theotential adjuvant effect of pharmacologicalgents or alterations in dialysis prescription onnemia outcomes in patients without concomi-ant ESA therapy. Among patients receiving ESAherapy, available evidence is restricted to pa-ients with HD-CKD. Among available ESAgents, evidence is restricted to use of epoetinlfa. As reported elsewhere in this document, auideline needs to be based on both high- oroderate-quantity evidence and consistently

emonstrated net medical benefit. Therefore, weonsidered appropriately designed, adequatelyowered RCTs to be the required foundation.ew such RCTs currently are available. Amongvailable RCTs, only hematologic outcomes weressessed: no evidence exists to confirm the as-umption that hematologic outcomes gained withdjuvant therapy share the same risk-benefit pro-le as those gained with ESA and iron therapylone. Finally, although the primary motivationehind adjuvant therapy is to decrease cost byecreasing ESA doses, information on the com-arative costs and benefits of ESA with and
ithout proposed noniron adjuvants is lacking.

Rcoiswp

woccc

pnntpdwtmwpoovcao

cemataaa

A

CPR 3.4.: TRANSFUSION THERAPY

ewatblmciwtqcscHrtimsmabwen

tnrrstvCrvtqce

roai

ed blood cell transfusions should be used judi-iously in patients with CKD, especially becausef the potential development of sensitivity affect-ng future kidney transplantation. However, de-pite the use of ESA and iron therapy, transfusionith red blood cells occasionally is required, inarticular in the setting of acute bleeding.3.4.1 In the opinion of the Work Group, no

single Hb concentration justifies orrequires transfusion. In particular,the target Hb recommended forchronic anemia management (seeGuideline 2.1) should not serve as atransfusion trigger.

RATIONALE

Anemia commonly is observed in patientsith CKD. The degree of anemia is a reflectionf the severity of CKD. Anemia impacts onardiac function and is associated with increasedardiovascular morbidity and mortality and de-reased QOL.262

Typically, the anemia of CKD is chronic, andatients compensate for the anemia through aumber of mechanisms. Thus, in determining theeed for red blood cell transfusions, it is impor-ant to evaluate the state of compensation of theatient. In general, otherwise healthy individualsisplay few symptoms or signs of anemia at resthen Hb level is greater than 7 to 8 g/dL, although

hey may show dyspnea with exertion. At 6 g/dL,ost patients will report some weakness and,ith progressive decreases in Hb values, dys-nea at rest and congestive heart failure (CHF)ccur.263 Also, the risk for relevant tissue hyp-xia increases, particularly in the presence ofascular disease. Therefore, in general, decisionsoncerning transfusion are not acute, and there isn opportunity to consider the risks and benefitsf transfusion as treatment.Before considering transfusion of red blood

ells for the treatment of chronic anemia, it isssential to assess signs and symptoms and deter-ine the cause of the anemia so that, when

ppropriate, treatment other than red blood cellransfusions may be used. Classic examples ofnemias that may be severe, but correctible bylternative therapies, are iron-deficiency anemia
nd pernicious anemia in adults. e

If red blood cell transfusions are deemed nec-ssary for the immediate treatment of patientsith chronic anemia, the goal should be to attain

n Hb concentration that will prevent inadequateissue oxygenation or cardiac failure. When redlood cell transfusions are considered for theong-term treatment of patients with chronic ane-ia, treatment goals (other than to maintain a

ertain Hb concentration) should be determinedn advance and assessed serially to ascertainhether the goals are being met. In this setting,

he physician and patient must consider suchuestions as: What symptoms and signs areaused or aggravated by the anemia? Can theseymptoms and signs be alleviated by red bloodell transfusions? What is the minimum level ofb at which the patient can function satisfacto-

ily? Do the potential benefits of red blood cellransfusions outweigh the risks (and possibly thenconveniences) for any given patient? In deter-ining the risk-benefit ratio for a given patient,

uch factors as lifestyle, the presence of otheredical conditions, the likely duration of the

nemia, and the patient’s overall prognosis shoulde considered. For example, a patient may beilling to tolerate a very limited capacity for

xertion if anemia is likely to be temporary, butot if the anemia will be permanent.In general, risks per unit of red blood cells

ransfused are the same as in any setting. Aumber of retrospective studies have identifiedisks related to aggressive transfusion support. Aeview of patients with acute coronary arteryyndromes revealed a greater mortality rate inransfusion recipients.264 In the presence of se-ere chronic anemia, transfusion may lead toHF, particularly in the elderly. In such cases,

ed blood cell transfusions must be administeredery slowly, and, in patients with HD-CKD,ransfusion during hemofiltration may be re-uired. The administration of many red bloodell transfusions over a prolonged period canventually lead to iron overload.

The use of ESAs can greatly reduce the need fored blood cell transfusions in patients with anemiaf CKD when target Hb concentrations are reachednd maintained.265,266 With the advent of newmmunosuppressant regimens after 1995, the ben-
fits of pretransplantation transfusion have been
), 2006: pp S79-S80 S79

rdddmtpssatgr

cam

sbitetw

lPPbtfrr


endered largely obsolete. There is some evi-ence that donor-specific transfusion with livingonor transplantation improves survival, but theecision to perform donor-specific transfusionust still be made on a case-by-case basis. Blood

ransfusions can induce antibodies to histocom-atibility leukocyte antigens that can reduce theuccess of kidney transplantation; thus, transfu-ions generally should be avoided in patientswaiting a renal transplant.267 If deemed essen-ial, red blood cell transfusions in this patientroup should be conducted in line with publishedecommendations.268

If therapy with an ESA is started at the Hboncentration recommended in these guidelinesnd Hb levels are maintained at the recom-
ended target concentrations, blood transfusions H
hould be necessary only for patients with acuteleeding (usually GI), acute hemolysis, or severenflammation or blood loss through surgery, andhen only in an emergency or if the patientxhibits a rapid decline in condition. Interna-ional guidelines provide criteria for decidinghen transfusion is necessary.269-271

Patients with CKD on HD therapy are moreikely to need blood transfusions than those onD therapy because of the HD procedure itself.atients on HD therapy lose blood from frequentlood tests, trapped blood in the dialyzer andubing,272 and increased risk for GI bleedingrom anticoagulants. However, aggressive ironeplacement has largely eliminated the need fored blood cell transfusions, even for patients on
D therapy.

Aipigtt

H

fi

A

CPR 3.5. EVALUATING AND CORRECTING PERSISTENTFAILURE TO REACH OR MAINTAIN

INTENDED HB

fsHIHifgpttdsdrtolc

A

dasattvqc

ptrats(wliruca

lthough relative resistance to the effect of ESAss a common problem in managing the anemia ofatients with CKD and is the subject of intensenterest, the bulk of available information sug-ests that—in the absence of iron deficiency—here are few readily reversible factors that con-ribute to ESA hyporesponsiveness.

3.5.1 Hyporesponse to ESA and irontherapy:In the opinion of the Work Group, thepatient with anemia and CKD shouldundergo evaluation for specific causesof hyporesponse whenever the Hblevel is inappropriately low for theESA dose administered. Such condi-tions include, but are not limited to:● A significant increase in the ESA

dose requirement to maintain acertain Hb level or a significantdecrease in Hb level at a constantESA dose.

● A failure to increase the Hb level togreater than 11 g/dL despite anESA dose equivalent to epoetingreater than 500 IU/kg/wk.

3.5.2 Evaluation for PRCA:In the opinion of the Work Group,evaluation for antibody-mediatedPRCA should be undertaken when apatient receiving ESA therapy formore than 4 weeks develops each ofthe following:● Sudden rapid decrease in Hb level

at the rate of 0.5 to 1.0 g/dL/wk, orrequirement of red blood cell trans-fusions at the rate of approximately1 to 2 per week, AND

● Normal platelet and white bloodcell counts, AND

● Absolute reticulocyte count lessthan 10,000/�L.

BACKGROUND

yporesponsiveness to ESAs

Hyporesponsiveness to ESAs is a common
nding of grave significance whether it is mani- c

ested by persistent, below-target Hb levels de-pite substantial ESA doses or by within-targetb levels attained only at very high ESA doses.

n patients with HD-CKD undergoing ESA therapy,b levels less than 11 g/dL are associated with

ncreased mortality and hospitalization rates, andailure to achieve an Hb level greater than 11/dL is a poor prognostic sign. Given the dispro-ortionate burden of morbidity and mortality thathe hyporesponsive patient population bears andhe ESA expense that hyporesponsiveness engen-ers, hyporesponsiveness to ESAs deserves morecrutiny than it has received. Although mostisorders associated with hyporesponsiveness areeadily apparent, a review of available informa-ion on patients with coexisting hematologic orncological disorders may be worthwhile. Simi-arly, a rare disorder, PRCA, deserves specialonsideration.

ntibody-Mediated PRCA

Rarely, patients undergoing ESA therapyevelop antibodies that neutralize both ESAnd endogenous erythropoietin. The resultingyndrome, antibody-mediated PRCA, is char-cterized by the sudden development of severeransfusion-dependent anemia. Rapid recogni-ion, appropriate evaluation, and prompt inter-ention can be effective in limiting the conse-uences of this life-threatening hyporesponseondition.

Antibody-mediated PRCA, although rare inatients administered ESAs, received urgent at-ention after 1998. Between 1989 and 1998, threeeports described the development of PRCA insmall number of patients with CKD adminis-

ered ESAs.273,274 Reports of PRCA increasedharply in 1998 and reached a peak in 2002Fig 17).273,275 These reports were associatedith SC administration of an epoetin alfa formu-

ation not available in the United States. In 1998,n this formulation, polysorbate 80 was used toeplace human albumin. Preparations of this prod-ct included single-dose syringes fitted with un-oated rubber stoppers and prefilled with epoetinlfa. Results of an intensive investigation indi-
ate that in the presence of polysorbate 80 and
), 2006: pp S81-S85 S81

utct

rpcodot

aNdabpg

wr8yf0tretiih

H

usggUbnrdriettdt

PcIbpks


ncoated rubber can release organic compoundshat may act as immunoadjuvants, thereby in-reasing the immunogenicity of SC-adminis-ered epoetin alfa.273-275

Between 2001 and late 2003, single-dose sy-inges with polysorbate 80 and uncoated stop-ers were replaced by syringes with fluoro-resin-oated stoppers.275 In addition, SC administrationf the agent had been prohibited in Europe andiscouraged in Canada. By 2004, the incidencef new antibody-mediated PRCA had decreasedo pre-1998 levels.

Isolated cases of PRCA have been observed inssociation with the use of other ESAs.273,274,276-279

o case of antibody-associated PRCA has beenocumented in patients treated with only IVdministration of ESAs.274 An increase in anti-ody-mediated PRCA has not been seen amongatients in the United States, where the immuno-enic formulation has not been available.

Fig 17. Exposure to Eprex® and case counts ofRCA. Relationship between reporting rate of newases of PRCA and route of administration (SC versus

V), stabilizer (human serum albumin versus polysor-ate 80), and coated versus uncoated stoppers inreparations of Eprex®, a form of epoetin alfa mar-eted outside the United States. Reprinted with permis-ion.275

The incidence rate of PRCA in patients whoere exposed to SC-administered ESA from sy-

inges with uncoated stoppers and polysorbate0 is estimated at 4.23 cases/10,000 patient-ears.275 The incidence with SC use of all otherorms of SC-administered ESA is estimated to be.5 cases/10,000 patient-years.275 The findinghat antibody-mediated PRCA develops onlyarely, even among patients exposed to adverselyquipped syringes, suggests that additional fac-ors must have been involved to render ESAmmunogenic, potentially including differencesn host immunoreactivity or product storage andandling.

RATIONALE

yporesponse to ESA and Iron Therapy

The patient with anemia and CKD shouldndergo evaluation for specific causes of hypore-ponse if Hb level is persistently less than 11/dL AND if ESA doses are equivalent to epoetinreater than 500 IU/kg/wk. Results from theSRDS national data system show that the distri-ution of epoetin alfa doses is quite broad, theumber of administrations per percentile range iselatively constant over the full spectrum ofoses, and the relationship between percentileange and mean epoetin dose per administrations distinctly nonlinear (Fig 18). In these uns-lected patients, the 99th percentile doses are 30imes greater than the 1st percentile doses, andhe top 20% of patients seem to be using aisproportionate amount of ESA compared withhe lower 80%.

Fig 18. Mean epoetin dose per patient peradministration by percentile of dose (1st, 5th to
95th, and 99th). Data are for December 2004,courtesy of USRDS.

ittaplsdv

t6i

dAatman

HEawltpa3mt

aid3pwtoaelt

imsqpbhm

walplbIiba

tplafsilm

T


Available information on hyporesponsivenesss weakened by the lack of a validated quantita-ive measure of ESA resistance. Although a resis-ance index—calculated by dividing the weight-djusted ESA dose by Hb level—has beenroposed, precisely how the ESA dose and Hbevel should be determined (area under the curve,ingle value, time averaged) has not been stan-ardized and reference values have not beenalidated.Factors most commonly associated with persis-

ent failure to achieve target Hb levels for at leastmonths despite ESA therapy include the follow-

ng280:

● Persistent iron deficiency● Frequent hospitalization● Hospitalization for infection● Temporary catheter insertion● Permanent catheter insertion● Hypoalbuminemia● Elevated C-reactive protein level.

In general, these problems do not pose aiagnostic challenge or yield to simple solutions.second set of disorders also may be identified

mong hyporesponsive patients. Unfortunately,hey also are found among those who do noteet criteria for hyporesponsiveness, and they

lso represent neither frequent nor elusive diag-oses280:

● Pancytopenia/aplastic anemia● Hemolytic anemia● Chronic blood loss● Cancer, chemotherapy, or radiotherapy● Inflammatory disease● Acquired immune deficiency syndrome● Infection.

Only a small percentage of patients with ab level less than 11 g/dL fail to respond toSA therapy. Persistency analysis shows thatpproximately 10% of patients with HD-CKDho enter a 6-month period with a Hb level

ess than 11 g/dL remain at less than thathreshold for 6 consecutive months.112 Amongatients with a Hb level less than 11 g/dLdministered high ESA doses (epoetin alfa �0,000 IU/wk), only 0.6% of patients re-ained at less than that threshold for 6 consecu-

ive months.

In short, the available evidence suggests thatpproximately 20% of patients with HD-CKDn the United States are administered ESAoses in excess of an epoetin equivalent of0,000 IU/wk, or 428 IU/kg/wk for a 70-kgatient (Fig 2). Approximately 10% of patientsith an Hb level less than 11 g/dL will persis-

ently fail to attain a target Hb level of 11 g/dLr greater. However, among US patients withn Hb level less than 11 g/dL and ESA doses inxcess of 30,000 IU/wk epoetin equivalents,ess than 1% will remain at less than the Hbarget for 6 months.

The patient with anemia, CKD, and a preexist-ng hematologic disorder represents an uncom-on, but challenging, cause of ESA hyporespon-

iveness and deserves special consideration. Theuality of reviewed material is insufficient torovide specific recommendations. However, arief review of the available literature may proveelpful to medical decision making in the treat-ent of these patients.

Management of anemia in patients with CKDith preexisting hematologic disorders associ-

ted with anemia may present specific prob-ems because of multifactorial causes. In someatients, anemia may result predominantly fromow endogenous erythropoietin levels and cane corrected readily by administration of ESAs.n other disorders, impaired marrow function,neffective erythropoiesis, and shortened redlood cell survival may contribute to anemiand ESA hyporesponsiveness.

We identified a small number of publica-ions that evaluated ESA responsiveness inatients with CKD and preexisting hemato-ogic disorders (Table 38). The publicationsre predominantly observational, taking theorm of individual case reports or reports of amall series of patients. Although the availablenformation is insufficient to support guide-ines or CPRs, the following summary state-ents may be helpful:

halassemia

● Patients with thalassemia have a poorresponse to ESA.281-283

● Higher doses of ESA are required to achieve
target Hb levels.281-284

H

H

M

G

mpdtpt

E

sEeHrrp


● Patients can become independent of trans-fusions on high doses of ESA.284

● The need for ESA increases in patientswith high levels of HbA2 chains in theserum.282

● Patients with �-thalassemia major showhigh endogenous erythropoietin levels.285

● Patients with HbS/�-thalassemia have ahigher-than-normal endogenous erythropoi-etin level.286

b H

● Patients are resistant to ESA.281,287

● Endogenous serum erythropoietin levelsand serum transferrin receptor levels areboth increased.287

● The mechanism of anemia is likely relatedto ineffective erythropoiesis andhemolysis.287

b S

● Patients show higher ESA dose require-ment to achieve target Hb level.288,289

● There may be a lower incidence of sicklecell crises while on ESA therapy.289

● Endogenous erythropoietin levels increase

Table 38. Published Experience in Patients With

Author, Year Location Adult/Ped/ Mean Age N Diagnosi

China Adult 4 Thal-t Cheng, 1993 281

HbH 1 Lai, 1992 283 China Adult 4 α-Thal-T, β-T

Di Iorio, 2003 282 Italy Adult 10 β-Thal-m

CKD Stage

eym elpitluMPowe, 1993 288 US Adult 59,462

sid llec elkciS

Tomson, 1992 289 UK Adult 3 Sickle cell dis

Tarng, 1997 296 Taiwan Adult 1 Hb J-MeinuDrueke, 1990 297 ecnarF Ataga, 2000 298 SU Drueke, 1991 299 ecnarF

Di Iorio, 2004 284 Italy 12 β-Thal-m

Di Iorio, 2003 282 Italy 10 β-Thal-m

5 β-Thal-t t-E bH 51Paritpokee, 2002 285 Thailand Children

55 β-Thal-m/H

3 Homocyg sickle cePapassotiriou, 2000 290 Greece

10 Hb S/β-Th

Papassotiriou, 1998 287 H bH 02 eceerG

Katopodis, 1997 286 Greece 16-59 17 S-β-Tha

with hydroxyurea therapy.290 l

ultiple Myeloma

● Higher levels of ESA are required toachieve target Hb levels in patients withHD-CKD.288

● Therapy with ESAs reduces transfusionsand improves QOL in anemic patients withor without kidney disease.291

eneral Comments

Patients with �-thalassemia and Hb S diseaseay require higher doses of ESA compared with

atients with CKD who do not have hematologicisorders. There is no apparent contraindicationo increase the ESA dose in either disorder. Someatients may require doses usually used in hema-opoietic disorders (40,000 to 60,000 U/wk).

valuation for PRCA

Evaluation for antibody-mediated PRCAhould be undertaken when a patient receivingSA therapy for more than 4 weeks developsach of the following: sudden rapid decline inb level at the rate of 0.5 to 1.0 g/dL/wk, or

equirement of red blood cell transfusions at theate of approximately 1 to 2 per week; normallatelet and white blood cell counts; and abso-

, CKD, and a Preexisting Hematologic Disorder

Type of Study EPO Response

(n = 4 ) Matched controls Different doses Higher doses of ESA to achieve target Hb

ASE ot tnatsiseR (n = 36) Randomly selected Different doses Poor response of Thal patients

Lab quantification of Hb chains Different doses ESA dose requirement higher in

patients with high levels of anomalous Hb chains

National logitudinal cohort Epo requirement

Less response, higher ESA requirement

Less response, higher ESA requirement

Case reports Increasing doses No sickle crisis on ESA, Hb S increased, no Tf for 12 weeks

Case reports Poor response to ESA weiveR weiveR weiveR

Case series Increasing doses Patients became Tf independent on high doses of ESA, sustained effect

Case series HbA2 levels and Epo Need for ESA increases with

presence of high levels of Hb A2

chains (see Ataga, 2000 298)Lab for endogenous Epo Lab study β-Thal major high levels of ESA

Intervention with HU Endogenous Epo levels

ESA levels increase on HU

slevel RfT dna opE seires esaCBoth are increased in patients with

HbH/ineffectiveerythropoiesis/hemolysis

Comparison with normal controls Epo levels, Hb High ESA levels in S-β-Thal

compared to normal, correlation with Hb

Anemia

s

hal-m

5

amol

esae

ease

ng

b E

ll disease

al

l

ute reticulocyte count less than 10,000/�L.

S

cidacdpap

D

boPpn

M

oaalwisgbIrBfccp


yndrome RecognitionThe characteristic sign of PRCA is almost

omplete cessation of erythropoiesis. Accord-ngly, a patient affected with PRCA evidences aecrease in Hb level of about 0.1 g/dL per daynd a reticulocyte count less than 10,000/�L,onsistent with the normal rate of red blood cellestruction and an absence of red blood cellroduction. Because nonerythroid marrow is un-ffected, leukocyte and platelet counts are ex-ected to be normal.274,276

iagnostic EvaluationRecommendations based on expert opinions have

een published to guide the workup and therapyf patients suspected to have antibody-mediatedRCA.274,277,279 The definitive diagnosis is de-endent upon demonstration of the presence of
eutralizing antibodies against erythropoietin. p
anagement and TreatmentIt is prudent to discontinue the administration

f any ESA product in patients with suspectednd confirmed diagnosis because the antibodiesre cross-reactive and continued exposure mayead to anaphylactic reactions.292 Patients likelyill require transfusion support. Treatment with

mmunosuppressive approaches is effective in aignificant number of patients.293 Renal allo-rafts usually result in a rapid decrease in anti-ody titers associated with therapeutic benefit.293

t is not clear whether treatment with ESA can beesumed safely after clearance of the antibody.ased on very preliminary data, this might be

easible; however, caution is advised.294 A singlease also has been reported in which Hb levelsould be restored in the presence of antierythro-oietin antibodies by switching to a different
roduct.295

titsmlfsdoasfGsbltdCucap

wO

S

III. CLINICAL PRACTICE RECOMMENDATIONS FOR ANEMIA
IN CHRONIC KIDNEY DISEASE IN CHILDREN
tlai5rstpm

oghfo

tatttlcf

aatg

CLINICAL PRACTICERECOMMENDATIONS FOR ANEMIA IN

PEDIATRIC PATIENTS WITH CKD

INTRODUCTIONPresentation of clinical practice recommenda-

ions for anemia in pediatric patients with CKDs warranted because the pediatric patient popula-ion, from newborn through adolescence, differsubstantially from the adult population in keyetabolic, growth, developmental, and psycho-

ogical factors.300 Nevertheless, providers caringor adult and pediatric patients with CKD largelyhare the same topics of concern regarding theiagnosis and management of anemia. More-ver, the bulk of information to support CPRsnd the only evidence of sufficient strength toupport evidence-based guidelines are availablerom studies of the adult patient population.iven the distinct needs of pediatric patients,

hared topics of concern among providers foroth pediatric and adult patients, the generallyow quality of evidence in pediatric patients, andhe unavoidable need to generalize from evi-ence in adults, the Work Group chose to presentPRs in pediatric patients as a separate section,sing adult guidelines as a frame of reference,hanging recommendations when appropriate,nd describing available evidence in pediatricatients under the guideline rationale.Here, we address issues pertinent to children

ith anemia and CKD at all stages of disease.
ur goal is to offer recommendations based on N
American Journal of K86

he best evidence available regarding issues re-ated to the identification, diagnosis, initial evalu-tion, and strategies for treatment and monitor-ng of children with anemia and CKD stages 1 to, including those treated with dialysis. Oureview is not exhaustive and our intent is not toubstitute for textbooks. Specific details on poten-ial dosing regimens, therapeutic choices, andractice options in caring for children with ane-ia and CKD are found elsewhere.301

Please note that to be consistent with the usef Hb levels, as opposed to Hct, in these newuidelines, all Hct values from studies quotedave been converted to Hb equivalents by aactor of 0.3 g/dL per percent of Hct; eg, an Hctf 33% is converted to an Hb level of 9.9 g/dL.All statements in the pediatric section assume

he preface In the opinion of the Work Group, andll statements are provided as CPRs becausehere is insufficient evidence in pediatric patientso support evidence-based guidelines. When, inhe opinion of the Work Group, the adult guide-ine statement applies equally well to adults andhildren, the statement is accompanied by theollowing:

(FULLYAPPLICABLE TO CHILDREN)When, in the opinion of the Work Group, the

dult guideline statement needs modification ordjustment for children, the following instruc-ion is given, followed by the pediatric-specificuideline statement.(APPLICABLE TO CHILDREN, BUT

EEDS MODIFICATION)

idney Diseases, Vol 47, No 5, Suppl 3 (May), 2006: p S86

Itc

S

plttbt

m

A

CPR FOR PEDIATRICS 1.1: IDENTIFYING PATIENTS AND
INITIATING EVALUATION
fktta3eiiGnbdwc

F

dpoote

D

Hatuaaltlcas

cfaf

dentifying anemia is the first step in evaluatinghe prognostic, diagnostic, and therapeutic signifi-ance of anemia in patients with CKD.

1.1.1 Stage and cause of CKD: (FULLYAPPLICABLE TO CHILDREN)In the opinion of the Work Group, Hbtesting should be carried out in allpatients with CKD, regardless of stageor cause.

1.1.2 Frequency of testing for anemia:(FULLY APPLICABLE TO CHIL-DREN)In the opinion of the Work Group, Hblevels should be measured at leastannually.

1.1.3 Diagnosis of anemia: (APPLICABLETO CHILDREN, BUT NEEDS MODI-FICATION)ADULT CPRIn the opinion of the Work Group,diagnosis of anemia should be madeand further evaluation should be un-dertaken at the following Hb concen-trations:● <13.5 g/dL in adult males.● <12.0 g/dL in adult females.PEDIATRIC CPRIn the opinion of the Work Group, inthe pediatric patient, diagnosis of ane-mia should be made and further evalu-ation should be undertaken wheneverthe observed Hb concentration is lessthan the fifth percentile of normalwhen adjusted for age and sex.

RATIONALE

tage and Cause of CKD

There is no evidence in the pediatric CKDopulation to contradict the principles as out-ined in the Adult Guideline 1.1 with respect tohe use of Hb level, not Hct, to define anemia andhe value of obtaining this at a standard time (eg,efore dialysis during the midweek run) in pa-ients on HD therapy.

It also is clear that children with CKD are


unction decreases. From USRDS 2004 data, wenow that the mean eGFR at initiation of dialysisherapy in children is 10.3 mL/min/1.73 m2 andhat, at this point, 35% to 40% of children arelready receiving ESA therapy.28 One study of5 children with various degrees of renal diseasexamined the role of erythropoietin and potentialnhibitors of its action. The study suggested thatn this group, the risk for anemia increased at aFR less than 35 mL/min/1.73 m2.302 Unfortu-ately, unlike the adult literature, there is noetter direct or observational evidence that clearlyelineates a particular cutoff level of function forhich the risk for CKD-associated anemia in-

reases significantly in children.

requency of Testing for Anemia

This guideline is considered applicable to chil-ren because there is no direct evidence to sup-ort a different recommendation. However, it isften the case that children (especially youngernes) will receive more frequent laboratory moni-oring of their CKD status caused, in part, byxpected changes in values during growth.

iagnosis of Anemia

In terms of defining a lower limit of “normal”b level before initiating a workup for anemia inchild with CKD, it seems reasonable to apply

he same approach, although not the same val-es, as in the adult Guidelines. In other words,nemia in a child with CKD should be diagnosednd evaluated at such time that the child’s Hbevel decreases to less than the fifth percentile forheir age and sex. Adjustment in normal Hbevels—and hence the definition of anemia—forhildren living at higher altitudes likely is reason-ble, as in the adult Guidelines, although age-pecific pediatric data are not available.

The normative values for this definition inhildren older than 1 year of age have been takenrom the NHANES III reference data, as indults (Table 39), whereas the values for childrenrom birth to 1 year are taken from data compiled

303
ore likely to develop anemia as their renal elsewhere (Table 40).
), 2006: pp S87-S88 S87

of Anemia Workupa

iation Anemia Definition Met if Value is <5th

Percentile

1.21 7.01 2.11 5.11 0.21 4.21 5.31

4.11 8.01 1.11 5.11 9.11 7.11 5.11

r Initiation of Anemia Workup a

DS 2– b

5.31 5.41 5.31 5.21 0.01 0.9 5.9 5.01

AN

EM

IAIN

CH

RO

NIC

KID

NE

YD

ISE

AS

EIN

CH

ILDR

EN

S88
Table 39. Hb Levels (g/dL) in Children Between 1 and 19 Years for Initiation
All Races/Ethnic Groups Number of Subjects Mean Standard DevBOYS

4.1 7.41 326,21 revo dna ry 1 8.0 0.21 139 ry 2-1 8.0 4.21 182,1 ry 5-3 8.0 9.21 907 ry 8-6 8.0 3.31 377 ry 11-9 1.1 1.41 045 ry 41-21 0.1 1.51 638 ry 91-51

GIRLS 1.1 2.31 947,31 revo dna ry 1 8.0 0.21 858 ry 2-1 8.0 4.21 733,1 ry 5-3 8.0 8.21 576 ry 8-6 8.0 1.31 437 ry 11-9

12-14 yrb 0.1 3.31 12615-19 yrb 0.1 2.31 059

a. Based on NHANES III data, United States, 1988-94; data abstracted from Tables 2 & 3.40

b. Menstrual loses contribute to lower mean and 5th percentile Hb values for group.

Table 40. Hb Levels (g/dL) in Children Between Birth and 24 Months fo

bH naeM egA 5.61 )doolb droc( mreT 5.81 d 3-1 5.71 kw 1 5.61 kw 2 0.41 om 1 5.11 om 2 5.11 om 6-3 0.21 om 42-6

a. Data taken from normal reference values.303

b. Values 2 standard deviations below the mean are equivalent to <2.5th percentile

Acltt

A

CPR FOR PEDIATRICS 1.2: EVALUATION OF ANEMIA IN CKD

ra1ionpuast

nemia in patients with CKD is not alwaysaused by erythropoietin deficiency alone. Initialaboratory evaluation therefore is aimed at iden-ifying other factors that may cause or contributeo anemia or lead to ESA hyporesponsiveness.

1.2.1 In the opinion of the Work Group,initial assessment of anemia shouldinclude the following tests: (APPLI-CABLE TO CHILDREN, BUT NEEDSMODIFICATION)1.2.1.1 A CBC including—in addi-

tion to the Hb concentration—red blood cell indices (MCH,MCV, MCHC), white bloodcell count and differential andplatelet count.

1.2.1.2 Absolute reticulocyte count.1.2.1.3 Serum ferritin to assess iron

stores.1.2.1.4 ADULT CPR

Serum TSAT or CHr to assess w


adequacy of iron for erythro-poiesis.PEDIATRIC CPRIn the pediatric patient, serumTSAT to assess adequacy ofiron for erythropoiesis.

RATIONALEThere is no evidence to support any different

ecommendations in children compared withdults with respect to statements 1.2.1.1 through.2.1.3. However, tests other than TSAT that arencluded in the recommendation for assessmentf iron available for erythropoiesis in adults haveot been well studied in the pediatric CKDopulation, with only 2 studies examining these of CHr in HD patients304,305 and none evalu-ting the use of PHRCs. This would seem touggest that until further data are available, theseests remain research-based methods in children
ith CKD.
), 2006: p S89 S89

Tstrt

tsacHtrHgpai

taclbsdpdsnsItba

S

CPR FOR PEDIATRICS 2.1: HB RANGE

disi

M

mc(Hwe9sicatr

T

ewcgbtftcmu

rdw5t1cdtlae

E

reatment thresholds in anemia management de-cribe the intended goal of current treatment forhe individual patient. The Hb treatment rangeepresents the intended goal of ESA and ironherapy.

2.1.1 Lower limit of Hb: (FULLY APPLI-CABLE TO CHILDREN)In patients with CKD, Hb level shouldbe 11.0 g/dL or greater. (MODER-ATELY STRONG RECOMMENDA-TION)

2.1.2 Upper limit of Hb: (FULLY APPLI-CABLE TO CHILDREN)In the opinion of the Work Group,there is insufficient evidence to recom-mend routinely maintaining Hb levelsat 13.0 g/dL or greater in ESA-treatedpatients.

RATIONALEDetermination of Hb targets in pediatric pa-

ients resists definitive recommendation. QOL,o significant to the development of the childnd life of the family, lends urgency to theonsideration of higher Hb level thresholds.owever, evidence lacks both quality and quan-

ity, rendering assessment of both benefit andisk uncertain. Age-specific variation in normalb levels introduces further uncertainty. Finally,iven key metabolic, growth, developmental, andsychological differences between children anddults, exclusive reliance on evidence in adults isnappropriate.

The Work Group presents lower and upperargets for Hb levels in children using values indults for reference. However, we add 2 signifi-ant qualifications. The first is that both theower and upper Hb targets serve only as opinion-ased CPRs, in keeping with the lack of pediatric-pecific evidence. The second is that medicalecision making to set Hb targets in individualatients should be informed by available evi-ence that is uniquely pediatric. Considerationhould be given, for example, to the potentialeed to make adjustments for the normal age-pecific Hb distribution (Table 39 and Table 40).n weighing the potential QOL benefits of Hbargets, the available evidence in adults shoulde enriched by consideration of QOL issues that
re crucial to children, including neurocognitive r

evelopment, school attendance, exercise capac-ty, and family support. To assist medical deci-ion making, the Work Group provides the follow-ng review of the literature.

ortality

Observational evidence relating Hb level toortality is available. Children in the NorthAmeri-

an Pediatric Renal Transplant Cooperative StudyNAPRTCS) database from 1992 to 2001 with anb level less than 9.9 g/dL compared with thoseith an Hb level greater than 9.9 g/dL showed an

levated risk for mortality: adjusted RR, 1.52;5% CI, 1.03 to 2.26; P � 0.05.306 The relation-hip between Hb level and mortality, when exam-ned at other cutoff values for Hb, appearedontinuous. Patients with more severe anemialso experienced increased risk for hospitaliza-ion (17.2% � 1.8% versus 12.3% � 2.1%,espectively; P � 0.01).

he Heart

A single RCT provides evidence for the ben-fit of treatment of anemia with ESA comparedith placebo. In a blinded crossover trial of 11

hildren aged between 2.3 and 12.3 years, under-oing HD or PD, and with a baseline Hb leveletween 4.3 and 8.1 g/dL, patients were assignedo either ESA therapy (Hb � 10 g/dL) or placeboor 24 weeks.126 Seven patients completed bothrial arms. ESA therapy was associated with partialorrection of an elevated cardiac index by 6onths and a significant reduction in left ventric-

lar mass by 12 months.Two observational studies have examined the

elationship between anemia and LVH in chil-ren with CKD.307,308 In these studies, patientsith severe LVH (left ventricular mass index �1 g/m2) showed a statistically lower Hb levelhan those without LVH (Hb, 9.5 � 1.8 versus0.9 � 2.3 g/dL; P � 0.027). Left ventricularompliance also was related to Hb level in chil-ren (r � –0.65; P � 0.02). The findings suggesthat severe anemia in children with CKD stage 5eads to chronic increases in cardiac workloadnd a consequent increase in both left ventricularnd-diastolic volume and mass.

In this RCT, exercise capacity improved withSA treatment (mean achieved Hb, 11.2 g/dL;

ange, 9.5 to 14.2 g/dL) compared with placebo


caapDnosd

coag0gwcEothiil

pcsrlmv

atgs0r

Q

bIvproo

sssbmglSmic

oq5csh(H

apthvoppaptowtiaie((

etdgttI

ANEMIA IN CHRONIC KIDNEY DISEASE IN CHILDREN S91

ontrol.126 Measures of capacity significantlyffected included a 2-minute walking test (n � 7)nd a formal treadmill testing using the Brucerotocol, full (n � 3) or modified (n � 3).istance walked, in meters, approached but didot reach statistical significance in the ESA armf the crossover, P � 0.06; similar results wereeen from both the regular or modified treadmillata, P � 0.07.In a nonrandomized interventional trial, 18

hildren with CKD stage 5 (15 patients, on HDr PD) and a Hb level less than 9.9 g/dL weredministered IV or SC ESA until Hb level wasreater than 9.9 g/dL; baseline Hb level of 6.5 �.8 g/dL changed to a final level of 10.0 � 0.6/dL; P � 0.001.309 Exercise time (treadmillith a modified Bruce protocol) increased signifi-antly (before ESA, 10.3 � 1.9 minutes; afterSA, 11.2 � 1.9 minutes; P � 0.01), and restingxygen consumption decreased from 7.8 � 1.8o 6.9 � 1.4 mL/min/kg; P � 0.01 with theigher Hb level. However, there was no changen stroke volume, blood pressure, or any cardiacndices after the first month at the higher Hbevel.

Similarly, a small cohort (n � 7) of HDatients showed an improvement in aerobic workapacity and effort tolerance, as evidenced bytatistically significant changes in the workloadeached, peak oxygen uptake, and average venti-atory anaerobic threshold after treatment of ane-ia with ESA (baseline Hb, 6.3 � 0.9 g/dL

ersus final Hb, 11.2 � 1.2 g/dL).310

Finally, 10 children undergoing PD were evalu-ted before and 18 months after limited correc-ion of anemia with ESA (baseline Hb, 5.9 � 0.9/dL versus final Hb, 8.7 � 1.5 g/dL). Patientshowed a significant slowing of heart rate, P �.01, but no improvement for other cardiac pa-ameters.311

OL and Neurocognitive Effects

The relationship between QOL and anemia haseen examined in children with CKD.126,312,313

n 2 trials,312,313 QOL instruments were notalidated in patients with CKD and were com-leted by parents. Only 1 study blinded parent-esponders to use of ESA or placebo, although 5f 7 parents in that study correctly identified use
f ESA during the appropriate treatment.126 a
In 116 children enrolled in a multicenter trial,leep, activity (in school, at home, or in socialituations), alertness, feelings, and a summarycore composed of all subscores were assessed ataseline and every 6 months during ESA treat-ent to attain a target Hb level of 9.6 to 11.2

/dL compared with baseline pretreatment Hbevel of 6.7 g/dL (range, 3.4 to 9.5 g/dL).313

cores at 1 year after ESA increased after treat-ent for all aspects examined, but only the 10%

ncrease in the summary score achieved signifi-ance (P � 0.05).

In the previously described randomized cross-ver trial,126 a 25-question modified parentaluestionnaire used a visual analog scale to assessdomains: sleep, school performance, diet, psy-

hosocial, and a physical performance/health con-truct. Only physical performance and generalealth showed a significant treatment effectagain, baseline Hb, 4.3 to 8.1 g/dL versus finalb, 11.2 g/dL; range, 9.5 to 14.2 g/dL).A generic health QOL questionnaire has been

dministered in a cross-sectional fashion to thearents of children with CKD stages 1 to 5 andransplant recipients.312 This instrument, whichas shown internal consistency and concurrentalidity and has been used in a single-center trialf children on HD therapy,314 measures 12 as-ects of health-related QOL in the domains ofhysical functioning; limitations in schoolworknd activities with friends, general health, bodilyain and discomfort, limitations in family activi-ies; emotional/time impact on the parent; impactf emotional or behavior problems on schoolork and other daily activities; self-esteem; men-

al health; behavior; family cohesion; and changen health. When evaluated as a continuous vari-ble, Hct was linked directly to measures ofmproved health, as seen in the single-item gen-ral health (r � 0.36; P � 0.003), general healthr � 0.29; P � 0.004), and physical functioningr � 0.35; P � 0.0004) domains.312

Further analysis of the same data, adjusting forGFR, age, sex, race, dialysis modality, andransplantation or chronic renal insufficiency andividing the patients into groups with Hb levelreater than or less than 10.8 g/dL (defined byhe investigators as anemic), showed an associa-ion between anemia and 4 domains: Parentalmpact-Time, Family Activities, Role–Physical,
nd Physical Functioning. Further multivariate

atgrhmtrlF0p0df

htatsdtcWi90

N

eacos

vurtHi

gfifg

H

ssmdIsw6itto

T

cttrtcttasm

E

dsss

ANEMIA IN CHRONIC KIDNEY DISEASE IN CHILDRENS92

nalysis done after division of the group into Hbertiles, less than 9.9 g/dL, 9.9 to 10.8 g/dL, andreater than 10.8 g/dL, showed a strong dose-esponse relationship between Hb level andealth-related QOL as measured by this instru-ent. It should be noted that differences between

he mid and upper tertile of Hb levels did noteach significance, whereas those between theowest and upper tertile in the areas of Physicalunctioning (P � 0.02), Role–Emotional (P �.05), Role–Physical (P � 0.02), Parental Im-act–Time (P � 0.004), Family Activities (P �.003), and Physical Summary score (P � 0.01)id. (Note: these results have been convertedrom Hct to Hb values.)

The neurocognitive effects of anemia alsoave been examined. In healthy children aged 6o 11 years, impairment in cognition is associ-ted with iron deficiency and an Hb level lesshan 11.8 g/dL.315 Furthermore, in a multicenteringle-arm interventional trial evaluating 22 chil-ren with CKD aged 4 months through 16 years,reatment of anemia was associated with a signifi-ant increase in IQ, determined by using theeschler intelligence test, although the relative

ncrease in Hb levels was small (Hb baseline,.2 � 1.6 versus final, 9.7 � 1.7 g/dL; P �.007).316

utrition and Growth

No reliable studies have been published thatxamine the relationship between treatment ofnemia and nutrition in children. The literatureonsists largely of subjective reports by the childr family or short small trials that fail to achieveignificant treatment effects.

Treatment of anemia apparently fails to re-erse growth retardation in children with CKDndergoing HD or PD.317,318 In a US phase III,andomized, double-blinded, placebo-controlledrial of ESA therapy in children, 81 children onD or PD therapy showed a substantial increase

n Hb levels with treatment (baseline, 6.3 to 6.6 w

/dL to final, 9.3 g/dL), and no effect was seenor any measured nutrition or growth parameter,ncluding midarm circumference, triceps skin-old thickness, weight gain, or the SD scores forrowth velocity or height.317

ypertension

The development or worsening of hyperten-ion during treatment with ESAs in children is ofignificant concern. In a study of children aged 4onths to 21 years, assignment to either high-

ose (epoetin, 450 IU/kg/wk) or low-dose (150U/kg/wk) ESA treatment was associated with aignificant increase in diastolic blood pressure byeek 12 compared with baseline (88 � 6.7 versus8 � 17 mm Hg; paired t-test, P � 0.01).319 Thenvestigators reported a nonsignificant trend be-ween increasing Hb levels and increasing sys-olic and diastolic blood pressures despite stabler lower ESA dose.

hrombotic Events

No thrombotic events, including vascular ac-ess thrombosis, were reported in either arm ofhe mentioned high-dose versus low-dose ESArial.319 However, the small number of patients,elatively short length of follow-up, and rela-ively few patients with HD preclude any reliableonclusions about safety. No other larger prospec-ive trials of pediatric patients treated with ESAso various Hb targets are available to furtherddress the issue of clotting or access thrombo-is, although it has been reported to occur inter-ittently in children.318,320–323

SA Therapy and Loss of Renal Function

In patients with ND-CKD assigned to high-ose compared with low-dose ESA treatment, noignificant difference in creatinine levels waseen; in the same trial, between-group compari-on showed no change in Kt/V among patients
ith HD-CKD.319

Eaatda

A

CPR FOR PEDIATRICS 3.1: USING ESAs

SAs are critical components in managing thenemia of patients with CKD. Available ESAsre each effective in achieving and maintainingarget Hb levels. Aspects of administration mayiffer between short-acting and long-actinggents.

3.1.1 Frequency of Hb monitoring: (FULLYAPPLICABLE TO CHILDREN)3.1.1.1 In the opinion of the Work

Group, the frequency of Hbmonitoring in patients treatedwith ESAs should be at leastmonthly.

3.1.2 ESA dosing: (FULLY APPLICABLETO CHILDREN)3.1.2.1 In the opinion of the Work

Group, the initial ESA doseand ESA dose adjustmentsshould be determined by thepatient’s Hb level, the targetHb level, the observed rate ofincrease in the Hb level, andclinical circumstances.

3.1.2.2 In the opinion of the WorkGroup, ESA doses should bedecreased, but not necessarilyheld, when a downward ad-justment of Hb level is needed.

3.1.2.3 In the opinion of the WorkGroup, scheduled ESA dosesthat have been missed shouldbe replaced at the earliest pos-sible opportunity.

3.1.2.4 In the opinion of the WorkGroup, ESA administration inESA-dependent patientsshould continue during hospi-talization.

3.1.2.5 In the opinion of the WorkGroup, hypertension, vascu-lar access occlusion, inad-equate dialysis, history ofseizures, or compromised nu-tritional status are not contra-indications to ESA therapy.

3.1.3 Route of administration: (APPLI-CABLE TO CHILDREN, BUT NEEDS
MODIFICATION)

3.1.3.1 ADULT CPRIn the opinion of the WorkGroup, the route of adminis-tration should be determinedby the CKD stage, treatmentsetting, efficacy consider-ations, and the class of ESAused.PEDIATRIC CPRIn the opinion of the WorkGroup, in the pediatric patient,the route of administrationshould be determined by theCKD stage, treatment setting,efficacy considerations, theclass of ESA used, and theanticipated frequency and painof administration.

3.1.3.2 In the opinion of the WorkGroup, convenience favors SCadministration in non–HD-CKD patients.

3.1.3.3 In the opinion of the WorkGroup, convenience favorsIV administration in patientswith HD-CKD.

3.1.4 Frequency of administration: (APPLI-CABLE TO CHILDREN, BUT NEEDSMODIFICATION)3.1.4.1 ADULT CPR

In the opinion of the WorkGroup, frequency of adminis-tration should be determinedby the CKD stage, treatmentsetting, efficacy consider-ations, and class of ESA.PEDIATRIC CPRIn the opinion of the WorkGroup, in the pediatric patient,the frequency of administra-tion should be determined bythe CKD stage, treatment set-ting, efficacy considerations,and class of ESA; as well,consideration should be givento the anticipated frequency of,and pain on administration ofeach agent and their potential
effects on the child and family.
), 2006: pp S93-S98 S93

F

dar

m2sercaiErowimpht

cpoTbHpe

E

lm

I

ftv

CEeda

ttdrip

vs

D

NitcwdaTqncag

t

icete3tbEfHn

r51


3.1.4.2 In the opinion of the WorkGroup, convenience favors lessfrequent administration, par-ticularly in non–HD-CKDpatients.

RATIONALE

requency of Hb Monitoring

This guideline is considered applicable to chil-ren because there are some data supporting thisssumption and there is no reason for a differentecommendation.

There are 2 reasons that may justify closeronitoring of all pediatric patients with 1- to

-week Hb levels when initiating and/or makingignificant change to the ESA dose. The first is tonsure that the patient is responding to the cur-ent dose. Although not as well described inhildren as in adult literature, it likely is true thatpatient who will reach an intended 1-g/dL

ncrease in Hb level after 1 month of a givenSA/iron regimen will have that increase occur

elatively evenly over each of the 4 weeks. Inther words, blood work weekly or every 2eeks will allow the clinician to institute an

ncrease in dosing if a rate of increase of approxi-ately 0.25 g/dL per week is not seen in the early

art of the month. (In adults, the rate of increaseas been estimated to be 0.3 g/dL per week [0.2o 0.5 g/dL] on appropriate doses of rHuEPO.324)

Similarly, a child for whom the rate of in-rease appears rapid, eg, greater than 0.5 g/dLer week, could have the dose adjusted beforevershooting at the end of that month of therapy.he greater frequency of monitoring likely iseneficial until the patient has reached a targetb level and is on a stable dose of ESA. At thisoint, less frequent monitoring may be indicated,g, every 4 weeks.

SA Dosing

In the opinion of the Work Group, this guide-ine is applicable in children, but needs someodification or adjustment.

nitial Dose and Dose Adjustments

Although there are many dosing guidelinesor the use of ESAs in children, it is importanto realize that, as in adults,123 there is a large
ariation in pediatric dosing of these drugs.325 t
urrently, the most robust evidence for dosingSA products in children is related to erythropoi-tin alfa and beta products, with information onarbepoietin alfa dosing just now becoming avail-ble.

All clinicians are advised to carefully evaluatehe individual patient’s particular issues relatedo their Hb level and likely response beforeeciding on a particular ESA product, dosingegimen, and frequency of monitoring before thenitiation of or changes in ESA and/or iron thera-ies.The following section is divided into dialysis

ersus nondialysis patients and short-acting ver-us long-acting ESA products.

ialysis Population (HD and PD)

1. Short-acting ESAs. Data from the latestAPRTCS annual report highlight the variation

n initial dose reported in children on dialysisherapy, with the younger child consistently re-eiving more rHuEPO on a per-kilogram-per-eek basis.325 The doses referred to next are noterived from RCTs, but rather from registry datand therefore should be interpreted with caution.hey represent approximations of the dose re-uired in an average cohort of children and areot represented as recommendations for any spe-ific child. (Note that 93% of these patients weredministered erythropoietin alfa as Epogen®;Am-en, Thousand Oaks, CA.)This variation in dosing can be seen in relation

o:a) The dialysis modality, with PD patients

nitially requiring approximately 225 U/kg/wkompared with nearly 300 U/kg/wk of erythropoi-tin alfa products to achieve target Hb levels forhose on HD therapy.325 Interestingly, this differ-nce in dosing disappears during the first 18 to0 months of follow-up. It should be noted thathe initial dosing difference persisted even whenoth groups of patients were administered theSA SC326 and may be caused in part by such

actors as blood loss and the use of IV ESAs inD patients as opposed to SC ESAs in PD orondialysis patients.319

b) Age, with patients younger than 1 yearequiring an average of 350 U/kg/wk; those 2 toyears, approximately 275 U/kg/wk; those 6 to

2 years, 250 U/kg/wk; and finally those older
han 12 years needing only slightly more than

2teymmcetehelHlsad

erdbtt

3pEtwga

pCpaps1ap

dtylItc

petmwbt

ttdmTw1TppgtHp

�aobmadbtHltr

hfi11w0tc9bg


00 U/kg/wk at the time of starting ESAherapy.325 One report speculates that this appar-ntly increased “clearance” of erythropoietin in aoung child is caused by the presence of nonhe-atopoietic binding sites for the erythropoietinolecule,327 which—in the fetus or developing

hild—appears to function as a nonhematopoi-tic cellular growth factor.328 Because internaliza-ion and, potentially, degradation of some of therythropoietin dose would limit the amount oformone available for stimulating erythropoi-sis, one could explain the need for higher abso-ute doses to achieve a given marrow response orb production. Furthermore, the authors specu-

ate that as the child ages, the number of theseites decreases as development slows, with anttendant decrease in the absolute hematopoieticose of erythropoietin required.327

No major differences were noted in relation toither race or sex with respect to initial ESA doseequired. There was a general tendency for alloses to decrease over time, presumably on theasis of a lower amount of ESA being requiredo maintain—as opposed to reach—a given Hbarget.

2. Long-acting ESAs. Currently, there are onlypublished articles329-331 and 1 abstract332 in theeer-reviewed literature related to long-actingSA products and children with CKD, including

hose on dialysis therapy. It is expected that thereill be other results in due course to assist inuiding the pediatric practitioner in using longercting ESA agents more effectively.

The first study evaluated the pharmacokineticroperties of darbepoetin alfa in children withKD and compared the results with prior studiesublished in adults.330 They showed that clear-nce, drug half-life, and bioavailability of darbe-oetin alfa, whether administered IV or SC, wereimilar between pediatric and adult patients. The

difference was that absorption of the drugdministered SC appeared to be more rapid inediatric than adult patients.The second study described the clinical use of

arbepoietin alfa in children.329 The investiga-ors switched 7 long-term HD patients aged 11.5ears (range, 7 to 15.2 years) with a stable Hbevel on erythropoietin therapy to darbepoietinV therapy. Results from this small study suggesthat (at least in the pediatric HD population) the
onversion dose of erythropoietin alfa to darbe- p
oietin is more likely to be closer to 0.5 �g forvery 200 U of erythropoietin alfa, rather thanhe 1 �g/200 U conversion recommended by theanufacturer. The authors themselves suggest aide range of doses, 0.25 to 0.75 �g/kg/wk, aseing reasonable for the initial switch betweenherapies.

The most recent report prospectively looked athe use of darbepoetin alfa in 8 children on PDherapy, 6 children on HD therapy, and 12 chil-ren with ND-CKD.331 All patients weighedore than 8 kg and were younger than 18 years.herapy with ESAs was initiated, if the patientas ESA-naïve, when Hb level was less than0.0 g/dL, and only patients judged iron-replete,SAT greater than 20%, were included. Therimary outcomes were: (1) the proportion ofatients with a mean Hb level greater than 10.0/dL between weeks 8 and 12 and then weeks 20o 28 of the study, and (2) the percentage of allb values greater than 10.0 g/dL at each timeoint.The initial dose of darbepoetin alfa was 0.45

g/kg/wk, administered IV in the HD patientsnd SC in the PD and ND-CKD patients. Muchf the data are presented in aggregate and includeoth the 26 patients enrolled prospectively and 7ore patients enrolled retrospectively. Statistical

nalysis by the investigators did not show aifference in terms of drug dose between theeginning and end of the study (P � 0.77), andhere was no difference in doses between theD, PD, and ND-CKD groups (P � 0.62) regard-

ess of their being in the prospective or retrospec-ive arm of the study (P � 0.92 and P � 0.73,espectively).

Data from 23 patients in the prospective co-ort, 18 of whom were available at weeks 20-28or analysis, showed a statistically significantncrease in Hb levels at 8 to 12 weeks of 11.7 �.1 g/dL compared with the baseline of 10.5 �.0 g/dL (P � 0.002), which was still present ateek 20 to 28 when Hb level was now 11.4 �.9 g/dL (P � 0.01 compared with baseline). Inhis group, 96% (CI, 0.90 to 1.0; P � 0.03)ompared with baseline at 8 to 12 weeks and4% (CI, 0.72 to 0.99; P � 0.06) compared withaseline at 20 to 28 weeks had mean Hb valuesreater than 10.0 g/dL. Similarly, proportions of
atients with total Hb values greater than 10.0

g2

tlpa

wvp

wews1cHtd

N

trrrd2o1oI1lfwat

statotoqt1

Nacpat

dEspC

R

tsi

romoafftTaggmtlrgsit

5ctUdTtmg


/dL were 94% at 8 to 12 weeks and 90% at 20 to8 weeks.In all ESA-naïve patients (n � 8), the average

ime to reach the target of 10.0 g/dL from base-ine of 9.0 � 1.4 g/dL was 3.4 weeks, with noatient requiring a higher dose of darbepoetinlfa to achieve this.

The overall Hb response to darbepoetin alfaas related to the age of the patient, higheralues for a given dose being achieved in olderatients (P � 0.02).Only 1 patient experienced a serious AE that

as thought to be possibly related to the darbepo-tin alfa. In this case, a girl on home HD therapyas admitted with a worsening of her hyperten-

ion; this was at a time when her Hb level was3.2 g/dL but concurrent with a withdrawal fromlonidine some 18 days before the admission.er blood pressure subsequently was well con-

rolled on fewer medications while remaining onarbepoetin alfa therapy.

ondialysis Population

1. Short-acting ESAs. In the ND-CKD popula-ion, a number of studies looked at the dose ofHuEPO required to achieve set targets. Cur-ently, there is only 1 published prospectiveandomized trial that has looked at rHuEPOosing in children with ND-CKD.319 In this trial,5 predialysis patients, CKD stages 3 to 5 but notn PD or HD therapy, were randomized to either50 U/kg/wk (n � 12) or 450 U/kg/wk (n � 13)f rHuEPO administered SC in 3 divided doses.n all 12 of the 150-U/kg/wk patients and 11 of3 of the 450-U/kg/wk patients, the Hb target ofess than 2 SDs less than, but less than the meanor age, was achieved. When at target, the doseas reduced to maintain the target Hb level; on

verage, this required 143 � 102 U/kg/wk forhe group of responders.

A nonrandomized open-labeled prospectivetudy took 11 patients aged 0.6 to 17 years withhe equivalent of CKD stages 4 and 5 (all predi-lysis) whose mean Hb level was 7.9 g/dL andreated them with a single dose of 150 U/kg/wkf SC rHuEPO.333 An increase in Hb level greaterhan 2 g/dL was seen in all 11 patients in a meanf 45 days, range of 14 to 119 days, and subse-uently, the patients maintained Hb levels be-ween 11.5 and 13.5 g/dL, with a mean dose of
33 U/kg/wk, range of 75 to 300 U/kg/wk. i
A trial reported on behalf of the Australian andew Zealand Paediatric Nephrology Association

lso looked at the use of SC ESA in predialysishildren.316 Unfortunately, although 10 of the 22atients were predialysis, their study does notllow the data to be abstracted specifically forhis group.

2. Long-acting ESAs. As discussed in moreetail in the preceding section (Long-ActingSAs in the Dialysis Population), a study showedimilar efficacy of darbepoetin alfa in the 15atients, 12 prospectively enrolled, with ND-KD treated with a dose of 0.45 �g/kg/wk.331

ate of Increase in Hb Levels

A few pediatric studies provide some informa-ion on which to base recommendations on theafety and side effects related to the rate ofncrease in Hb levels.

A prospective trial that examined the safety ofHuEPO therapy in children on HD or PD therapyr predialysis, randomized 44 children (aged 4onths to 21 years) to either low (150 U/kg/wk)

r high (450 U/kg/wk) doses of epoetin alfadministered in 3 divided doses.319 Patients wereollowed up for a total of 12 weeks and targetedor individual Hb levels of between 2 SD lesshan and the mean value for that child’s age.aking the groups as a whole, there was anverage increase of 4.2 � 2.1 versus 2.4 � 1.5/dL per month in the high-dose versus low-doseroups. Hypertension appeared to be more com-on, but did not reach statistical significance, for

hose in the high-dose group compared with theow-dose group, 8 of 21 versus 5 of 23 patients,espectively; chi-squared P � 0.17. The investi-ators noted that the trend in systolic and dia-tolic blood pressure was to increase as Hb levelncreased. No other side effects seemed relatedo the rate of increase in Hb levels.

Another study randomized 20 anemic childrento 16 years of age who were on a stable

ontinuous ambulatory PD regimen for 3 monthso examine the effects of low-dose rHuEPO, 50/kg/wk (group A), versus high-dose rHuEPO,efined as 50 U/kg 3 times a week (group B).334

ranslating their data to Hb values from Hct,hose in group A showed a steady increase over 6onths from an Hb level of approximately 6.3

/dL to 9.9 g/dL compared with the increase seen
n group B, for which Hb level went from 6.4 to

101tbmr0ttt(ihttd

rcrgrPrgaprsm

HGd

Gdoa

ia

R

sEfw

pt

oEt

pirrenaTEtCrdtcc

banhesmawbt

ijibsdethmrctd


0.7 g/dL in only 3 months; an approximately.6-g/dL increase per month in group A versus.4-g/dL increase per month in group B. Al-hough mean arterial blood pressure increased inoth groups during the study (group A, 83 to 87m Hg; group B, 85 to 101 mm Hg), it only

eached statistical significance in group B, P �.05. This was borne out by the need to increasehe baseline antihypertensive medications in 8 ofhe 10 group B patients and initiate these medica-ions in the remaining 2 patients in this group.Note: rHuEPO therapy was discontinued brieflyn 4 patients in group B; 2 patients because ofypertensive encephalopathy; conversely, no pa-ient in group A required an increase in antihyper-ensive medication or initiation of such therapyuring the study.)If one examines a number of recent pediatric

ecommendations for the acceptable rate of in-rease in Hb values, they vary widely. One groupecommends a rate of increase between 1 and 2/dL per month for all children below the targetange.301 Recent guidelines from the Europeanaediatric Peritoneal Dialysis Working Groupecommend an increase of approximately 0.66/dL per month as minimally acceptable335 andn increase of more than approximately 2.5 g/dLer month as unacceptable.An often-quoted studyecommends, without evidence, that the goalhould be an increase in Hb of 1 g/dL peronth.336

ESA dosing should be decreased, not held, ifb level is elevated. In the opinion of the Workroup, this guideline is fully applicable to chil-ren.Missed ESA doses. In the opinion of the Work

roup, this guideline is fully applicable to chil-ren. ESA dosing during hospitalizations. In thepinion of the Work Group, this guideline is fullypplicable to children.

Contraindications to ESA therapy. In the opin-on of the Work Group, this guideline is fullypplicable to children.


As in adults, convenience in an outpatientetting favors use of the SC route for delivery ofSAs; with the added realization that even in the

ace of IV access, a short-acting ESA product
ill be more efficacious administered SC com- i
ared with IV, as confirmed in an observationalrial in children.325

As of the 2004 NAPRTCS annual report, 96%f children on PD therapy were administered anSA by the SC route as opposed to only 14% in

he HD population.However, in children, the psychological im-

act of frequent and/or painful injections also ismportant to assess when deciding on a dosingoute. Currently, the single-dose preloaded sy-inges of both epoetin alfa (Eprex®) and darbepoi-tin alfa available in many parts of the world doot contain benzyl alcohol, which acts as a localnesthetic, in the epoetin alfa multidose vials.his means that injections with the preloadedprex® syringes generally are more painful than

hose from the multidose vials. Similarly, in aanadian study, 8 of 14 patients with prior expe-

ience using epoetin alfa (Eprex®) reported thatarbepoetin alfa caused more pain on injection;he remaining 6 patients did not specificallyomment about whether they believed Eprex®

aused more pain on injection.331

Note: Multidose vials of epoetin alfa shoulde avoided if at all possible in premature infantsnd newborns because of a rare, but well-recog-ized, complication from the use of benzyl alco-ol in the preparation of the compound. Thisxcipient has been described to cause numerouserious and potentially fatal reactions, includingetabolic acidosis, intraventricular hemorrhage,

nd neurological problems. Sixteen neonatal deathsere reported that were thought to be caused byenzyl alcohol toxicity, generally described ashe so-called “gasping syndrome.”337,338

The issue of dosing epoetin alfa through thentraperitoneal route in children to eliminate in-ection pain also has been studied by variousnvestigators.339,340 In general, the added costsecause of a higher dose required to achieve theame target Hb level, the need for at least 1 dryay dwell (or more) per week to achieve thepoetin alfa absorption required, and the poten-ial for more frequent episodes of peritonitisave lead most centers away from use of thisodality routinely. As of the 2004 NAPRTCS

eport, less than 2% of children on PD therapyurrently are administered epoetin alfa throughhe peritoneal cavity.325 At present, there are noata available on the use of darbepoietin alfa
ntraperitoneally.

F

tpiitt

RpEt7rsawHawtt

catdsmtiir

qpdcdddd

0b6dwpoa(tgt

iifibpEbEcma

pd

rmut4aWBpiss


requency of Administration

As in the adult population, there is a moveoward extending the dosing interval of all ESAroducts to minimize injections while maintain-ng efficacy of the product; ie, not having toncrease dose significantly more than the gain inime between dosing, to maintain or achieve thearget Hb level.

1. Short-acting ESAs. At present, there is noCT evidence to show that this strategy is appro-riate in children with the current short-actingSA products on the market. However, data from

he 2004 NAPRTCS annual report highlight that5% to 80% of children on HD therapy willeceive short-acting ESA products IV during atandard (3 times per week) HD regimen, whereassmaller number (15% to 20%) receive it twice aeek, and other dosing regimens are uncommon.owever, 70% of children on PD therapy gener-

lly receive only once-weekly or perhaps twice-eekly injections, with 25% receiving injections

hrice weekly, and approximately 5% receivinghe drug less than once per week.325

It also may be reasonable on occasion toonsider more frequent SC dosing of the short-cting ESAs, eg, thrice weekly, when the pa-ient’s Hb level is well less than the target Hbesired, although the absolute rate of increasehould not exceed 2 g/dL per month. Here, theore-frequent dosing ensures that the therapeu-

ic threshold of the hormone is maintained, givents short half-life, and—in concert with adequateron stores—may assist in achieving a moreapid increase in Hb level.

2. Long-acting ESAs. Data on the dosing fre-uency of darbepoietin alfa in pediatric HDatients comes from 7 patients, all of whom wereosed once weekly after HD.329 From a pharma-okinetic study,330 it is clear that extended-osing regimens with darbepoietin alfa in chil-ren should be possible, although currently, fewata have been published outlining strategies for
osing frequency. u
In 1 study, to appropriately dose patients at.45 �g/kg/wk with the available preloaded dar-epoetin alfa syringes, the investigators started3% of their patients on every 10-, 14-, or 21-dayosing regimens; the remainder were on once-eekly dosing.331 Their results showed no im-act of the various dose intervals on the Hb valuever time (P � 0.01), but showed that both HDnd older patients required more frequent dosingP � 0.0001 and P � 0.01, respectively), al-hough the dose amount was not different in anyroup based on age or mode of renal replacementherapy.

As outlined in CPR 3.1.3.1, the psychologicalmpact of frequent and painful injections also ismportant to assess when deciding on a dosingrequency in children. Use of less-frequent dos-ng strategies is, in theory, of benefit by reducingoth the absolute number of injections and theain associated with injections for the child onSA treatment. However, this may be mitigatedy the fact that currently, the only long-actingSA on the market produces a noticeably in-reased degree of pain at time of injection forany children compared with some of the short-

cting ESA therapies.At present, there are no good data from the

ediatric ND-CKD population with regard to theosing frequency of various ESAs.Finally, the Work Group also was aware of

esults from a soon-to-be-published open-labelulticenter noninferiority trial examining the

se of darbepoetin alfa versus epoetin alfa in thereatment of anemia in children with CKD stagesto 5, including patients on HD and PD therapy

nd the nondialysis CKD population (Bradleyarady, personal communication, June 7, 2005).ecause the results were not yet peer reviewed orublished at the time the guidelines were final-zed and were not blieved to alter the guidelinetatements, this study is not incorporated in thiset of guidelines, but will provide data related to
se of darbepoetin alfa in children.

Aeaaddipa

A

CPR FOR PEDIATRICS 3.2: USING IRON AGENTS

rc

tueidtol

nemia therapy in patients with CKD requiresffective use of iron agents, guided by appropri-te testing of iron status. Efficacy of iron therapyppears not to be limited to patients with evi-ence of iron deficiency. (See Guideline 1.2 foriagnosis of iron deficiency.) Thus, the goals ofron therapy are to avoid storage iron depletion,revent iron-deficient erythropoiesis, and achievend maintain target Hb levels.

3.2.1 Frequency of iron status tests:(FULLY APPLICABLE TO CHIL-DREN)In the opinion of the Work Group,iron status tests should be performedas follows:3.2.1.1 Every month during initial

ESA treatment.3.2.1.2 At least every 3 months dur-

ing stable ESA treatment or inpatients with HD-CKD nottreated with an ESA.

3.2.2 Interpretation of iron status tests:(FULLY APPLICABLE TO CHIL-DREN)In the opinion of the Work Group,results of iron status tests, Hb level,and ESA dose should be interpretedtogether to guide iron therapy.

3.2.3 Targets of iron therapy: (APPLI-CABLE TO CHILDREN, BUT NEEDSMODIFICATION)In the opinion of the Work Group,sufficient iron should be administeredto generally maintain the followingindices of iron status during ESAtreatment:3.2.3.1 ADULT CPR HD-CKD:

● Serum ferritin > 200 ng/mL,AND

● TSAT > 20%, or CHr > 29pg/cell.PEDIATRIC CPRHD-CKD:

● Serum ferritin > 100 ng/mL;AND

● TSAT > 20%.

3.2.3.2 ND-CKD and PD-CKD: f


● Serum ferritin > 100 ng/mLAND

● TSAT > 20%.

3.2.4 Upper level of ferritin: (FULLY AP-PLICABLE TO CHILDREN)In the opinion of the Work Group,there is insufficient evidence to recom-mend routine administration of IViron if serum ferritin is greater than500 ng/mL. When ferritin level isgreater than 500 ng/mL, decisionsregarding IV iron administrationshould weigh ESA responsiveness, Hband TSAT level, and the patient’sclinical status.

3.2.5 Route of administration: (FULLYAP-PLICABLE TO CHILDREN)3.2.5.1 The preferred route of admin-

istration is IV in patients withHD-CKD. (STRONG RECOM-MENDATION)

3.2.5.2 In the opinion of the WorkGroup, the route of iron ad-ministration can be either IVor oral in patients with ND-CKD and PD-CKD.

3.2.6 Hypersensitivity reactions: (FULLYAPPLICABLE TO CHILDREN)In the opinion of the Work Group,resuscitative medication and person-nel trained to evaluate and resuscitateanaphylaxis should be available when-ever a dose of iron dextran isadministered.

BACKGROUNDAs in adults, the most commonly identified

eason for poor responsiveness to ESA therapy inhildren is iron deficiency.341

The need for iron supplementation in childreno maintain iron stores and promote the efficientse of ESAs can be predicted from the knowl-dge of mean daily blood—hence iron—lossesn both those who are predialysis and those onialysis therapy. Predialysis patients, and likelyhose on PD therapy, lose on average 6 mL/m2/df blood, mainly from the GI tract, which trans-ates to a cumulative yearly iron loss and there-
ore requirement of 0.9 g/1.73 m2.342 This is just
), 2006: pp S99-S104 S99

mpmlyg

hdtaslpalsTpt

F

dpd

I

dpd

T

H

tliisiilEflnw

roe

tnppsntn

Gcat1pN

tcanwp7in

etbogriUiawcCdtc

h


ore than half of that predicted for pediatric HDatients, for whom the mean GI blood loss is 11L/m2/d, and when coupled with the dialyzer

osses of 8 mL/m2 per treatment, translates to aearly cumulative loss of approximately 1.6/1.73 m2.342

As in the adult population, several studiesave shown that supplementation of iron in chil-ren receiving ESA therapy allows a reduction inhe ESA dose required per unit of Hb levelchieved.343,344 However, constipation and nau-ea, as well as poor GI iron absorption, oftenimit effective supplementation with oral ironreparations.166,345,346 These facts and the avail-bility of newer IV iron preparations believedess likely to induce AEs recently led to moretudies with IV preparations of iron in children.he majority of these studies examined onlyatients in CKD stage 5, especially those on HDherapy.304,305,344,347,348

RATIONALE

requency of Iron Tests

This guideline is considered applicable to chil-ren because there are no special data in theediatric population and there is no reason for aifferent recommendation.

nterpretation of Iron Tests



D-CKD

Caution must be exercised in applying theargets or normal ranges as outlined in the guide-ine for adult patients with HD-CKD because thencrease in ferritin target from 100 to 200 ng/mLn adult HD patients is based on evidence touggest that a level of 100 ng/mL underestimatesron deficiency,98,99,151–156 and data from a studyn which patients with an average serum ferritinevel of 730 ng/mL showed a 40% reduction inSA dose compared with those with an average

erritin level of 297 ng/mL.108 There is no simi-ar RCT-level evidence for this in children;amely, that achieving a specific ferritin level
ill produce a consistent decrease in ESA doses c
equired, and there are no adult or pediatric datan the safety of supraphysiological ferritin lev-ls.

One pediatric study in older children on HDherapy suggested that a TSAT less than 20%, butot a ferritin level less than 100 ng/mL, wasredictive of iron deficiency.349 However, otherediatric studies in the CKD population havehown that although a normal ferritin level can-ot exclude iron deficiency, absolute or func-ional,348,350 a low ferritin level, less than 60g/mL, is a specific predictor of its presence.351

Therefore, we recommend that the currentuidelines be followed in children with the ex-

eption that until data are available on the risksnd benefits of higher ferritin targets in children,he targets be left at a ferritin level greater than00 ng/mL and TSAT greater than 20% foratients with HD-CKD, as well as PD-CKD andD-CKD populations.With respect to the use of CHr, which has been

outed as a valuable screening test for iron defi-iency in “normal” children even before theppearance of iron-deficient anemia, the cutofformal and abnormal values remain unclear andide. For example, a cutoff value of 26 pg onlyroduced sensitivity and specificity of 70% and8% for iron deficiency and 83% and 75% forron deficient anemia in this select group ofon-CKD young children, respectively.352

In the pediatric CKD literature, CHr has beenxamined in a limited fashion in children on HDherapy.304,305 In both studies, an increase fromaseline CHr levels was observed in response toral iron, IV iron dextran, and IV sodium ferricluconate in patients judged to be both ironeplete (oral iron and IV iron dextran)304 andron-deficient (IV sodium ferric gluconate).305

nfortunately, cutoff values for use of this markern the pediatric CKD population are not clear,nd this is shown clearly in these 2 studies, inhich, in nearly identical patient populations (ie,

hildren on HD therapy), the baseline value forHr was higher in the group judged as ironeficient based on current DOQI guidelines305

han in those judged iron-replete by those sameriteria.304

Therefore, whereas it is clear that CHr may yetave a prognostic or diagnostic role in anemia in
hildren with CKD, further research clearly is

nt

N

dpd

U

dpd

oftl

R

dpd

dtCaooi

O

a31dhftbi(cidi

E

snafapowogacs

s0dwNd4taaacrHcitBtic

tptAKfaIp2i


eeded to understand and define the value of thisest in the pediatric CKD population.

D-CKD and PD-CKD



This guideline is considered applicable to chil-ren because there are no special data in theediatric population and there is no reason for aifferent recommendation.Note: As in the adult guidelines, this refers

nly to the intentional targeting of a patient’serritin level to greater than 500 ng/mL, not tohe individual’s achieved or acquired ferritinevel, which may be at or greater than this level.


This guideline is considered applicable to chil-ren because there are no special data in theediatric population and there is no reason for aifferent recommendation.Suggestions for iron supplementation in chil-

ren with CKD vary in terms of dose, as well asype of preparation. Many children in the ND-KD or PD-CKD populations may benefit fromnd receive oral iron therapy,325 whereas thosen HD therapy are likely to require and mostften receive IV agents to allow for sufficientron stores for ongoing erythropoiesis.325,348,350

ral Iron

For oral iron therapy, the recommendationsre for doses of elemental iron ranging from 2 tomg/kg/d up to 6 mg/kg/d, with a maximum of

50 to 300 mg of elemental iron per day in 2 to 3ivided doses335,336 taken 2 hours before or 1our after all calcium-containing binders andood to maximize GI absorption.353 A prospec-ive randomized trial of 35 pediatric patientsetween 1 and 20 years of age on HD therapy, allron replete, examined response to oral or IV ironmore details discussed next).304 This studylearly showed a much better response to IV ironn terms of an increased serum ferritin level, butid not show any advantage of IV over oral iron
n terms of maintaining iron stores. N
fficacy of IV Iron

To date, the largest randomized prospectivetudy to address this issue is a multicenter, inter-ational, double-blind, parallel-group, efficacynd safety study that examined the use of sodiumerric gluconate in anemic children with a meange of 12.1 � 2.6 years on HD therapy.305 Allatients at the time of enrollment met 1 or bothf the current KDOQI targets for iron deficiencyhile on ESA therapy, ie, a TSAT less than 20%r ferritin level less than 100 ng/mL. Of thisroup, data from 56 patients were available tossess the efficacy of the 2 dosing regimenshosen: 1.5 versus 3.0 mg/kg administered for 8equential HD sessions.

All patients in both dosing arms showed aignificant increase in their baseline Hb levels of.9 g/dL at 2 weeks; 0.9 g/dL in the 1.5-mg/kgose and 1.0 g/dL in the 3.0-mg/kg dose arm at 4eeks from the last dose of IV iron, all P � 0.02.o patient had any change in rHuEPO doseuring the iron therapy; however, during the-week follow-up period, 5 patients had reduc-ions in rHuEPO dose of 14%, 20%, 50%, 50%,nd 67%, all at the 2-week point. Evaluation ofll other indices studied (TSAT, ferritin level,nd CHr) also showed a significant mean in-rease from baseline values in both arms, whichemained significant at 4 weeks after infusion.owever, only ferritin levels showed a signifi-

ant change between the low-dose and high-doseron arms, seen at both the 2-week and 4-weekime points following the last dose of IV iron.ased on their data, the investigators concluded

hat IV sodium ferric gluconate was efficaciousn both repleting and maintaining iron stores inhildren on HD up to 4 weeks after infusion.

In a separate and earlier randomized prospec-ive study, the investigators studied 35 pediatricatients between 1 and 20 years of age on HDherapy for their response to oral or IV iron.304

ll patients were iron replete, as defined byDOQI, with a TSAT greater than 20% and

erritin level greater than 100 ng/mL. They werell well dialyzed and randomized to either weeklyV iron dextran, which was dosed by weight androvided as 2 sets of 6 weekly doses with two-week breaks to monitor levels, or daily oralron at a dose of 6 mg/kg/d as outlined in the
KF-KDOQI 2000 Anemia Guidelines for 16

wtfiiHataiAmnticscdbip

iITdcqwtdwe2lgpctnedwblgqctd

(wcttcd

d1pidTidvttaa

pniatami01i

D

pmbpte

ttwqit


eeks.2 Data showed that only the IV iron dex-ran produced a significant increase in serumerritin levels, P � 0.001. Those treated with IVron dextran also showed a significant decreasen dose of rHuEPO required to maintain targetb levels, P � 0.046, and an increase in CHr,

lthough this was not statistically different fromhose seen in the oral iron group. Both the oralnd IV preparations maintained all patients in theron-replete state, as when the study was started.lthough there was a significant difference inean ferritin levels (259.1 compared with 138.5

g/mL; P � 0.003) and rHuEPO doses (reduc-ion of 33% from baseline; P � 0.046) in the IVron group during the study, there was no statisti-ally significant difference between the IV ver-us oral iron arms as a whole. The investigatorsoncluded from this short-term study that IV ironextran seemed more effective in improving—ut no more effective in maintaining—iron storesn pediatric HD patients on ESA therapy com-ared with oral iron.Another prospective randomized trial exam-

ned the issue of intermittent versus maintenanceV iron in pediatric patients on HD therapy.347

he study group of 20 patients received IV ironextran targeted to initial ferritin levels and aalculation of the net projected iron stores re-uired to target an Hb level of 11.55 g/dL,hereas the 20 patients in the control group were

reated with intermittent courses of 10 weeklyoses of IV iron dextran as defined by bodyeight (repeated as necessary based on the pres-

nce of a ferritin level � 100 ng/mL, TSAT �0%, or Hct � 33%). All patients had basal Hbevels of approximately 8 g/dL and reached 10/dL by 3 months in both arms. The study’s endoints were ferritin, TSAT, and Hb levels. Suc-ess was defined as maintaining an acceptablearget range of ferritin between 100 and 800g/mL and TSAT of 20% to 50%. The studynrolled both absolute and functionally iron-eficient patients. A large number of patients, 20,ere excluded during this study; 13 patientsecause of iron overload, defined as a ferritinevel greater than 800 ng/mL (9 from the controlroup). Three patients in the control group re-uired a blood transfusion and also were ex-luded. Using the study’s iron and rHuEPO pro-ocols, there was a significant difference in iron
ose required during the study, 6 mg/kg/mo a
95% CI, 3.3 to 8.8) in the study group comparedith 14.4 mg/kg/mo (95% CI, 12 to 16.8) in the

ontrol arm, P � 0.001. The investigators showedhat patients in the study arm achieved and main-ained a stable Hb value, whereas those treated asontrols had a much more variable increase andecrease in Hb values.Four other nonrandomized trials in chil-

ren,344,348,350,354 all involving HD patients andincluding patients with ND-CKD and/or trans-lant recipients,354 examined the utility of IVron in maintaining or increasing Hb levels andecreasing the dose of ESA required to do so.wo trials used iron gluconate,350,354 1 trial usedron dextran,348 and 1 trial used iron sucrose344;oses ranged from 1 to 4 mg/kg/wk of thearious products as maintenance therapy, andime of therapy varied from 2 to 24 weeks. All 4rials showed increases in either Hb level or Hctnd a decrease in ESA requirements between 5%nd 62% per week or per dose of ESA.

A recent meta-analysis on the use of IV iron inediatric HD patients used pooled data that didot include the 2 most recent trials,304,347 butncluded the other 4 studies described, as well as

number of abstracts. Meta-analysis showedhat in terms of an increase in Hb, Hct, ferritin,nd TSAT values and decrease in ESA require-ents, there was a positive correlation with IV

ron therapy with an effect size that varied from.62 (95% CI, 0.11 to 1.13) to 1.86 (95% CI,.58 to 2.15) when evaluated using a standard-zed weighted-mean difference approach.343

osing of IV Iron

The use of IV iron preparations and the appro-riate dosage of each is a complex topic. It isade more so because one needs an approach to

oth the immediate repletion of iron stores in aatient who is deficient and a strategy for main-aining an effective level of iron for ongoingrythropoiesis.

The goal of the initial iron therapy is to replenishhe body store of functional iron and thus assist inhe production of red blood cells and Hb in concertith an ESA. The exact dosing regimens, fre-uency of IV iron therapy, and appropriate monitor-ng for effectiveness and safety will be related tohe iron preparation chosen.2,305,344,355

Currently published pediatric studies looking
t the issue of chronic or maintenance therapy

weanta

tfhfrpm

UP

utuir

atdsdh(tbidtersm

S

etmianbt

(mftwroc

ddtrlta

udaap

al8tivgterlldtttf

prnrVosd


ith IV iron have provided 1 to 2 mg/kg/wk oflemental iron and targeted TSATs between 20%nd 50% and serum ferritin levels of 100 to 800g/mL, based on the prior Anemia Guidelines,2

o decide on further doses and frequency ofdministration.344,350

It is important to remember that it is possibleo have acceptable levels of both TSAT anderritin and still benefit from IV iron if the patientas so-called functional iron deficiency; there-ore, occasionally, after careful assessment of theisk and benefits, a “trial” of IV iron in an anemicatient—even one who appears iron replete—ay be indicated.

se of IV Iron in Patients with ND-CKD andD-CKD

The issue around the utility and practicality ofsing IV agents in the non-HD population needso be addressed in children because it is notncommon that these patients either show annability to tolerate or fail to respond to oraleplacement of iron stores.

Currently, in pediatrics, the lack of easy IVccess hampers the use of the strategies used inhe HD population, namely, small, but frequent,osing. In the non-HD population, much higheringle doses of the various IV irons, such asextran,356–358 sucrose,359,360 or gluconate,361

ave been administered at less frequent intervalseg, monthly) in adults to obtain the benefit of IVherapy while minimizing the inconvenience ofoth the need for IV starts and hospital monitor-ng during the therapy. However, this may carryifferent risks in terms of either acute or chronicoxicities. Currently there is little comparablevidence in children, with only 1 published studyeporting a maximum delivered dose of ironucrose of 200 mg344 and another reporting aaximum dose of 250 mg of iron gluconate.354

afety of IV Iron

One concern in the use of IV iron in children,specially in an outpatient setting, is the poten-ially fatal acute AEs.179 All forms of IV ironay be associated with acute AEs, which may

nclude hypotension, anaphylactoid reactions, andvariety of other symptoms. Immune mecha-

isms with activation of mast cells or release ofioactive partially unbound iron into the circula-
ion resulting in oxidative stress and hypotension m
labile or free iron reactions) are both possibleechanisms, and the underlying cause may dif-

er depending on the type of IV iron. Anaphylac-oid reactions appear to occur more frequentlyith iron dextran,173 and labile or free iron

eactions, more frequently with nondextran formsf iron.174 (For further discussion, please see theorresponding Adult Guidelines.)

Although very rare in pediatrics, of 28 chil-ren enrolled in 2 separate studies involving ironextran,304,348 1 child had an allergic reactionhat necessitated stopping the medication.348 Cur-ent evidence would suggest that the risk forife-threatening reactions is greater with IV dex-ran products than sodium ferric gluconate175

nd iron sucrose products.187

Although both iron sucrose and gluconate prod-cts seem to have better safety profiles thanextran, side effects—presumably caused bycute iron toxicity during rapid free iron release—lso have been described with both of theseroducts.With respect to sodium ferric gluconate, pedi-

tric safety data from the trial described ear-ier305 were available in 66 patients administered

IV doses. One patient in the group adminis-ered 1.5 mg/kg per dose was reported to havesolated episodes of mild nausea, diarrhea, andomiting, whereas a patient in the 3.0-mg/kgroup had an episode of severe anemia ascribedo the drug by the investigator at that site. How-ver, no patient had an allergic or anaphylacticeaction during the immediate treatment; no de-ayed reactions occurred in the 4 weeks after theast iron dose, and no deaths were reporteduring the study. Together with data from 2 otherrials in which 21 children were administeredhis product without serious AEs, this observa-ion offers some proof about the safety of sodiumerric gluconate in children.350,354

Iron sucrose safety data are sparse in theediatric CKD literature, with only 2 studieseported. One was a retrospective study that didot report serious AEs in the 8 patients who hadeceived at least 1 dose of IV iron sucrose asenofer (American Regent, Shirley, NY).344 An-ther was a prospective trial that looked at only amall number of patients (n � 14) divided into 3ifferent treatment groups with various iron regi-
ens and did not specifically report on AEs.362

IesiIlcfti

duofavtc

dl0eto

rtciasrawmod


The issue of iron overload as a “side effect” ofV iron therapy also should be addressed. Ironxcess is believed to generate cellular oxidativetress, and iron stored as ferritin can assist innitiating lipid peroxidation of cell membranes.363

n humans, increased ferritin levels have beeninked to a variety of conditions, including in-reased severity of strokes364 and acute renalailure,365 although direct evidence for tissueoxicity related to serum ferritin level is lackingn the CKD population.

In children, a study comparing 2 differentosing strategies of iron dextran showed, bysing Kaplan-Meier analysis, a hazard of ironverload (defined by the investigators as a serumerritin level � 800 ng/mL or TSAT � 50% atny time during the trial) of 20% in the study armersus 100% in the control arm after 6 months ofreatment.347 Patients with functional iron defi-
iency also were statistically more likely to p
evelop iron overload than those with an abso-ute iron deficiency, 70% versus 19%; P �.005. Note: There was no direct or indirectvidence of organ damage offered by the inves-igators in support of their definition of ironverload.Finally, the Work Group also was aware of

esults from a soon-to-be-published prospec-ive multicenter trial of sodium ferric glu-onate complex for maintenance iron therapyn iron-replete children on HD therapy anddministered rHuEPO (Bradley Warady, per-onal communication, June 7, 2005). Becauseesults were not yet peer reviewed or publishedt the time these guidelines were finalized andere not believed to alter the guideline state-ents, the study is not incorporated in this set

f guidelines, but will provide data related toosing, safety, and efficacy of rHuEPO in the
ediatric HD-CKD population.

mtaani

L

dpd

a

A

CPR FOR PEDIATRICS 3.3: USING PHARMACOLOGICALAND NONPHARMACOLOGICAL ADJUVANTS TO ESA

TREATMENT IN HD-CKD

Pppmts

osc

sckwdecoLdt

aot

V

dpd

A

dp

Several pharmacological agents and nonphar-acological manipulations of the HD prescrip-

ion have been examined for potential efficacy asdjuvants to ESA treatment. Studies are not avail-ble to address the use of pharmacological oronpharmacological adjuvants to ESA treatmentn patients with ND-CKD and PD-CKD.

3.3.1 L-carnitine: (FULLY APPLICABLETO CHILDREN)In the opinion of the Work Group,there is insufficient evidence to recom-mend the use of L-carnitine in themanagement of anemia in patientswith CKD.

3.3.2 Vitamin C: (FULLY APPLICABLETO CHILDREN)In the opinion of the Work Group,there is insufficient evidence to recom-mend the use of vitamin C (ascorbate)in the management of anemia in pa-tients with CKD.

3.3.3 Androgens: (FULLY APPLICABLETO CHILDREN)Androgens should not be used as anadjuvant to ESA treatment in anemicpatients with CKD. (STRONGRECOMMENDATION)

RATIONALE

-carnitine

This guideline is considered applicable to chil-ren because there are no special data in theediatric population and there is no reason for aifferent recommendation.There are only a few small studies published

ddressing the topic of L-carnitine in children. d


ediatric patients on HD therapy may have lowlasma carnitine levels366-368; this is less clear inediatric PD patients, for whom the data areore conflicting.369,370 However, any justifica-

ion for use of L-carnitine in children is muchparser than in the adult literature.

One extremely small trial in which 2 childrenn HD therapy were administered IV L-carnitinehowed an increase in their Hct by 34% with nohange in erythropoietin dose delivered.371

A relatively small study of 16 pediatric dialy-is patients, 11 on HD therapy, administered oralarnitine divided twice daily at a dose of 20 mg/g/d for 26 weeks and did not show a benefitith respect to increased Hb or Hct values orecreased dose requirement for erythropoi-tin.372 There also is indirect evidence that be-ause the study was not designed to look at Hbr Hct levels, achieving much higher serum-carnitine levels using a 5 times greater oralose in children on continuous ambulatory PDherapy would not change the Hb levels.370

Finally, a word of caution is warranted: therelso has been concern expressed over the use ofral carnitine because it may produce toxic me-abolites.202

itamin C


ndrogens

This guideline is considered applicable to chil-ren because there are no special data in theediatric population and there is no reason for a
ifferent recommendation.
), 2006: p S105 S105

jcaetrb

dwtlTs

lwHtfoHf

S

CPR FOR PEDIATRICS 3.4: TRANSFUSION THERAPY

or

cpTsutcsgas0

rpbpin1bcdiavWsssb

Red blood cell transfusions should be usedudiciously in patients with CKD, especially be-ause of the potential development of sensitivity,ffecting future kidney transplantation. How-ver, despite the use of ESA and iron therapy,ransfusion with red blood cells occasionally isequired, in particular in the setting of acuteleeding.3.4.1 (FULLY APPLICABLE TO CHIL-

DREN) In the opinion of the WorkGroup, no single Hb concentrationjustifies or requires transfusion. Inparticular, the target Hb recom-mended for chronic anemia manage-ment (see Guideline 2.1) should notserve as a transfusion trigger.

RATIONALE

There is no good evidence to support anyifferent recommendations in children comparedith adults with respect to this guideline because

he physiological principles underlying this guide-ine hold true in children with anemia and CKD.he pediatric practitioner also may wish to con-ider the following evidence.

Currently, there are no specific guidelines re-ated to transfusion of red blood cells in childrenith any level of CKD, on or off dialysis therapy.owever, it should be recognized that any of

hese children, as with an adult, will benefit mostrom red blood cell transfusions only in the facef impaired oxygen delivery, ie, not based on anb “number.” Poor oxygenation is a universally

ollowed indication for transfusions in children m

American Journal of Ki106

lder than the neonate who do not have concur-ent hematologic symptoms or CVD.271,373,374

It also should be remembered that red bloodell transfusions, at least in the critically illediatric patient, may not be “benign” therapy.his was highlighted by a retrospective cohorttudy of 240 children in 5 pediatric intensive carenits, 130 of whom received red blood cellransfusions. The study showed that even afterontrolling for a number of factors, such transfu-ions were associated with increased use of oxy-en, days of mechanical ventilation, vasoactivegent infusions, length of intensive care unittay, and total length of hospital stay (all P �.05).373

Finally, with respect to transfusions in pediat-ic patients awaiting renal transplantation, it isossible that the need for or use of packed redlood cell transfusions may benefit the pediatricatient if chosen carefully and provided undermmunosuppressive coverage in a planned man-er. The most current and largest study involved93 children, 91 of whom received 2 sequentiallood transfusions, either random or donor spe-ific if a living related donation was expected,one 1 month apart under cover of oral cyclospor-ne.375 Significant improvements in both 1-yearnd 5-year graft survival were reported: 96%ersus 78% and 90% versus 64% (P � 0.001).hereas not minimizing the risk for transmis-

ion of infectious agents from blood transfu-ions, especially if that transfusion is unneces-ary, data suggest further prospective trials of redlood cell transfusion before transplantation
ight be of value in children.
dney Diseases, Vol 47, No 5, Suppl 3 (May), 2006: p S106

AiCbtrh

H

d

A

CPR FOR PEDIATRICS 3.5: EVALUATING AND CORRECTINGPERSISTENT FAILURE TO REACH OR MAINTAIN

INTENDED HB LEVEL

pd

D

swtGcfs

ctpetwwluwgeiil

P

gutomrrwpspfsti

lthough relative resistance to the effect of ESAss a common problem in managing the anemia ofKD and is the subject of intense interest, theulk of available information suggests that—inhe absence of iron deficiency—there are feweadily reversible factors that contribute to ESAyporesponsiveness.

3.5.1 Hyporesponse to ESA and irontherapy: (FULLY APPLICABLE TO)CHILDRENIn the opinion of the Work Group, thepatient with anemia and CKD shouldundergo evaluation for specific causesof hyporesponse whenever the Hblevel is inappropriately low for theESA dose administered. Such condi-tions include, but are not limited to:● A significant increase in the ESA

dose requirement to maintain a cer-tain Hb level or a significant decreasein Hb levels at a constant ESA dose.

● A failure to increase the Hb level togreater than 11 g/dL despite anESA dose equivalent to epoetingreater than 500 IU/kg/wk.

3.5.2 Evaluation for PRCA: (FULLY AP-PLICABLE TO CHILDREN)In the opinion of the Work Group, evalu-ation for antibody-mediated PRCAshould be undertaken when a patientreceiving ESA therapy for more than 4weeks develops each of the following:● Sudden rapid decline in Hb level at

the rate of 0.5 to 1.0 g/dL/wk, orrequirement of red blood cell trans-fusions at the rate of approximately1 to 2 per week, AND

● Normal platelet and white bloodcell counts, AND

● Absolute reticulocyte count lessthan 10,000/�L.

RATIONALE

yporesponsiveness to ESA and Iron

This guideline is considered applicable to chil-
ren because there are no special data in the r

ediatric population and there is no reason for aifferent recommendation.

efinition of Hyporesponsiveness

The principles outlined in the adult guidelinehould be kept in mind when assessing a childho appears to have hyporesponsiveness to ESA

herapy; however, the indications as outlined inuideline 3.5.1 may not be directly applicable to

hildren because there are no published datarom which we can confidently define an exces-ive epoetin dose to maintain a given Hb target.

In terms of the mean ESA dose required, it islear from the NAPRTCS 2004 annual reporthat in all children, the average dose never ap-ears to exceed approximately 350 U/kg/wk,ven in the youngest children and even during upo 30 months of follow-up.325 What is not clear ishat the upper limit of this dose is in childrenho seem to respond with an increase in Hb

evel; hence, it is not currently feasible to set anpper limit dose that, if exceeded in a childhose Hb level is persistently less than 11.0/dL, should trigger a consideration for the pres-nce of hyporesponsiveness, although the targetn children younger than 5 years would intu-tively be greater than that set in the adult guide-ines.

otentially Treatable Disorders

In terms of the factors outlined in the adultuideline as being associated with persistent fail-re to achieve target Hb levels, these are relevanto children as well, and in a retrospective reviewf 23 patients on HD therapy for more than 6onths, it was shown that there appeared to be a

elationship between the need for high doses ofHuEPO (defined as � 450 U/kg/wk) in patientsho were younger, weighed less, had greaterarathyroid hormone levels, and had more epi-odes of bacteremia (all P � 0.03).341 An unex-ected finding in this study, relating a high serumerritin level to an increased risk for hyporespon-iveness, likely (as suggested by the investiga-ors) was related to the presence of inflammationn patients with more frequent episodes of bacte-
emia.
), 2006: pp S107-S108 S107

Eb

dpd

p

PpS1p1PtsoER

yodEadTfo“

fPettsadc


valuation for Diagnosing and Treating Anti-ody-Mediated PRCA

This guideline is considered applicable to chil-ren because there are no special data in theediatric population and there is no reason for aifferent recommendation.A brief review of pediatric PRCA cases is

resented next.A study reviewed all 191 confirmed cases of

RCA up until April 2004, including 3 pediatricatients; an 11-year-old boy from the Unitedtates, a 17-year-old girl from Brazil, and a9-year-old boy from France.278 Two of theseatients, the 11- and 17-year-olds, received onlyESA, epoetin alfa (Procrit®; Ortho Biotech

roducts, LP, Bridgewater, NJ and Eprex®; Or-ho Biotech Products, LP, Bridgewater, NJ, re-pectively) before developing PRCA. The 19-year-ld received both epoetin alfa and epoeten beta,prex® and Neorecormon® (F. Hoffmann-La
oche, Ltd, Basel, Switzerland). The 11- and 19- i
ear old patients developed PRCA after 18 monthsf exposure to an ESA, whereas the 17-year-oldeveloped it 7 months after first exposure to anSA. The latter subsequently died of cardiacrrest 20 months after the original diagnosis; noata about any form of therapy are available.here are no outcome or therapy data available

or the 19-year-old patient; however, the 11-year-ld received a renal transplant and subsequentlyrecovered” from PRCA.

Obviously, these numbers are very small and,or practical purposes, suggest a very low risk forRCA in children compared with the risk inher-nt in being anemic or requiring repeated bloodransfusions. However, it should be recognizedhat this problem can occur in children andhould be part of the differential for a child withlow reticulocyte anemia in the presence of a

ecreasing Hb level and preserved white bloodell and platelet lines that fail to respond to
ncreased iron and/or ESA therapy.

IV. CLINICAL PRACTICE RECOMMENDATIONS FOR ANEMIAIN CHRONIC KIDNEY DISEASE IN TRANSPLANT RECIPIENTS

toa

toCaftiwtrpAgEtipiggp

tr

t

S

ANEMIA IN CKD IN TRAN

fpspceft

neatmr1fhtrmlaqi

pemceocr

disorders. allograft function.

American Journal of Kidney Di110

SPLANT RECIPIENTS

BACKGROUND

Anemia is relatively common after transplan-ation. Regular screening and careful evaluationf the multiple factors that can contribute tonemia after transplantation are recommended.

Table 41 summarizes the key features of post-ransplantation anemia (PTA). As in other formsf CKD, the prevalence of anemia in transplantKD clearly is associated with the level ofllograft function. However, a number of otheractors unique to transplant recipients may con-ribute to the development of PTA. There is littlenformation regarding the association of anemiaith either graft or patient outcomes. Similarly,

here is limited information to suggest that theesponse to treatment with ESAs differs betweenatients with CKD with and without a transplant.lthough there are reports of increased delayedraft function and hypertension with the use ofSAs, there is insufficient evidence to suggest

hat these agents should not be used in either themmediate posttransplantation or late posttrans-lantation period. Conversely, with the existingnformation, it is recommended that treatmentuidelines for management of anemia in theeneral CKD population be followed in the trans-lant population.

INTRODUCTION

Transplant recipients are a subgroup of pa-ients with CKD with unique considerations withegard to anemia management.

Transplant recipients have variable exposureo CKD before transplantation. Patients with

Table 41. Literature Review of AnemiPrevalence of

AnemiaPathophysiology Clinica

Prevalence varies by time after

transplantation and by level of graft

function.Relationship

between Hb and eGFR may not be the same as that

seen in other CKD

Level of transplant kidney function is

important, but other factors, including medications, may

decrease erythropoietin production or increase

resistance to erythropoietin in

patients with stable

Evideanemiatreatmeor patie

includcard

dishospi

li

unctioning transplants include preemptive trans-lant recipients, recipients with variable expo-ure to dialysis, and repeat and multiorgan trans-lant recipients. Consequently, the burden ofomorbid disease varies among transplant recipi-nts, and this may have important implicationsor the severity and management of anemia afterransplantation.

Most transplant recipients have decreased kid-ey function. Among 40,963 transplant recipi-nts studied in the United States between 1987nd 1996, mean eGFR achieved at 6 months afterhe time of transplantation was 49.6 � 15.4 (SD)L/min/1.73 m2.376 In a study of transplant

ecipients in the United States between 1987 and998, more than 70% of patients with allograftunction at 1, 3, and 5 years after transplantationad CKD stage 3 or higher.377 Transplant func-ion may change over time. Although the meanate of GFR decline was only 1.66 � 6.51L/min/1.73 m2 per year in a large cohort of

ong-term kidney transplant recipients, kidneyllograft function may change rapidly; thus, fre-uent evaluation of kidney function and Hb levels desirable.376

Transplant recipients differ from most otheratients with CKD because they are chronicallyxposed to immunosuppressive medications thatay suppress erythropoiesis. The current KDOQI

lassification of CKD includes transplant recipi-nts.4 A recent worldwide consensus statementf KDIGO also confirmed that the CKD classifi-ation system should be applied to transplantecipients and suggested to add the index letter

ransplant CKD: Key Conclusionsmes Response to

treatment Side effects of

treatment ing emia graft omes, ival, lar n is

Transplant patients may be relatively resistant to ESA.

The precise mechanisms have

not been elucidated.

Evidence is insufficient to determine the relationship, if any, between ESA use

and potential adverse events in the transplant CKD patient, including delayed graft function,

decline in kidney function, or hypertension.

a In Tl outco

nce link and annt with

nt outcing surviovascuease, &talizatiomited.

seases, Vol 47, No 5, Suppl 3 (May), 2006: pp S110-S116

“ptCa

rcaeba

tuedt

atvapadeei

pitetlacdmaqra

ibDa

pstirasE(rpMh1htpmdSaaattet21g(2amtNcg

depsiaptial

ANEMIA IN CHRONIC KIDNEY DISEASE IN TRANSPLANT RECIPIENTS S111

T” to the CKD stage category for theseatients.377A Although many features distinguishransplant recipients from other patients withKD, transplant recipients are clearly at risk fornemia because of decreased kidney function.

This section reviews the available informationegarding the prevalence, pathophysiology, clini-al correlates, and treatment considerations ofnemia in kidney transplant recipients. The rel-vant considerations for anemia managementefore transplantation and after transplant failurelso are discussed.

PREVALENCE

There is no accepted definition of anemia inransplant recipients, and variable definitions aresed in the literature. A second important consid-ration is that the prevalence of anemia is depen-ent on the time of observation after transplanta-ion.

During the early posttransplantation period,rbitrarily defined as the first 6 months afterransplantation, anemia of varying degrees isery common. The prevalence and degree ofnemia during this period are dependent on theretransplantation Hb level, amount of perioper-tive blood loss, frequency of blood draws, ironepletion,378-383 persistence of uremia,382 endog-nous erythropoietin levels,382,384,385 erythropoi-tin responsiveness,382,384-387 and exposure tommunosuppressive agents.388,389

The time course of erythropoiesis after trans-lantation has been studied by a number ofnvestigators,378-382,385,390,391 and reviews onhis subject are available.389,391,392 A transientarly peak of erythropoietin is detectable withinhe first 24 hours after transplantation, particu-arly in patients with delayed graft function,nd is not associated with a measurable in-rease in Hb level. Within the first number ofays after successful transplantation, a smaller,ore sustained erythropoietin peak is detect-

ble. This peak is associated with the subse-uent onset of erythropoiesis and recovery ofenal anemia during the next several monthsfter transplantation.The prevalence and degree of anemia in the

mmediate posttransplantation period also wille dependent on the pretransplantation Hb level.espite the widespread availability of ESAs,

nemia continues to be a significant issue in w

atients presenting for kidney transplantation. Atudy found that the prevalence of pretransplan-ation anemia (defined as Hct � 33%) was 41%n adults.393 In a study of pediatric transplantecipients, the prevalence of pretransplantationnemia (defined as Hct � 2 SDs less than age-pecific means) was 67%.394 In the Transplanturopean Survey on Anemia Management

TRESAM), 4 cohorts of prevalent transplantecipients were defined by the duration of trans-lantation (6 months and 1, 3, and 5 years).ean pretransplantation Hb levels in these co-

orts were 11.9 � 1.7 (SD), 11.7 � 1.8, 11.2 �.8, and 10.8 � 1.8 g/dL, respectively. Theigher mean Hb levels in cohorts that underwentransplantation more recently suggested an im-rovement in pretransplantation anemia manage-ent over time.395 In a study of adult first

eceased-donor transplant recipients in the Unitedtates between 1995 and 2000, the prevalence ofnemia before transplantation was describedmong the subset of patients who had Medicares the primary payer for the 12 months beforeransplantation and who received ESAs beforeransplantation. Mean pretransplantation Hb lev-ls recorded in the 6 months before transplanta-ion by transplantation year were: 1995 (n �296), 10.5 � 0.02 (SE) g/dL; 1996 (n � 2394),0.7 � 0.02 g/dL; 1997 (n � 2694), 10.9 � 0.02/dL; 1998 (n � 2838), 11.0 � 0.02 g/dL; 1999n � 2723), 11.4 � 0.02 g/dL; and 2000 (n �857), 11.6 � 0.02 g/dL. The higher Hb levelsmong patients who underwent transplantationore recently suggested an improvement in pre-

ransplantation anemia management over time.onetheless, in 20% of patients, Hb levels de-

reased to less than the KDOQI target of 11/dL.395A

Table 42 summarizes the published studiesescribing the prevalence of PTA. Together, thexisting literature indicates that PTA is highlyrevalent. The results from the few longitudinaltudies showed a very high prevalence of anemian the early posttransplantation period; anemiappears to be least prevalent 1 year after trans-lantation and then increases in prevalence withime after transplantation. This increase possiblys related to declining allograft function. Thevailable information suggests that the preva-ence of anemia is greater in pediatric compared
ith adult patients.

so

F

lCiwep

K

twtlctotl

C6

wot9aw3tsiid

lCtrpchr

Seve

ANEMIA IN CHRONIC KIDNEY DISEASE IN TRANSPLANT RECIPIENTSS112

PATHOPHYSIOLOGY

A number of factors may cause PTA; some arehared with other patients with CKD, whereasthers are unique to transplant recipients.398

actors Shared With Other Patients With CKD

In general, the evaluation of PTA should paral-el that among nontransplantation patients withKD. The discussion regarding factors contribut-

ng to PTA that are shared with other patientsith CKD is limited to the most common consid-

rations and to unique considerations in the trans-lantation setting.

idney Function

Level of allograft function is clearly an impor-ant determinant of PTA. In the TRESAM, thereas a strong association of anemia with kidney

ransplant function. Of 904 patients with an SCr

evel greater than 2 mg/dL, 60.1% were anemicompared with 29% of those with an SCr lesshan 2 mg/dL, P � 0.01. In a single-center studyf 459 patients at least 6 months after transplan-ation, prevalences of anemia, defined as an Hb

Table 42. Prevalence of PTA by

Author, Year Location

Adult/ Pediatric or Mean Age N

Saito, 1998 396, 397 Japan Adult 60

Yorgin, 2002 393 821 ry 81> SU

Mix, 2003 398 042 tludA SU

Lorenz, 2002 399 Austria Adult 438

Winklelmayer, 2004 400 US Adult 374

Vanrenterghem, 2004 395 Europe 48 ±13 yr included children

>10 yr

4,263

Yorgin, 2002 394 261 cirtaideP SU

Shibagaki, 2004 401 US Adult 192

Kausman, 2004 402 Australia Pediatric 50

evel less than 11 g/dL, among patients with a

KD stages 1, 2, 3, 4, and 5 were 0%, 2.9%,.6%, 27%, and 33%, respectively.403

The association of level of allograft functionith Hb level appears to vary with the time ofbservation after transplantation. One study foundhat, among patients with an eGFR greater than0 mL/min/1.73 m2, 11% and 7% of patients hadnemia at 6 and 12 months after transplantation,hereas among patients with an eGFR less than0 mL/min/1.73 m2, at 6 and 12 months afterransplantation, 60% and 76% were anemic, re-pectively.398 These findings suggest that factorsn addition to level of allograft function may bemportant determinants of anemia, particularlyuring the early posttransplantation period.Whether the association between anemia and

evel of kidney function differs in patients withKD who did and did not undergo transplanta-

ion is uncertain. In a study of 23 renal transplantecipients with stable kidney function, 12 anemicatients were compared with the 11 nonanemicontrol patients.386 Of the 12 anemic patients, 10ad low erythropoietin levels suggestive of eryth-opoietin deficiency, 2 patients had higher than

n of Posttransplantation Period

finition of Anemia

Timing of Anemia Determination after

Transplantation Prevalence ale Hb <12.8 g/dL male Hb <11.5 g/dL

Cross-sectional 23%

)ry( tnalpsnart-tsop emiT ry 5 rof ylraeY %33< tcH 0 = 43% 1 = 12% 2 = 12% 3 = 14% 4 = 18% 5 = 26%

)ry( tnalpsnart-tsop emiT ry 5 revo lanidutignoL %63< tcH0 = 76% 1 = 21% 4 = 36%

Male Hb <13 g/dL emale Hb <12 g/dL

Cross-sectional mean 4.9 yr

39.7%

Hct <33% Cross-sectional Mean 7.7 ± 6.7 yr post-

transplantation

28.6%

Male Hb ≤13 g/dL emale Hb ≤12 g/dL

4 cohorts

6 mo (n = 1003) 12 mo (n = 960) 3 yr (n = 1254) 5 yr (n = 1046)

38.6% overall

No significant difference in prevalence among cohorts

ficeps-ega wole ic means Longitudinal 67% at transplant 84% 1 mo

64%-82% between 0-60 mo Male Hb ≤13 g/dL emale Hb ≤12 g/dL

6 mo

12 mo

6 mo = 41%

12 mo = 45%

Hb ≤11 g/dL in women, ≤12 g/dL in men was 19% and 20% at 6

mo and 12 mo Hb <110 g/L

re anemia Hb <100 g/L

Cross-sectional 60% Hb <110 g/dL

30% Hb <100 g/dL

Duratio

DeM

Fe

F

F

b DS 2

F

nticipated erythropoietin levels suggestive of

emesamtcbprwte

I

tttttcraewn

gcdwtwpsl4(p

T

A

sandfa

tHbroms

M

opmamtapo

afi4

a(

tcrmttacrnbsb

noa

agabT


rythropoietin resistance, whereas 5 of 11 nonane-ic control patients had higher than expected

rythropoietin levels. Thus, there appears to beignificant variation in erythropoietin productionnd responsiveness in transplant recipients, whichay alter the association between kidney func-

ion and anemia in transplant recipients. Otherlinically evident examples of the dissociationetween Hb level and kidney function in trans-lant recipients include posttransplantation eryth-ocytosis and, as in nontransplantation patientsith CKD, the lower incidence of anemia among

ransplant recipients with polycystic kidney dis-ase.395

ron Deficiency

Iron deficiency may be an important factor inhe development of anemia after transplanta-ion.404 There is limited information regardinghe prevalence of iron deficiency after transplan-ation. In a cross-sectional study of 438 prevalentransplant recipients, the prevalence of iron defi-iency, defined as a percentage of hypochromiced blood cells of 2.5% or greater, was 20.1%. Innother study of 439 prevalent transplant recipi-nts, 41% of patients had a TSAT less than 20%,hereas 44% had a ferritin level less than 100g/mL.403

The prevalence of iron deficiency may bereater in the early transplantation period be-ause of low pretransplantation iron stores inialysis patients and increased iron utilizationith the onset of erythropoiesis after successful

ransplantation.383 In 1 study, 24 of 51 patientsere found to be iron deficient in the earlyosttransplantation period.381 In a prospectivetudy of 112 transplant recipients, serum ferritinevels decreased from 109.6 �g/L (range, 21 to,420 �g/L) at transplantation to 54.9 �g/Lrange, 2 to 1,516 �g/L) at 6 months after trans-lantation.405

ransplant-Specific Factors

cute RejectionEarly acute rejection is reported to cause a

harp decrease in erythropoietin production andnemia.406 Insights into the molecular mecha-isms involved in the development of anemiauring allograft rejection have been elucidatedrom gene expression studies.407 Among 4 pedi-
tric renal allograft recipients with acute rejec- i
ion and anemia, a cluster of 11 genes involved inb transcription and synthesis, iron and folateinding, and transport were found to be down-egulated.An additional mechanism for the devel-pment of anemia during rejection is thromboticicroangiopathy, which may develop during epi-

odes of severe vascular rejection.

edicationsImmunosuppressive medications. The use

f myelosuppressive medications for immunosup-ression and antiviral prophylaxis or treatmentay be important factors in the development of

nemia after transplantation. Azathioprine andycophenolate mofetil are myelosuppressive;

herefore, anemia caused by these drugs often isssociated with leukopenia and/or thrombocyto-enia. Very rarely, PRCA may occur with the usef these drugs.388,408,409

Calcineurin inhibitors infrequently are associ-ted with anemia. The most common mechanismor PTA associated with the use of calcineurinnhibitors is microangiopathy and hemolysis.410-

14 The immunosuppressant OKT3 also has beenssociated with hemolytic uremic syndromeHUS) and microangiopathy.415,416

Anemia was a significant AE in a phase IIIrial in which sirolimus was administered withyclosporine and corticosteroids.417 A groupeviewed the 10-year experience with siroli-us and reported a dose-dependent associa-

ion of anemia with the drug in phase I and IIrials.418 The association of sirolimus withnemia also recently was shown in single-enter analyses.419 Sirolimus may inhibit eryth-opoiesis by interfering with intracellular sig-aling pathways normally activated after theinding of erythropoietin to its receptor, andirolimus also may be associated with throm-otic microangiopathy.419,420

Antiviral and antimicrobial medications. Aumber of commonly used antivirals and antibi-tics may cause anemia, including ganciclovirnd trimethoprim-sulfamethoxazole.

Angiotensin-converting enzyme inhibitorsnd angiotensin II receptor antagonists. An-iotensin-converting enzyme (ACE) inhibitorsnd angiotensin receptor blockers (ARBs) maye associated with PTA. Anemic patients in theRESAM had higher odds of receiving ACE

nhibitors or ARBs (odds ratio, 1.55; 95% CI,

1rrAmotroi

I

(bm

cibnbasmFsEg9(vlpesda

H

rotbtiist7b

sTocvpcrbnar

HG

frAsdg

ti

clcdltsevsimwe0

ioabol


.34 to 1.80; P � 0.001).395 In a single-centeretrospective study, a significant curvilinear dose-esponse relationship was identified betweenCE-inhibitor dose and Hct.400 The underlyingechanisms are complex and include inhibition

f endogenous erythropoietin production, inhibi-ion of angiotensin II–mediated stimulation ofed blood cell precursors,421 and the generationf an erythropoiesis-inhibiting protein by ACEnhibitors.422

nfections and MalignancyAnemia may be a feature of cytomegalovirus

CMV) infection. Parvovirus B19 infection haseen reported in transplant recipients with ane-ia and may cause PRCA.423,424

Hemophagocytic syndrome (HPS) is a rareause of PTA. The syndrome often is caused bynfectious or neoplastic disease and is defined byone marrow and organ infiltration by activatedonmalignant macrophages that phagocytose redlood cells. A retrospective analysis of 17 casesmong deceased donor transplant recipientshowed that the syndrome developed after aedian duration of 52 days after transplantation.ever was present in all patients and hepato-plenomegaly was present in 9 of 17 patients.leven patients had received antilymphocytelobulins in the 3 months before presentation. Inpatients, HPS was related to viral infections

CMV, Epstein-Barr virus, and human heprusirus 6 and 8); other infections included tubercu-osis, toxoplasmosis, and Pneumocystis cariniineumoniae. Posttransplantation lymphoprolif-rative disease was present in 2 patients. Theyndrome has a poor prognosis—8 of 17 patientsied despite the use of anti-infectious therapynd tapering of immunosuppression.425

emolytic Uremic SyndromeHUS may recur after transplantation and can

esult in allograft loss.426 De novo HUS mayccur associated with the use of cyclosporine,acrolimus, or OKT3. The syndrome also haseen associated with CMV and influenza A infec-ion in transplant recipients.427,428 The possibil-ty that erythropoietic agents may be beneficialn patients with HUS after transplantation isuggested by observations from the nontransplan-ation population. Plasma from approximately5% of patients with sporadic thrombotic throm-
ocytopenic purpura (TTP)/HUS induces apopto- c
is in cultured microvascular endothelial cells.429

he mechanism appears to be linked to inductionf Fas (CD95) on cultured endothelial cells be-ause the erythropoietin receptor is expressed onascular endothelial cells.430, 431 Erythropoietinrevents lipopolysaccharide-induced apoptosis inultured endothelial cells, suggesting that eryth-opoietin may have a protective effect and maye of therapeutic benefit in TTP/HUS in theontransplantation setting.432 The use of ESAsfter transplantation in patients with HUS war-ants further study.

emolytic Anemia Associated With Minor Bloodroup A, Group B, Group O IncompatibilityBlood group A recipients receiving transplants

rom blood group O donors or blood group ABecipients receiving transplants from either group

or B donors may develop evidence of hemoly-is caused by anti-A or anti-B antibodies of theonor or from autoantibodies produced by passen-er lymphocytes.433-435

CLINICAL OUTCOMES

There is only limited information regardinghe association of anemia with clinical outcomesn transplant recipients.

Transplant recipients are known to be at in-reased risk for cardiovascular events, particu-arly during the perioperative period. In a single-enter study of 404 transplant recipients withiabetes between 1997 and 2000, patients with ateast 1 monthly Hct level less than 30% duringhe first 6 months after transplantation had aignificantly greater incidence of cardiovascularvents compared with patients with monthly Hctalues greater than 30%. In a multivariate analy-is that also included patient age and history ofschemic heart disease (IHD), an increase inonthly Hct to greater than 30% was associatedith a significantly lower risk for cardiovascular

vents (RR, 0.65; 95% CI, 0.33 to 0.91; P �.02).436

Among long-term transplant recipients, theres limited information regarding the associationf anemia with adverse cardiovascular events. Inretrospective study of 638 transplant recipientsetween 1969 and 1999 who were alive and freef cardiac disease 1 year after transplantation,ower Hb levels were associated with an in-
reased risk for de novo CHF (RR, 1.24/10-g/dL

d0a(gt

ry4fai1vrcRt

srdi0

U

tabtcsaadHnpr

E

ipi

ip

tEawrnt6rENoaat�Tsfie

r1tg5gHE1y(dl1gplitra

ephi


ecrease in Hb; 95% CI, 1.10 to 1.39; P �.001).437 In a follow-up study, anemia wasssociated with increase in left ventricular massas measured by Cornell voltage on electrocardio-ram) during the first 5 years after transplanta-ion.438

In a recent study, 438 prevalent transplantecipients were followed up for a median of 7.8ears. Laboratory parameters obtained during a-week enrollment period in 1995 were testedor their association with all-cause mortality andllograft failure.439 The investigators did notdentify an association between anemia (Hb �0 g/dL) and all-cause mortality or graft sur-ival. Compared with patients with hypochromiced blood cells less than 5%, patients with hypo-hromic red blood cells greater than 10% had anR of 2.06 for all-cause mortality (95% CI, 1.12

o 3.79; P � 0.02).In a retrospective single-center study of re-

ource utilization among 220 kidney transplantecipients, patients with a higher Hct had aecreased risk for hospitalization (RR, 0.95/1%ncrease in Hct; 95% CI, 0.92 to 0.98; P �.001).440

RESPONSE TO TREATMENT WITHESAs AND SAFETY OF TREATMENT

se of ESAs Before Transplantation

The issue of whether ESAuse before transplan-ation is associated with delayed graft functionfter transplantation has largely been dispelledy the decreased incidence of delayed graft func-ion in registry data over time despite the in-reased use of ESAs. A few small retrospectivetudies had suggested that ESA use may bessociated with delayed graft function, presum-bly because of altered intrarenal blood flowuring rewarming in patients with a higherct.441,442 Previous treatment with ESAs doesot blunt the production of endogenous erythro-oietin after transplantation or the ability toespond to endogenous erythropoietin.391,443

arly Posttransplantation Period

Erythropoietic agents are effective in correct-ng anemia during the early posttransplantationeriod. Two small prospective randomized stud-
es to study the efficacy of ESAs during the c
mmediate posttransplantation period have beenerformed.One study randomized 14 transplant recipients

o receive and 15 patients not to receive anSA.387 The ESA (150 U/kg/wk) was started atn Hct less than 30% and was increased ateekly intervals by 30 U/kg/wk as long as Hct

emained at less than 25%. Hct increased from aadir of 22% � 4% 2 weeks after transplantationo 30% � 4% at week 4 and 36% � 4% at week

(P � 0.001 and P � 0.0001 versus week 2,espectively). Corresponding values in the non-SA group were 25% � 6%, 28% � 6% (P �S), and 32% � 6% (P � 0.05 versus week 2;verall ESA versus non-ESA, P � 0.038 bynalysis of variance). The maximum ESA dosefter transplantation was more than 2 times higherhan that required before transplantation (197.1

45.1 versus 85.0 � 76.0 U/kg/wk; P � 0.05).he investigators concluded that ESAs couldafely and effectively correct anemia during therst weeks after transplantation despite relativerythropoietin resistance.

In a recent study, patients were randomized toeceive (n � 22) or not receive (n � 18) ESA,00 U/kg 3 times per week, if Hb level was lesshan 12.5 g/dL.444 Time to reach an Hb levelreater than 12.5 g/dL was 66.5 � 14.5 versus2.6 � 23.7 days in the non-ESA and ESAroups, respectively (P � 0.05). After 3 months,b levels were not different between the non-SA and ESA groups (12.6 � 1.5 versus 12.0 �.5 g/dL, respectively). In a Cox regression anal-sis, ESA use (RR, 7.2; P � 0.004) and doseRR, 0.63; P � 0.04) were retained as indepen-ent variables predicting the time to reach an Hbevel greater than 12.5 g/dL. In the ESA group,4 of 22 patients reached the target Hb level ofreater than 12.5 g/dL compared with 12 of 18atients in the non-ESA group (P � NS). SCr

evels were not different between groups. Thenvestigators concluded that the use of ESAs inhe immediate posttransplantation period had noelevant clinical impact on the correction ofnemia after transplantation.

Together, these studies suggest that ESAs areffective in correcting anemia after renal trans-lantation. The dose of ESA required may beigher than that before transplantation. The stud-es were not designed to determine whether the
orrection of anemia was associated with im-

ptowtt

agrtttwssti

snncs

L

ilr7tTspanacnwc

sad

edprcCabtptrtrtfdtt4Hgt

P

mmiiimHo(dc


rovement in clinical outcomes, resource utiliza-ion, or QOL. Further, few patients with delayedr impaired graft function were studied. Thus,hether there are clinically relevant benefits to

he early correction of anemia after transplanta-ion remains uncertain.

These studies did not report significant AEsssociated with the use of ESAs, such as delayedraft function or hypertension. A recent studyeported a significantly increased incidence ofransplant renal artery stenosis among pediatricransplant recipients administered ESAs duringhe first week after transplantation. All patientsere enrolled in a steroid-free immunosuppres-

ion protocol. Results of DNA microarray analy-is showed a series of 12 genes that differentiatedhe patients who developed renal artery stenosisn this setting.444A

Erythropoietin modulates the cellular re-ponse to stress and may attenuate apoptosis andecrosis in various organs, including the kid-ey.445-451 Whether use of erythropoietic agentsan minimize ischemic reperfusion injury, ashown experimentally, warrants investigation.

ate Posttransplantation Period

There are only a few uncontrolled studies describ-ng the use of ESAs to treat late PTA.452-455 In theargest of these studies, in 40 patients with failingenal allografts, mean Hb levels increased from8.9 � 10.4 to 102.6 � 18.4 g/L after 24 weeks ofreatment with ESA, 50 U/kg 3 times per week.453

he increase in Hb level was associated with aignificant improvement in QOL measures. Twelveatients returned to dialysis therapy. These patientsll had poor allograft function, and the study couldot exclude the possibility that treatment with ESAccelerated renal allograft decline. Although nohange in systolic or diastolic blood pressure wasoted, the need for antihypertensive medicationsas significantly increased in 18 patients. An in-

rease in hypertension also was noted in another a

tudy.452 In a single-center study, correction ofnemia was associated with a decreased rate ofecline in allograft function.456

Together, these studies suggest that ESAs arefficacious and likely do not accelerate renalecline, but may aggravate hypertension. Whetheratients in the late posttransplantation periodequire higher doses of ESAs to correct anemiaompared with nontransplantation patients withKD is unclear.457 A decreased response to ESAsmong transplant recipients may be anticipatedecause of the use of myelosuppressive medica-ions, chronic inflammation, or other factors. Theropensity of specific immunosuppressive agentso affect the action of ESAs in kidney transplantecipients is unclear. There is an inverse correla-ion between ESA dose and CCr in transplantecipients, and a sudden change in Hct in ESA-reated patients may indicate a change in graftunction.453 The response to ESAs is impaireduring episodes of allograft rejection.407,458 Inhe TRESAM, the median dose among ESA-reated patients was 4,000 IU/wk (mean, 5,831 �,217 IU/wk), but ESA-treated patients had lowerb values than non–ESA-treated patients, sug-esting that the ESA was underdosed and pa-ients were ESA resistant.395

osttransplantation Failure

Patients with allograft failure have a highortality that is related primarily to CVD. Theanagement of anemia among patients with fail-

ng allografts is suboptimal. In a study of patientsnitiating dialysis therapy after transplant failuren the United States between 1995 and 1998,ean Hct was 27.5% � 5.9% and 67% had anct less than 30%. The use of ESAs at the timef dialysis therapy initiation was infrequent35%).459 Anemia management may be moreifficult in patients with transplant failure be-ause of the presence of chronic inflammation
nd relative resistance to ESAs.460

A

2WuatwHdeltc

O

r

A

V. APPENDIX 1: METHODS OF EVIDENCE REVIEW
AND SYNTHESIS
C

CsocvntcdptIc

tufGfifemldet

lEpCatmp

im

The overall aim of the project is to update the000 KDOQI CPGs for Anemia of CKD.2 Theork Group sought to update the guidelines by

sing an evidence-based approach. After topicsnd relevant clinical questions were identified,he available scientific literature on those topicsas systematically searched and summarized.igh-quality or moderately high-quality evi-ence formed the basis for the development ofvidence-based CPGs. When evidence was ofow or very low quality or was entirely lacking,he Work Group could develop CPRs based ononsensus of expert opinion.

verview of Process

Update of the guidelines required many concur-ent steps to:

● Form the Work Group and ERT that wereto be responsible for different aspects ofthe process

● Confer to discuss process, methods, andresults

● Develop and refine topics● Create draft guideline statements and ra-

tionales● Define exact populations, interventions,

predictors, comparisons groups and out-comes of interest and study design andminimum follow-up time criteria (PICOD)

● Create and standardize quality assessmentand applicability metrics

● Create data extraction forms● Develop literature search strategies and

run searches● Screen abstracts and retrieve full articles● Review articles● Extract data and perform critical appraisal

of the literature● Tabulate data from articles into summary

tables● Grade quality and applicability of each

study● Grade the quality of evidence for each

outcome and assess the overall quality ofthe evidence across all outcomes with the
aid of evidence profiles p

● Write guideline recommendations and sup-porting rationale statements and grade thestrength of the recommendations

● Write CPRs based on consensus of theexpert Work Group in the absence ofsufficient evidence.

reation of Groups

The KDOQI Co-Chairs appointed the Co-hairs of the Work Group, who then as-

embled groups to be responsible for the devel-pment of the guidelines. The Work Grouponsisted of domain experts, including indi-iduals with expertise in adult and pediatricephrology, hematology, nursing and nutri-ion, cognitive function, QOL, and CVD out-omes in patients with CKD. Support in evi-ence review and methods expertise wasrovided by an ERT contracted by the NKF athe NKF Center for CPG Development andmplementation. The Work Group and the ERTollaborated closely throughout the project.The first task of the Work Group members was

o define the overall topics and goals for thepdate. Smaller groups of 2 to 4 individuals wereormed and assigned to each topic. The Workroup and ERT then further developed and re-ned each topic and specified screening criteriaor PICOD, literature search strategies, and dataxtraction forms (described next). Work Groupembers were the principal reviewers of the

iterature, and from their reviews and detailedata extractions, they summarized the availablevidence and took the primary roles of writinghe guidelines and rationale statements.

The ERT consisted of individuals (staff, fel-ows, and research assistants) from Tufts–Newngland Medical Center with expertise in ne-hrology and development of evidence-basedPGs. It instructed the Work Group members inll steps of systematic review and critical litera-ure appraisal. The ERT also coordinated theethodological and analytical process of the re-

ort; it defined and standardized the method of
erforming literature searches, data extraction, and
), 2006: pp S117-S125 S117

seofndtteoqm

Ro

Codai

ba“tpbqna

dsnrtcua

L

rl

sHa2oNwnIntc2tfSAas

riwssEmeieqtabGrdocsasm

APPENDIX 1: METHODS OF EVIDENCE REVIEW AND SYNTHESISS118

ummarizing the evidence in summary tables andvidence profiles. It performed literature searches,rganized abstract and article screening, createdorms to extract relevant data from articles, orga-ized Work Group member data extraction, checkedata, and tabulated results. Throughout the project,he ERT conducted seminars and provided instruc-ion on systematic review, literature searches, dataxtraction, assessment of quality and applicabilityf articles, evidence synthesis, and grading of theuality of evidence and strength of guideline recom-endations.

efinement of Topics and Developmentf Materials

The Work Group reviewed the 2000 KDOQIPGs forAnemia of CKD2 and determined whichf the guideline recommendations required up-ates and which could remain unchanged. Thesessessments were based primarily on expert opin-

* First Look

† Narrative Review ‡ Systematic Review

Fig 19. Process of triaging a topic to a systematiceview or a narrative review. *First Look Topic: Top-cs for which the substance of the evidence baseas unclear were first explored to determine theiruitability for systematic review. A sensitive Ovidearch was performed for each first look topic by theRT. Abstracts were reviewed by the Work Groupembers to determine whether there was an ad-

quately defined and sufficient base of scientificnformation from which to answer the clinically rel-vant question or resolve controversies. Topics thatualified were submitted to systematic review, while

opics lacking a sufficient evidence base for system-tic review were summarized by Work Group mem-ers in narrative reviews. †Narrative Review: Workroup members had wide latitude in summarizing

eviews and original articles for topics that wereetermined not to be amenable to a systemic reviewf the literature. Under special circumstances, fo-used literature search was performed by ERT for apecific subtopic. ‡Systematic Review: A system-tic review entailed systematic screening, data ab-traction, appraisal, and synthesis of studies in sum-ary tables and evidence profiles.

on regarding the likelihood of new evidence e

eing available. When experts were uncertainbout the current evidence basis of a topic, afirst look” of the topic was undertaken to informhis process (Fig 19). After literature review ofotentially relevant abstracts and studies, mem-ers of the Work Group focused the specificuestions deemed clinically relevant and ame-able to systematic review or decided to producenarrative summary of the literature.The Work Groups and ERT developed: (1)

raft guideline statements, (2) draft rationaletatements that summarized the expected perti-ent evidence, and (3) data extraction formsequesting the data elements to be retrieved fromhe primary articles. The topic refinement pro-ess began before literature retrieval and contin-ed through the process of reviewing individualrticles.

iterature Search

A master reference list was compiled fromeferences used in previous evidence-based guide-ines on Anemia and CKD:

1. EBPG II, 20042. EBPG I, 20003. KDOQI Anemia Guideline Update, 20004. DOQI Anemia Guideline, 19975. Caring forAustralasians with Renal Impair-

ment (CARI) Anemia Guideline, 2003

For the topics addressed in EBPG II, updateearches of MEDLINE were performed. Forb Targets, a module for (Anemia and ESA

nd Kidney) was run on articles from January003 through March 2004. Selective updatesf literature searches were performed throughovember 2004. A pre-MEDLINE search alsoas performed to capture more recent trialsot yet indexed in MEDLINE. For the topic ofron Targets, the (Anemia and ESA and Kid-ey) module was modified by adding addi-ional iron terms and was run to include publi-ations between January 2003 and November004. For the topics of adjuvants to ESAreatment, a MEDLINE search was conductedor [(Anemia and Kidney) and (Androgens,tatins, Carnitine, Vitamin E, or Ascorbiccid)] for all articles published from Janu-

ry1989 through September 2004. A separateearch for studies on prevalence of anemia by
GFR was conducted from January 1999

tsG

waSsb

mp4PGtta

G

tmscsaroqcaGaaGd

G

dsctiaWoatemt

F

ifi4iar

fiasta

tmbdg

.5)

APPENDIX 1: METHODS OF EVIDENCE REVIEW AND SYNTHESIS S119

hrough February 2005. The searches also wereupplemented by articles identified by Workroup members through September 2005.Only full journal articles of original dataere included. Editorials, letters, abstracts,

nd unpublished reports were not included.elected review articles identified in theearches were provided to the Work Group forackground material.MEDLINE search results were screened byembers of the ERT for relevance by using

redefined eligibility criteria, described in Table4. Retrieved articles were screened by the ERT.otentially relevant studies were sent to Workroup members for rescreening and data extrac-

ion. Domain experts, along with the ERT, madehe final decision for inclusion or exclusion of allrticles.

eneration of Data Extraction Forms

Data extraction forms were designed to cap-ure information on various aspects of the pri-ary studies. Data fields for all topics included

tudy setting, demographics, eligibility criteria,auses of kidney disease, numbers of subjects,tudy design, study funding source, dialysis char-cteristics, comorbid conditions, descriptions ofelevant risk factors or interventions, descriptionf outcomes, statistical methods, results, studyuality (discussed later), study applicability (dis-ussed later), and free text field for commentsnd assessment of biases. Training of the Workroup members to extract data from primary

rticles occurred during Work Group meetingsnd by E-mail and teleconference calls. Workroup members then were assigned the task of

Table 43. Examp

Arm 1

Arm 2Author, Year N

CK

D S

tage

Bas

elin

e a

Hb

(g/d

L)

Follo

w-u

p (

mo)

App

licab

ility

Arm 3

Mean Hb(g/dL) Targ(Achieved

ESA vs. ESA

ESA High 14.0 (12.7-13.3Besarab, 1998 108 1,233 HD-CKD 10.2 14

ESA Low 10.0 (10.0

ESA High 13.5-14.5

(13.3) Parfrey, 2005 109 596 HD-CKD 11.0 24

ESA Low 9.5-11.5(10.9)

ESA High 13-14 (13Foley, 2000 110 146 HD-CKD 10.4 11

ESA Low 9.5-10.5 (10

ata extraction of articles. A

eneration of Evidence Tables

The ERT condensed the information from theata extraction forms into evidence tables, whichummarized individual studies. These tables werereated for the Work Group members to assisthem with review of the evidence and are notncluded in this document. All extracted articlesnd all evidence tables were made available to allork Group members. During the development

f the evidence tables, the ERT rescreened theccepted articles to verify that each of them methe initial screening criteria and checked the dataxtraction for accuracy. If the criteria were notet, the article was rejected, in consultation with

he Work Group.

ormat for Summary Tables

Summary tables describe the studies accord-ng to the following dimensions: study size andollow-up duration, applicability or generalizabil-ty, results, and methodological quality (see Table3). The ERT generated summary tables by us-ng data from extraction forms, evidence tables,nd/or the articles. All summary tables wereeviewed by the Work Group members.

In the summary tables, studies were orderedrst by method quality (best to worst), then bypplicability (most to least), and then by studyize (largest to smallest). Results are presented inheir appropriate metric or in summary symbols,s defined in the table footnotes.

To provide consistency throughout summaryables, data sometimes were converted or esti-ated. Follow-up times were converted to monthsy estimating 1 month as 4 weeks. In general,ata provided as percent Hct was converted intorams per deciliter of Hb by dividing by 3.

ummary Table

Clinical Outcomes (Arm 1 vs. Arm 2 vs. Arm 3)

vents ) LVH

Mortality (%)

Hospitali- zation

Dialysis Adequacy

Transfusion (%) QOL b Q

ualit

y

tal MI s. 2.3

c

—*29.6 vs.

24.4 NS c

NS∆Kt/V:

–0.03 vs. +0.06 P <0.001

21 vs. 31 P = 0.001

See QOL Table

A:s. 1 .045

CVD: S

*NS NS — ∆URR:

0 vs. +2 % P <0.05

—See QOL

Table

S *NS NS — Kt/V:

LVD: 1.41 vs. 1.50 P = 0.025

—See QOL

Table

le of a S

et )

CVD E(%

) )

*Nonfa3.1 v

NS

CV4 v

P = 0Other

N

) N

dditionally, results sometimes were estimated

fa

SC

ldt

L

saw8ib

ir

ag

A

S

opamsspspsc

A

o


rom graphs. All estimated values have beennnotated as such.

ystematic Review Topics, Study Eligibilityriteria

The topics covered by systematic review areisted in Table 44. The screening criteria wereefined by the Work Group members in conjunc-ion with the ERT.

iterature Yield

For systematic review topics, the literatureearches yielded 2,756 citations. Of these, 137rticles were reviewed in full. An additional 19ere added by Work Group members. A total of3 were extracted and of these, 51 studies arencluded in Summary Tables. Details of the yieldy topic can be found in Table 45.The literature search yields for first-look top-

cs can be found in Table 46. Upon reviewing theesultant abstracts, only the topics of noniron

Table 45. Literature Search Yield of Prim

Guideline Topic Search Strategy Dates a

1.1: Identifying patients and initiating evaluation

Anemia AND kidney AND GFR

1999-2005

2.1: Setting Hb targets Anemia AND kidney AND ESA search as update to

master reference list

2003-2004

3.2: Using iron agents

Anemia AND kidney AND ESA AND iron terms search as update to master reference list

2003-2004

3.3: Using pharmacological and nonpharmacological adjuvants to ESA treatment in HD-CKD

Anemia AND kidney AND androgens, statins, carnitine, vitamin E,

ascorbic acid

1989-2004

a. Additional articles were identified by work group members through September 20b. Does not include articles included in tables other than summary tables. c. Includes articles that were post hoc analysis of larger studies.

djuvants (carnitine, ascorbic acid, and andro-ens) proceeded to systematic review.

ssessment of Individual Studies

tudy Size and DurationThe study (sample) size is used as a measure

f the weight of a study. In general, large studiesrovide more precise estimates of prevalencend associations. In addition, large studies areore likely to be generalizable; however, large

ize alone does not guarantee applicability. Atudy that enrolled a large number of selectedatients may be less generalizable than severalmaller studies that included a broad spectrum ofatient populations. Similarly, longer durationtudies may be of better quality and more appli-able, depending on other factors.

pplicabilityApplicability (also known as generalizability

r external validity) addresses the issue of whether

ticles for Systematic Review Topics

tracts ened

FullArticles

Retrieved

Articles Added by experts

Articles Data

Extracted

Articles Included in Summary Tables b

25 13 3 6 6

013 38 2 28 24 c

848 50 6 34 9

70 36 8 15 12

ary Ar

AbsScre

1

2,

1,

3

05.

ttocednswmppw3swtgeps

S

t

sds

aReboicnws

saati

R

dt


he study population is sufficiently broad so thathe results can be generalized to the populationf interest at large. The study population typi-ally is defined primarily by the inclusion andxclusion criteria. The target population wasefined to include patients with anemia and kid-ey disease and subdivided into those with CKDtages 3 to 5 not on dialysis therapy and thoseith CKD stage 5 on HD or PD therapy. Further-ore, topic 3.6 includes such special patient

opulations as kidney transplant recipients andatients with nonrenal anemias. Applicabilityas specified for each study according to a-level scale (Table 45A). In making this as-essment, sociodemographic characteristicsere considered, as well as comorbid condi-

ions and prior treatments. Applicability israded in reference to the population of inter-st as defined in the clinical question. Targetopulations are specified in the titles of eachummary table (discussed later).

tudy QualityMethod quality (or internal validity) refers to

he design, conduct, and reporting of the clinical

Table 46. Details of First-Look Topi

rtS hcraeS cipoTPediatric patients Anemia AND kidneySpecial populations: transplant

Anemia AND kidney

A yendik DNA aimenA ycnangerP

Sickle cell/ hemoglobinopathies Anemia AND kid

hemoglobino yendik DNA aimenA VIH

Cancer: MM, MDS, etc. Anemia AND kidneyDNA aimenA ssenevisnopseropyHsalpa llec der eruP ACRP

latoT

tudy. Because studies with a variety of types ofesign were evaluated, a 3-level classification oftudy quality was devised (Table 46A).

Quality of studies of interventions. The evalu-tion of questions of interventions was limited toCTs. The grading of these studies included consid-ration of the methods (ie, duration, degree oflinding, number and reasons for dropouts, and son), population (ie, does the population studiedntroduce bias?), outcomes (ie, are the outcomeslearly defined and properly measured?), thorough-ess/precision of reporting, statistical methods (ie,as the study sufficiently powered and were the

tatistical methods valid?), and the funding source.Quality of studies of prevalence. The ideal

tudy design to assess prevalence of anemia and itsssociation with eGFR is a cross-sectional study ofpopulation representative of the general popula-

ion. Criteria for evaluation of cross-sectional stud-es to assess prevalence are listed in Table 47.

esultsThe type of results used from a study was

etermined by the study design, the purpose ofhe study, and the question(s) being asked for

id Literature Searches, and Yield by Topic

setaDNo. of

Citations

Relevant Abstracts

Submitted to Experts for

Review ildren 1989-2004 2,101 192

splant 1989-2004 680 107

01 602 4002-9891 ycnan

1989-2004 582 20

21 822 4002-9891 SDIA/ncer 1989-2004 1,557 15

64 895,1 4002-1002 641 881 4002-3002 AC 845 041,7

cs, Ov

ygeta AND ch

AND tran

gerp DNney AND

pathies VIH DNA

AND ca yendik RP RO ai

wbo

SO

s

G

d4““

tsgb

RS

eoattto

ability of


hich the results were used. Decisions wereased on the screening criteria and prespecifedutcomes of interest (Table 47).

ummarizing Reviews and Selectedriginal Articles

Work Group members had wide latitude inummarizing reviews and citing original articles.

uideline Format

The format for each section containing an evi-ence-based guideline or a CPR is outlined in Table8. Each guideline contains 1 or more specificguideline or statements,” which are presented asbullets” that represent recommendations to the

Table 47. Evaluation

Evaluation of Validity Cross-sectional study design Was there a representative and well-defin

• Minimize nonresponse • Define sampling strategy • Subgroups defined in advance

Were objective and unbiased criteria useWere methods for data collection appliedWas there adjustment for important prognEvaluation of Results How large is the prevalence of cases? How precise are the estimates of prevaleAre there important differences among suEvaluation of Clinical ApplicabilityIs the population, or subgroups of the popfrom which my patients are drawn? Were the definitions and measures usefuAre the results useful for estimating prob

Table 48. Form

Introductory Statement Guideline or CPR Statement Guideline or CPR Statement

BACKRAT

Definitions (if appropriate) Strength of Evidence Rationale statement 1

Supporting text, summa(where applicable) and d

Rationale statement 2 Supporting text, summaapplicable) and descript

LIMITATI

arget audience. Implementation issues and re-earch recommendations were formulated after thisuideline document had been completed and wille presented in another supplement.

ating the Quality of Evidence and thetrength of Guideline Recommendations

A structured approach, facilitated by the use ofvidence profiles and modeled after the Gradesf Recommendation, Assessment, Developmentnd Evaluation (GRADE) approach,461 was usedo grade the quality of the overall evidence andhe strength of recommendations. For each topic,he discussion on grading of the quality of theverall evidence and the strength of the recom-

dies of Prevalence

le of the population of interest?

e cases and controls? o all study participants? tors?

?

under study similar to the population

ice? disease?

r Guidelines

ngth of recommendation) ngth of recommendation) UNDLE

les and evidence profiles tion of quality of evidence

es and evidence profiles (where quality of evidence

of Stu

ed samp

d to defin equally tostic fac

nce? bgroups ulation,

l in pract

at fo

1 (stre2 (streGROIONA

ry tabescrip

ry tablion of

ONS

meGa

G

prveosbqqtliriwthqpm

tfe

otErbcw

ttmeGjWsptnmqotb

amatfg


endations was led by the primary expert review-rs of each topic, with participation by the Workroup chairs, all other Work Group members,

nd the ERT members.

rading the Quality of Evidence

The quality of a body of evidence pertaining to aarticular outcome of interest initially was catego-ized based on study design. For questions of inter-entions, the initial quality grade was high if thevidence consisted of RCTs, low if it consisted ofbservational studies, or very low if it consisted oftudies of other study designs. Work Group mem-ers decided a priori to include only RCTs foruestions of interventions other than harm. Theuality rating for each intervention/outcome pairhen was decreased if there were some or seriousimitations to the quality of the aggregate of stud-es, there were important inconsistencies in theesults across studies, the applicability of the stud-es to the population of interest was limited or thereas uncertainty about the directness of evidence,

he data were imprecise or sparse, or there was aigh likelihood of bias. The final grade for theuality of the evidence for an intervention/outcomeair could be 1 of the following 4 grades: high,oderately high, low, or very low.The quality of the overall body of evidence

hen was determined based on the quality gradesor all outcomes of interest, taking into accountxplicit judgments about the relative importance

Table 49. Balance

When there was enough evidence to determine the balance of following conclusions were drawn:

• There is net benefit • There is no net benefit • There is net harm

When there is not enough or not enough good quality evidenceharm), then the balance of benefit and harm was classified as:

• It is uncertain that there is benefit

Table 50. Definitions of Grad

Grade Definition High Further research is unlikely to chanModerately High Further research is likely to have an

may change the estimate. Low Further research is very likely to ha

and is likely to change the estimate
Very Low Any estimate of effect is very uncertain
f each of the outcomes (eg, death and accesshrombosis having greater weight than change inSA dose or Hb level). The actual results were

eviewed for each outcome to judge the balanceetween benefits and harm (Table 49). Four finalategories for the quality of overall evidenceere used, as shown in Table 50.Evidence profiles were constructed by the ERT

o record decisions about grades and interpreta-ion of summary effects by the Work Groupembers. These profiles serve to make transpar-

nt to the reader the thinking process of the Workroup in systematically combining evidence and

udgments. Each evidence profile was filled in byork Group experts with ERT guidance. Deci-

ions were based on facts and findings from therimary studies listed in corresponding summaryables; additional information related to AEs inontarget populations, when applicable; and judg-ents of the Work Group. Judgments about the

uality, consistency, and directness of evidenceften were complex, as were judgments abouthe importance of an outcome or the net medicalenefit across all outcomes.The evidence profiles provided a structured

pproach to grading, rather than a rigorousethod of quantitatively summing up grades. In

n effort to balance simplicity with full andransparent consideration of the important issues,ootnotes were placed to provide the rationale forrading (Table 51).

enefit and Harm

l benefits and harm of an intervention to a patient, one of th

h benefit and harm (for example, inconsistency, unclear

Quality of Overall Evidence

onfidence in the estimate of effect. ant impact on our confidence in the estimate of effect and

portant impact on our confidence in the estimate of effect

of B

medica

to weig

es for

ge our c import

ve an im.

G

apgdtidwwfrt

tsrtqmscgqmsbcgpsaabg

oa

drgew

qaeWcdWtttspqrs

L

cLwsvakt


rading the Strength of the Recommendations

The quality of evidence for each outcome andcross all outcomes was graded in the evidencerofile. The guideline recommendation wasraded based on the quality of the overall evi-ence, as well as additional considerations. Addi-ional considerations, such as feasibility, availabil-ty of a service, and regional and populationifferences were implicitly considered. Costs alsoere considered implicitly, but, in most cases, itas believed that the grading of the evidence and

ormulation of a guideline and its strength shouldest primarily on the evidence for medical benefito a patient.

The strength of each guideline recommenda-ion was rated as either “strong” or “moderatelytrong.” A “strong” rating indicates “it is stronglyecommended that clinicians routinely followhe guideline for eligible patients. There is high-uality evidence that the practice results in netedical benefit to the patient.” The “moderately

trong” rating indicates “it is recommended thatlinicians routinely follow the guideline for eli-ible patients. There is at least moderately high-uality evidence that the practice results in netedical benefit to the patient.” Overall, the

trength of the guideline recommendation wasased on the extent to which the Work Groupould be confident that adherence will do moreood than harm. Strong guidelines require sup-ort by evidence of high quality. Moderatelytrong guidelines require support by evidence oft least moderately high quality. Incorporation ofdditional considerations modified the linkageetween quality of evidence and strength of

Tabl

Outcome No. of Studies &

Study Design

Total N of

Patients

Methodological Quality of Studies

Consistency across Studies

DirectEvidinclu

Applic

Hb/Hct Level / ESA dose

3 RCTs 63 Serious

limitations aImportant

inconsistencies b Dire

AEs


General population: trials, case reports, narrative reviews

63+ Mild to severe AEs noted in RCTs included se

from androgens in non-CKD populations which carcinoma. Mechanism of action and pro


Footnotes: a. 1 Grade B and 2 Grade C studies.b. Statistically significant effect with only 1 of 3 studies. c. The studies used different ESA and iron protocols and had different definitions for the Hb/Hct outcome. d. The studies used different ESA and iron protocols and had different definitions for the Hb/Hct outcome. e. Aspartate transaminase

uidelines, usually resulting in a lower strength a

f the recommendation than would be support-ble based on the quality of evidence alone.

After grading the quality of the overall evi-ence for a topic, the Work Group triaged theecommendations to either an evidence-baseduideline recommendation when the quality ofvidence was high or moderately high or other-ise to an opinion-based CPR.In the absence of strong or moderately strong

uality evidence or when additional consider-tions did not support strong or moderately strongvidence-based guideline recommendations, theork Group could elect to issue CPRs based on

onsensus of expert opinions. These recommen-ations are prefaced by “In the opinion of theork Group,” and are based on the consensus of

he Work Group that following the recommenda-ions might improve health outcomes. As such,he Work Group recommends that clinicians con-ider following the recommendation for eligibleatients. Issues considered in the grading of theuality of the evidence and the strength of theecommendation are discussed in the Rationaleection of each recommendation.

imitations of Approach

While the literature searches were intended to beomprehensive, they were not exhaustive. MED-INE was the only database searched, and searchesere limited to English-language publications. Hand

earches of journals were not performed, and re-iew articles and textbook chapters were not system-tically searched. However, important studiesnown to the domain experts that were missed byhe electronic literature were added for consider-

mple of an Evidence Profile

Summary of Findings

OtherConsiderations


Outcome Qualitative Description of Effect Size Importance of

Outcome


No consistent benefit. Only 1 of 3 papers showing significant between-arm

comparison in Hb/Hct (difference in Hb of 1.6 g/dL). c

Moderate

levated AST e, discomfort at injection site. This is consistent with reported AEs zation, priapism, peliosis hepatis, liver enzyme abnormalities, and hepatocellular f androgens are believed to be similar in non-CKD and CKD populations.

High


e 51. Exa

ness of ence, ding ability

ct c,d

vere acne, einclude virilifile of AEs o

tion.

Jtto1Mowss1faiHmhpotAmtmIe1bFviCrapfc

Plitdnaprpm

S

WORK GROUP BIOGRAPHIES

KGPHPmtatSpcsRa

WcMHAoctcogDDpkwoRaDaNcwgOA

CNoh

ohn W. Adamson, MD, has served as Execu-ive Vice President for Research and Director ofhe Blood Research Institute of the Blood Centerf Southeastern Wisconsin in Milwaukee since998. He holds the position of Professor ofedicine (Hematology) at the Medical College

f Wisconsin. Before moving to Milwaukee, heas Director of the Lindsley F. Kimball Re-

earch Institute of the New York Blood Centerince 1989 and President of the Center from989 to 1997. Dr Adamson received his MDrom the University of California, Los Angeles,fter which he trained at the University of Wash-ngton in Seattle and at the National Institutes ofealth in Bethesda, MD, in the fields of internaledicine and hematology. Before assuming

is position in New York, Dr Adamson wasrofessor of medicine and head of the Divisionf Hematology at the University of Washing-on. Dr Adamson is a past-President of themerican Society of Hematology and past chair-an of its committees on scientific affairs and

ransfusion medicine. Dr Adamson served as aember of the Advisory Council of the National

nstitute of Diabetes, Digestive and Kidney Dis-ases of the National Institutes of Health. In988, he was designated clinical research professory the American Cancer Society and elected aellow of the American Association for the Ad-ancement of Science. Dr Adamson is past editor-n-chief of Blood, past editor of the Journal ofellular Physiology, and founding editor of Cur-

ent Opinion in Hematology. Altogether, he hasuthored or co-authored more than 400 scientificublications. Dr Adamson has received researchunds, grants, or contracts from Watson Pharma-euticals and Navigant Biotechnologies.

George R. Bailie, MSc, PharmD, PhD, isrofessor of Pharmacy Practice at Albany Col-

ege of Pharmacy. He has 20 years of experiencen teaching, practice, and research in pharmaco-herapeutics and pharmacokinetics in CKD andialysis. He has published more than 100 origi-al research papers, plus numerous chapters,bstracts, reviews, and cases in the medical andharmacy literature. He has served on the edito-ial board and is a regular reviewer for manyharmacy and nephrology journals. Dr Bailie is a
ember of the Advisory Board for the NKF- s

DOQI. He was a member of the KDOQI Workroup that developed the guidelines for Bloodressure and Antihypertensive Agents in CKD.e is a member of the International Society oferitoneal Dialysis’ Work Group for the Manage-ent of Peritonitis. He was designated Fellow of

he Royal Pharmaceutical Society of Great Brit-in for his sustained contributions to the litera-ure of pharmacy and is a Fellow of the Americanociety of Nephrology. He is a director of Ne-hrology Pharmacy Associates, Inc, a privateonsulting company. Dr Bailie has received re-earch funds, grants or contracts from Renalesearch Institute, American Regent, Genzymend Omnicare.

Jeffrey S. Berns, MD, earned his MD at Caseestern Reserve University, then went on to

omplete his internship and residency in Internaledicine at University Hospitals of Cleveland.e did a fellowship in Nephrology and was anssociate Research Scientist in the Departmentf Physiology at Yale University. Dr Berns re-ently was promoted to Professor of Medicine athe University of Pennsylvania School of Medi-ine, where he is Director of Clinical Nephrol-gy and Director of the Renal Fellowship Pro-ram for the Renal, Electrolyte and Hypertensionivision. Dr Berns was a member of the NKF-OQI and KDOQI Anemia Workgroup. He hasublished and lectured on topics related to chronicidney disease, anemia management in patientsith CKD, and other areas in clinical nephrol-gy. He is co-editor of Drug Prescribing inenal Failure-Dosing Guidelines for Adults. Helso serves on the editorial board of Seminars inialysis, American Journal of Kidney Diseases,

nd Clinical Journal of the American Society ofephrology. He is an active investigator in clini-al trials related to anemia treatment in patientsith CKD. Dr Berns has received research funds,rants or contracts from Hoffman La Roche,rtho Biotech, Advanced Magnetics, Inc., andmgen.Kai-Uwe Eckardt, MD (Work Group Co-

hair), is Professor of Medicine and Chief ofephrology and Hypertension at the Universityf Erlangen–Nuremberg, Germany. He receivedis MD from the Westfälische Wilhelms-Univer-
ität Münster, Germany. In 1993, following post-

goPRuoloipoPotcAertatsC

NmtoMDdsNpgCCDmDoLat

ascJpM

2fAsFnocattoR

PLrtIScetetseAcrAAKmU

t1iatTasaNarki

WORK GROUP BIOGRAPHIES S127

raduate training in internal medicine, pathol-gy, and physiology, he was appointed Assistantrofessor of Physiology at the University ofegensburg, Germany. Subsequently, he contin-ed his training in internal medicine and nephrol-gy at the Charité, Humboldt University in Ber-in, where he was appointed Associate Professorf Nephrology in 2000. His major scientificnterests are in the molecular mechanisms andhysiological/pathophysiological relevance ofxygen sensing and the management of anemia.rofessor Eckardt is Subject Editor of Nephrol-gy, Dialysis and Transplantation and serves onhe editorial board of several other journals. Heontributed to the development of the EBPGs fornemia Management and is a member of the

xecutive committee of KDIGO. Dr Eckardt haseceived research funds, grants or contracts fromhe German Research Organization. Addition-lly, Dr Eckardt has received lecture and consul-ant fees from Amgen, Roche, Johnson & John-on, and Affymax. He is also associated withREATE and TREAT studies.Steven Fishbane, MD, currently is Chief of

ephrology and Associate Chair of the Depart-ent of Medicine at Winthrop-University Hospi-

al (WUH) in Mineola, NY, as well as Professorf Medicine at SUNY Stony Brook School ofedicine. He is the Medical Director of WUHialysis Network, which includes 4 outpatientialysis units and 3 hospital units. Dr Fishbaneerves as the Chairman of the Long Island Healthetwork Quality Council; Chairman of the De-artment of Medicine Quality Improvement Pro-ram, WUH; Chairman of Clinical Guidelinesommittee, WUH; Co-Chairman of WUH Patientare Committee; and Associate Chairman of theepartment of Medicine, WUH. Dr Fishbane is aember of the Network 2 Medical Review Board.r Fishbane has received research funds, grantsr contracts from Shire Inc., Amgen Inc., Abbottabs Inc., Roche Inc., and Watson Inc. Addition-lly, Dr Fishbane is associated with Ortho Bio-ech and Watson Pharmaceuticals.

Robert N. Foley, MD, was born in Irelandnd received his undergraduate MD from Univer-ity College Cork. He completed Internal Medi-ine training in Cork, later moving to Saintohn’s, Newfoundland, Canada, where he com-leted a residency in nephrology, as well as a
asters in Clinical Epidemiology. From 1999 to d
002, Dr Foley worked at Hope Hospital, Sal-ord, UK, and has been Director, Nephrologynalytical Services, Minneapolis Medical Re-

earch Foundation since September of 2002. Droley also is a Co-Editor of the American Jour-al of Kidney Diseases. His major interest is inutcomes research, especially the interplay ofardiovascular and renal disease. Dr Foley isctive in anemia correction trials, as well as inhe USRDS Cardiovascular Special Study Cen-er. Dr Foley has received research funds, grantsr contracts from Ortho Biotech, Amgen andoche.Sana Ghaddar, PhD, RD, is an Assistant

rofessor at the American University of Beirut,ebanon. She has over 10 years experience in the

enal and clinical dietetics field. She was one ofhe renal dietitians at the Peninsula Nephrologync., in San Mateo, CA, currently a division ofatellite Healthcare, and has served as a Prin-iple Investigator for two research studies thatxamined the ability of heme-iron-polypeptideo sustain response to Recombinant Erythropoi-tin in both hemo and peritoneal dialysis pa-ients. She has presented these and other studieshe has been involved in at many national confer-nces, including National Kidney Foundation,merican Dietetics Association and Gerontologi-al Society of America. Dr Ghaddar has receivedesearch funds, grants or contracts from themerican University of Beirut Research Board.dditionally, Dr Ghaddar is associated with theidney Nutrition Education & Life Improve-ent (K/NELI) study funded by the Americannivesity of Beirut.John S. Gill, MD, MS, obtained his MD from

he University of British Columbia (UBC) in995. He completed his internal medicine train-ng at the University of Western Ontario in 1998nd his nephrology training in 2000 at UBC. Hehen completed his transplantation training atufts–New England Medical Center in Bostonnd obtained in Masters in Clinical Care Re-earch from Tufts in 2002. Dr Gill currently isssistant professor of medicine in the division ofephrology at UBC and has a cross appointment

t Tuft–New England Medical Center. Dr Gill’sesearch interests focus on clinical outcomes inidney transplant recipients. He is the principalnvestigator and co-investigator on current Cana-
ian Institutes of Health Research (CIHR), Kid-

niTddBCgFIc

wdmaTdDCoMlCoWas

taPaoaeBE

msCttKoieiEc

lrPAbaaTeaTrHsaHsg

apfMAnoMiNGpEga

BgeadthrmMgrtat

WORK GROUP BIOGRAPHIESS128

ey Foundation, and Michael Smith Funded stud-es. Dr Gill is chair of the Canadian Society ofransplantation Work Group for Pan-Canadianatabase development, member of the Cana-ian Organ Replacement Register Advisoryoard, and member of a number of NKFommittees. Dr Gill received research funds,rants or contracts from the Michael Smithoundation for Health Research, the Canadiannstitute for Health Research, Wyeth Pharma-euticals, and Roche Pharmaceuticals.Kathy Jabs, MD, is a Pediatric Nephrologist

ho trained at Babies Hospital, NY, and Chil-ren’s Hospital, Boston. She has been a facultyember at Children’s in Boston (1988 to 1996)

nd was the Director of Dialysis and Renalransplantation at Children’s Hospital of Phila-elphia (1996 to 2000). She currently is theirector of Pediatric Nephrology at Vanderbilthildren’s Hospital and an Associate Professorf Pediatrics at Vanderbilt University School ofedicine, Nashville, TN. Dr Jabs has had a

ong-standing interest in the care of children withKD. Dr Jabs has received research funds, grantsr contracts from King Pharmaceuticals andatson Pharmaceuticals. Additionally, Dr Jabs is

ssociated with the CKid and FSGS studies spon-ored by the NIH.

Francesco Locatelli, MD, is Scientific Direc-or and Head of the Department of Nephrologynd Dialysis of A. Manzoni Hospital, Lecco, andostgraduate Professor of Nephrology at Bresciand Milan Universities in Italy. He is past-Presidentf the European Renal Association–European Di-lysis and TransplantationAssociation, Italian Soci-ty of Nephrology, and International Society oflood Purification and was Chairman of theBPGs.Iain C. Macdougall, MD, is a combinededical and science graduate of Glasgow Univer-

ity, Scotland, from which he was awarded a Firstlass Honours BSc in Pharmacology in 1980. For

he last 10 years, Dr Macdougall has been Consul-ant Nephrologist and Honorary Senior Lecturer ating’s College Hospital in London. He has devel-ped both a clinical and a basic science researchnterest in factors affecting responsiveness torythropoietic agents. He has served on the Work-ng Parties responsible for both (1999 and 2004)BPGs on Renal Anaemia Management, and he
urrently is a member of the US Anemia Guide- e
ines Working Group, the KDIGO Board of Di-ectors, the Global Scientific Advisory Board forRCA, and the Council of the European Renalssociation. He is frequently invited to lectureoth nationally and internationally on this topic,nd he has co-authored the section on renalnaemia for the last 2 editions of the Oxfordextbook of Clinical Nephrology and the currentdition of Comprehensive Clinical Nephrology. Helso is Subject Editor for Nephrology Dialysisransplantation. Dr Macdougall has receivedesearch funds, grants or contracts from Amgen,offman La Roche, Affymax, Vifor, and John-

on & Johnson. Additionally, Dr Macdougall isssociated with the CERA (Phase III), OPUS,ematide (Phase II), TREAT (Phase IV) studies

ponsored by Roche, Amgen, Affymax, and Am-en, respectively.Patricia Bargo McCarley, RN, MSN, NP, isnephrology nurse practitioner at Diablo Ne-

hrology Medical Group in Walnut Creek, Cali-ornia. Ms. McCarley received her BSN and

SN from Vanderbilt University. She is active inNNA having served on local, regional andational committees. She is currently a memberf the Nephrology Nursing Journal Board. Ms.cCarley has authored many publications includ-

ng most recently chapters in the 2005 ANNAephrology Nursing Standards of Practice anduidelines for Care and the Contemporary Ne-hrology Nursing: Principles and Practice (2nd

d.). Dr McCarley has received research funds,rants or contracts from Amgen, Ortho Biotechnd Renal Care Group.

Hans H. Messner, MD, is the Director of thelood and Marrow Program at the Princess Mar-aret Hospital. He has a long-standing interest inxploring the role of transplantation in the man-gement of patients with various hematopoieticiseases. In the laboratory, he has used cultureechniques to examine normal and malignantematopoietic progenitor cell populations. In theecent past, he has been involved in the establish-ent of a cell-processing facility at the Princessargaret Hospital that meets the standards of

ood manufacturing practices (GMP). This labo-atory will facilitate clinical skill of cell separa-ion procedures, cell expansions, and vector trans-ctions into relevant cell populations. Thisechnology also will be instrumental in faciliting
xplorations of regenerative capability of stem

crO

ogUsNrUcsCCDhEtPviPrtsP1tatmsihdNrChitEmctttddi

mdpmSgR

sPCDgMcfCUaamtmtasamanSnmKga

OAoUSfhUahote

WORK GROUP BIOGRAPHIES S129

ells for other organ systems. Dr Messner haseceived research funds, grants or contracts fromrtho Biotech.Allen R. Nissenson, MD, FACP, is Professor

f Medicine and Director of the Dialysis Pro-ram at the David Geffen School of Medicine atCLA, where he has developed a comprehen-

ive dialysis program. He is President of theational Anemia Action Council (NAAC) and

ecently chaired a Chancellor’s committee atCLA on Financial Conflicts of Interest in Clini-

al Research. He currently is serving on a Univer-ity of California Task Force on Institutionalonflicts of Interest in Research. Dr Nissenson ishair of the Faculty Executive Council for theavid Geffen School of Medicine at UCLA. Heas served as Chair of the Southern CaliforniaSRD Network during its organizational years in

he early 1980s and recently was elected asresident-elect. He is Chair of the Medical Re-iew Board. Dr Nissenson currently is consult-ng for RMS Disease Management, Inc and forhiltre, Ltd, an organization developing newenal replacement therapies based on the applica-ion of nanotechnology to this field. Dr Nissen-on served as a Robert Wood Johnson Healtholicy Fellow of the Institute of Medicine in994 to 1995. He is Immediate Past President ofhe Renal Physicians Association and has serveds a member of the Advisory Group overseeinghe entire NKF-DOQI, as well as serving as aember of the anemia Work Group. Dr Nissen-

on’s major research interests focus on the qual-ty of care for patients with CKD. His researchas included extensive clinical trials of newevices and drugs related to renal disease. Drissenson is co-principal investigator on a

ecently obtained National Institutes of Healthenter Grant looking at issues of disparities inealth care delivery for patients with CKD. Hes the author of 2 dialysis textbooks, both inheir fourth editions, and was the foundingditor-in-Chief of Advances in Renal Replace-ent Therapy, an official journal of the NKF. He

urrently is Editor-in-Chief of Hemodialysis In-ernational, the official journal of the Interna-ional Society for Hemodialysis. He has morehan 340 publications in the field of nephrology,ialysis, anemia management, and health careelivery and policy. Among his numerous honors
s the President’s Award of the NKF. He delivers t
ore than 25 invited lectures each year andeveloped and chairs an annual second-year ne-hrology fellows preceptorship program, servingore than 65 Fellows from throughout the Unitedtates. Dr Nissenson has received research funds,rants or contracts from Amgen, Ortho Biotech,oche, Watson and ARL.Gregorio T. Obrador, MD, MPH, is Profes-

or of Medicine and Dean at the Universidadanamericana School of Medicine in Mexicoity. He also serves as Adjunct Staff at theivision of Nephrology of the Tufts–New En-land Medical Center and Assistant Professor ofedicine at the Tufts University School of Medi-

ine in Boston. While doing a clinical researchellowship at the Tufts–New England Medicalenter and a Master of Public Health at Harvardniversity, he began a line of investigation in the

rea of CKD. Through several publications, hend others showed that the pre–ESRD manage-ent of patients with CKD is suboptimal, and

hat this is an important factor for the highorbidity and mortality observed in these pa-

ients. A particular area of interest has beennemia management before the initiation of dialy-is therapy. By using population registry data, hend his colleagues have reported trends in ane-ia and iron management. Dr Obrador has served

s reviewer for several journals, including Kid-ey International, the Journal of the Americanociety of Nephrology, and the American Jour-al of Kidney Diseases. He also has been aember of the Advisory Board of the NKF-DOQI. Dr Obrador has received research funds,rants or contracts from Amgen, and is associ-ted with the TREAT study.

John C. Stivelman, MD, is Chief Medicalfficer of the Northwest Kidney Centers andssociate Professor of Medicine in the Divisionf Nephrology, Department of Medicine, at theniversity of Washington School of Medicine ineattle. Dr Stivelman obtained his MD degreerom the University of Pennsylvania, completedis residency in Internal Medicine at Harbor-CLA Medical Center, and nephrology training

t Brigham and Women’s Hospital. Dr Stivelmanas been involved in investigative efforts toptimize hematopoietic therapy for dialysis pa-ients since the phase III recombinant erythropoi-tin trials in 1986. His major interests and litera-
ure contributions center on iron utilization,

mtttmMFHNtoNSc

CtTiWzrpfwaaaOptG

tsGFlonmmamsIc

gcBcOpcPiHicaaHM

WORK GROUP BIOGRAPHIESS130

echanisms of resistance of erythropoietinherapy, improved dialytic survival in disadvan-aged populations, and the interaction of regula-ory issues with optimization of care. Dr Stivel-an has served as the Chair of the Network 6edical Review Board and a member of the

orum of ESRD Networks Board of Directors.e currently serves as medical director of one oforthwest Kidney Centers’ free-standing facili-

ies and as a member of the Boards of Directorsf the Renal Physicians’ Association and theorthwest Renal Network (Network 16). Drtivelman has received research funds, grants orontracts from Watson, Amgen and Shire.

David B. Van Wyck, MD (Work Group Co-hair), is Professor of Medicine and Surgery at

he University of Arizona College of Medicine inucson. After completing his undergraduate stud-

es at Washington University, St Louis, Dr Vanyck earned his MD at the University of Ari-

ona College of Medicine. There, he undertook aesearch fellowship in Surgical Biology and com-leted his residency in Internal Medicine andellowship in Nephrology. Dr Van Wyck hasritten or contributed to books, book chapters,

rticles, and abstracts on basic iron metabolismnd reticuloendothelial function and on clinicalspects of iron and anemia in patients with CKD.n the subject of anemia and kidney disease, heursues research, provides consultation to indus-ry including American Regent, Amgen, and
ambro Healthcare, and reviews manuscripts for t
he major nephrology journals. Dr Van Wyckerved on the original KDOQI Anemia Workroup. He assumed Chair responsibilities in 2002.requently invited to speak, Dr Van Wyck hasectured on the molecular and cellular controlf erythropoiesis and iron homeostasis, diag-ostic and treatment issues in anemia and ironanagement, protocol development in the treat-ent of dialysis-associated anemia, and new

pproaches to iron and erythropoietin replace-ent therapy. Dr Van Wyck has received re-

earch funds, grants or contracts from Amgennc., American Regent Inc., Gambro Health-are and Shire Pharmaceuticals.Colin T. White, MD, is a pediatric nephrolo-

ist at BC Children’s Hospital in Vancouver andlinical assistant professor at the University ofritish Columbia in Canada. He completed medi-al school in Ottawa and Pediatrics in London,ntario. There, he did 3 years of pediatric ne-hrology training before moving to Vancouver toomplete 3 more years. He has been on staff as aediatric Nephrologist since 2003 and currently

s the Director of Dialysis at BC Children’sospital. He has a number of research interests,

ncluding medical education, optimizing dialysisare in children, estimation of GFR, and CKDnd its complications. Dr White’s interest innemia management is geared toward children.e is presently completing a Masters degree inedical Education. Dr White is associated with

he CKid study and various NAPRTC protocols.

TopwsiAtRt

rAAPnRDCNBMgMLLLL

A

ACKNOWLEDGMENTS

DAMNfPMASSMREWMWC

iri

tsGp

he Work Group appreciates the careful reviewf the draft guidelines and suggestions for im-rovement by external reviewers. Each commentas carefully considered and, whenever pos-

ible, suggestions for change were incorporatednto the final report. As a result, the KDOQInemia in Chronic Kidney Disease guidelines is

he product of the Work Group, the Evidenceeview Team, the NKF, and all those who con-

ributed their effort to improve the Guidelines.The following individuals provided written

eview of the draft guidelines: Nihal Younisbosaif, MD, Harith Aljebory, MD, Beth Annvanzado, BSN, RN, CNN, George R. Bailie,harmD, PhD, Beth Bandor McCarthy, RN, Vi-od K. Bansal, MD, Sally Burrows-Hudson, MS,N, Carlos A. Caramelo, Dennis Cotter, MSE,aniel W. Coyne, MD, Robert E. Cronin, Vetaumbaa, RN, BA, CCA, Mike Cunningham,eval Duman, MD, Earl J. Dunnigan, MD, FACP,riggett C. Ford, Cheryl Gilmartin, PharmD,arc Giovannini, Takanobu Imada, Atul V. In-

ale, MD, Mark Kasselik, MD, Pam Kimball,D, Janice Knouff, RN, BS, Chn, Craig B.

angman, MD, David J. Leehey, MD, Nathan W.evin, MD, FACP, Yao-Lung Liu, MD, Francescoocatelli, MD, Gerard M. London, MD, Victor
orenzo, MD, Samir G. Mallat, MD, FASN, i

onna Mapes, DNSc, MS, Luz Maria Munoz,letha Matsis, BSN, RN, CNN, Seiichi Matsuo,D, Marva M. Moxey-Mims, MD, Andrew S.arva, MD, Suzanne Norby, MD, Nancy J. Pel-

rey, MSN, NP, Allen G. Peplinski, Suannaetroff, Luana Pillon, MD, Francesco Pizzarelli,D, Karthik Ranganna, MD, Pawan Rao, MD,nton C. Schoolwerth, MD, FAHA, Douglaschram, MD, Stephen Seliger, MD, Surendralalhah, MD,Amita Sharma, MD, Bhupinder Singh,D, Leah Smith, Stephanie J. Stewart, MSW,achel L. Sturdivant, MD, David Tovbin, MD,dgar V. Lerma, MD, FACP, FASN, Lynne S.eiss, Cheryl Weller, LCSW, Nanette Wenger,D, Joseph W. Eschbach, MD, David C.heeler, MD, FRCP, Holly Whitcombe, MBA,FRE,Yu Yang, Karen Yeates, MD, MPH.Participation in the review does not necessar-

ly constitute endorsement of the content of theeport by the individuals or the organization ornstitution they represent.

The National Kidney Foundation, as well ashe Work Group, would like to recognize theupport of Amgen for the development of theuidelines. The National Kidney Foundation isroud to partner with Amgen on this important
nitiative.
), 2006: p S131 S131

GF

G2

ti2

tcS

RI2

tt2

GK

tK

tP

nU3

kD

c

T2

oB

h

EaT

r

Eta1

S

REFERENCES

Er

f

ru

m

Mpo

Bu1

Ra

oaHr

AN1

RND

pd

ld

BcS

Wou

mp

Io4

J

1. National Kidney Foundation: DOQI Clinical Practiceuidelines for the Treatment of Anemia of Chronic Renalailure. Am J Kidney Dis 30:S192-S240, 1997 (suppl 3)2. National Kidney Foundation: K/DOQI Clinical Practice

uidelines for Anemia of Chronic Kidney Disease: Update000. Am J Kidney Dis 37:S182-S238, 2001 (suppl 1)3. National Kidney Foundation: K/DOQI Clinical Prac-

ice Guidelines on Hypertension andAntihypertensiveAgentsn Chronic Kidney Disease. Am J Kidney Dis 43:S1-S290,004 (suppl 1)4. National Kidney Foundation: K/DOQI Clinical Prac-

ice Guidelines for Chronic Kidney Disease: Evaluation,lassification, and stratification. Am J Kidney Dis 39:S1-266, 2002 (suppl 1)5. US Renal Data System: USRDS 2000 Annual Data

eport. Bethesda, MD, National Institutes of Health, Nationalnstitute of Diabetes and Digestive and Kidney Diseases,0006. National Kidney Foundation: K/DOQI Clinical Prac-

ice Guidelines for Management of Dyslipidemias in Pa-ients With Kidney Disease. Am J Kidney Dis 41:S1-S91,003 (suppl 3)7. National Kidney Foundation: K/DOQI Clinical Practice

uidelines for Bone Metabolism and Disease in Chronicidney Disease. Am J Kidney Dis 42:S1-S201, 2003 (suppl 3)8. National Kidney Foundation: K/DOQI Clinical Prac-

ice Guidelines for Nutrition in Chronic Renal Failure. Am Jidney Dis 35:S1-S140, 2000 (suppl 1)9. National Kidney Foundation: K/DOQI Clinical Prac-

ice Guidelines for Cardiovascular Disease in Dialysisatients. Am J Kidney Dis 45:S1-S153, 2005 (suppl 3)10. Gilbertson DT, Liu J, Xue JL, et al: Projecting the

umber of patients with end-stage renal disease in thenited States to the year 2015. J Am Soc Nephrol 16:3736-741, 200511. Donnelly S: Why is erythropoietin made in the

idney? The kidney functions as a critmeter. Am J Kidneyis 38:415-425, 200112. Metzen E, Ratcliffe PJ: HIF hydroxylation and

ellular oxygen sensing. Biol Chem 385:223-230, 200413. Koury MJ, Ponka P: New insights into erythropoiesis:

he roles of folate, vitamin B12, and iron. Annu Rev Nutr4:105-131, 200414. De Maria R, Testa U, Luchetti L, et al: Apoptotic role

f Fas/Fas ligand system in the regulation of erythropoiesis.lood 93:796-803, 199915. Andrews NC: Anemia of inflammation: The cytokine-

epcidin link. J Clin Invest 113:1251-1253, 200416. Locatelli F, Aljama P, Barany P, et al: Revised

uropean Best Practice Guidelines for the management ofnaemia in patients with chronic renal failure. Nephrol Dialransplant 19:Sii1-Sii47, 2004 (suppl 2)17. Eschbach JW, Adamson JW: Anemia of end-stage

enal disease (ESRD). Kidney Int 28:1-5, 198518. Radtke HW, Claussner A, Erbes PM, Scheuermann

H, Schoeppe W, Koch KM: Serum erythropoietin concen-ration in chronic renal failure: Relationship to degree ofnemia and excretory renal function. Blood 54:877-884,
979 c

19. McGonigle RJ, Wallin JD, Shadduck RK, Fisher JW:rythropoietin deficiency and inhibition of erythropoiesis in

enal insufficiency. Kidney Int 25:437-444, 198420. Fisher JW: Mechanism of the anemia of chronic renal

ailure. Nephron 25:106-111, 198021. Erslev AJ, Besarab A: The rate and control of baseline

ed cell production in hematologically stable patients withremia. J Lab Clin Med 126:283-286, 199522. Besarab A, Levin A: Defining a renal anemia manage-ent period. Am J Kidney Dis 36:S13-S23, 2000. (suppl 1)23. Chandra M, Miller ME, Garcia JF, Mossey RT,cVicar M: Serum immunoreactive erythropoietin levels in

atients with polycystic kidney disease as compared withther hemodialysis patients. Nephron 39:26-29, 198524. Eschbach JW Jr, Funk D, Adamson J, Kuhn I, Scribner

H, Finch CA: Erythropoiesis in patients with renal failurendergoing chronic dialysis. N Engl J Med 276:653-658,96725. Hsu CY, Bates DW, Kuperman GJ, Curhan GC:

elationship between hematocrit and renal function in mennd women. Kidney Int 59:725-731, 2001

26. Hsu CY, McCulloch CE, Curhan GC: Epidemiologyf anemia associated with chronic renal insufficiency amongdults in the United States: Results from the Third Nationalealth and Nutrition Examination Survey. J Am Soc Neph-

ol 13:504-510, 200227. Astor BC, Muntner P, Levin A, Eustace JA, Coresh J:

ssociation of kidney function with anemia: The Thirdational Health and Nutrition Examination Survey (1988-994). Arch Intern Med 162:1401-1408, 200228. US Renal Data System: USRDS 2004 Annual Data

eport. Bethesda, MD, The National Institutes of Health,ational Institute of Diabetes and Digestive and Kidneyiseases, 200429. McClellan W, Aronoff SL, Bolton WK, et al: The

revalence of anemia in patients with chronic kidneyisease. Curr Med Res Opin 20:1501-1510, 200430. Levin A, Thompson CR, Ethier J, et al: Left ventricu-

ar mass index increase in early renal disease: Impact ofecline in hemoglobin. Am J Kidney Dis 34:125-134, 199931. Obrador GT, Ruthazer R, Arora P, Kausz AT, Pereira

J: Prevalence of and factors associated with suboptimalare before initiation of dialysis in the United States. J Amoc Nephrol 10:1793-1800, 199932. Guralnik JM, Eisenstaedt RS, Ferrucci L, Klein HG,oodman RC: Prevalence of anemia in persons 65 years and

lder in the United States: Evidence for a high rate ofnexplained anemia. Blood 104:2263-2268, 200433. Ishimura E, Nishizawa Y, Okuno S, et al: Diabetesellitus increases the severity of anemia in non-dialyzed

atients with renal failure. J Nephrol 11:83-86, 199834. Bosman DR, Winkler AS, Marsden JT, Macdougall

C, Watkins PJ: Anemia with erythropoietin deficiencyccurs early in diabetic nephropathy. Diabetes Care 24:495-99, 200135. Thomas MC, MacIsaac RJ, Tsalamandris C, Power D,

erums G: Unrecognized anemia in patients with diabetes: A
ross-sectional survey. Diabetes Care 26:1164-1169, 2003

bnp

Hmt

emR1

rdA

BaU

mU

AgO

p1

Aa1

Dd1

r(

mK

haeT

bls

p1

J

om

CeR

CL

t

H

Lla4

RnO

ia

ttE

Bt

dbE

au1

bsC

PsT

f(

Pd6

E

REFERENCES S133

36. Thomas MC, MacIsaac RJ, Tsalamandris C, et al: Theurden of anaemia in type 2 diabetes and the role ofephropathy: A cross-sectional audit. Nephrol Dial Trans-lant 19:1792-1797, 200437. El-Achkar TM, Ohmit SE, McCullough PA, et al:

igher prevalence of anemia with diabetes mellitus inoderate kidney insufficiency: The Kidney Early Evalua-

ion Program. Kidney Int 67:1483-1488, 200538. Roger SD, McMahon LP, Clarkson A, et al: Effects of

arly and late intervention with epoetin alpha on left ventricularass among patients with chronic kidney disease (stage 3 or 4):esults of a randomized clinical trial. J Am Soc Nephrol5:148-156, 200439. Levin A, Djurdjev O, Thompson C, et al: Canadian

andomized trial of hemoglobin maintenance to prevent orelay left ventricular mass growth in patients with CKD.m J Kidney Dis 46:799-811, 200540. Hollowell JG, van Assendelft OW, Gunter EW, Lewis

G, Najjar M, Pfeiffer C: Hematological and iron-relatednalytes—Reference data for persons aged 1 year and over:nited States, 1988-94. Vital Health Stat 11:1-156, 200541. Centers for Disease Control and Prevention: Recom-endations to prevent and control iron deficiency in thenited States. MMWR Recomm Rep 47:1-29, 199842. World Health Organization: Iron Deficiency Anaemia:

ssessment, Prevention and Control. A Guide for Pro-ramme Managers. Geneva, Switzerland, World Healthrganization, 200143. Levin A: How should anaemia be managed in

re-dialysis patients? Nephrol Dial Transplant 14:S66-S74,999 (suppl 2)44. Xue JL, St Peter WL, Ebben JP, Everson SE, Collins

J: Anemia treatment in the pre-ESRD period and associ-ted mortality in elderly patients. Am J Kidney Dis 40:1153-161, 200245. Parfrey PS, Foley RN, Harnett JD, Kent GM, Murray

C, Barre PE: Outcome and risk factors for left ventricularisorders in chronic uraemia. Nephrol Dial Transplant1:1277-1285, 199646. Levin A, Foley RN: Cardiovascular disease in chronic

enal insufficiency. Am J Kidney Dis 36:S24-S30, 2000suppl 1)

47. Kausz AT, Obrador GT, Pereira BJ: Anemia manage-ent in patients with chronic renal insufficiency. Am Jidney Dis 36:S39-S51, 2000 (suppl 1)48. Locatelli F, Conte F, Marcelli D: The impact of

aematocrit levels and erythropoietin treatment on overallnd cardiovascular mortality and morbidity—The experi-nce of the Lombardy Dialysis Registry. Nephrol Dialransplant 13:1642-1644, 199849. Canadian Erythropoietin Study Group: Association

etween recombinant human erythropoietin and quality ofife and exercise capacity of patients receiving haemodialy-is. BMJ 300:573-578, 1990

50. Ritz E, Eisenhardt A: Early epoetin treatment inatients with renal insufficiency. Nephrol Dial Transplant5:S40-S44, 2000 (suppl 3)51. Pugh LG: Muscular exercise on Mount Everest.

Physiol 141:233-261, 1958 r

52. Beall CM, Goldstein MC: Hemoglobin concentrationf pastoral nomads permanently resident at 4,850-5,450eters in Tibet. Am J Phys Anthropol 73:433-438, 198753. Richalet JP, Souberbielle JC, Antezana AM, et al:

ontrol of erythropoiesis in humans during prolongedxposure to the altitude of 6,542 m. Am J Physiol 266:R756-764, 199454. Whitehead TP, Robinson D, Hale AC, Bailey AR:

linical chemistry and haematology: Adult reference values.ondon, UK, BUPA Medical Research, 199455. National Kidney Foundation: Kidney Early Evalua-

ion Program. Am J Kidney Dis 45:S1-S135, 2005 (suppl 2)56. Berkahn L, Keating A: Hematopoiesis in the elderly.

ematology 9:159-163, 200457. Svanberg B, Arvidsson B, Norrby A, Rybo G, Solvell

: Absorption of supplemental iron during pregnancy—Aongitudinal study with repeated bone-marrow studies andbsorption measurements. Acta Obstet Gynecol Scand Suppl8:S87-S108, 197558. Puolakka J, Janne O, Pakarinen A, Jarvinen PA, Vihko

: Serum ferritin as a measure of iron stores during and afterormal pregnancy with and without iron supplements. Actabstet Gynecol Scand Suppl 95:S43-S51, 198059. Taylor DJ, Mallen C, McDougall N, Lind T: Effect of

ron supplementation on serum ferritin levels during andfter pregnancy. Br J Obstet Gynaecol 89:1011-1017, 1982

60. Meyers LD, Habicht JP, Johnson CL: Components ofhe difference in hemoglobin concentrations in blood be-ween black and white women in the United States. Am Jpidemiol 109:539-549, 197961. Cresanta JL, Croft JB, Webber LS, Nicklas TA,

erenson GS: Racial difference in hemoglobin concentra-ion of young adults. Prev Med 16:659-669, 1987

62. Pan WH, Habicht JP: The non-iron-deficiency-relatedifference in hemoglobin concentration distribution betweenlacks and whites and between men and women. Am Jpidemiol 134:1410-1416, 199163. Jackson RT: Separate hemoglobin standards for blacks

nd whites: A critical review of the case for separate andnequal hemoglobin standards. Med Hypotheses 32:181-89, 199064. Johnson-Spear MA, Yip R: Hemoglobin difference

etween black and white women with comparable irontatus: Justification for race-specific anemia criteria. Am Jlin Nutr 60:117-121, 199465. Tirlapur VG, Gicheru K, Charalambous BM, Evans

J, Mir MA: Packed cell volume, haemoglobin, and oxygenaturation changes in healthy smokers and non-smokers.horax 38:785-787, 198366. Taralov Z, Koumtchev E, Lyutakova Z: Erythrocyte

erritin levels in chronic renal failure patients. Folia MedPlovdiv) 40:65-70, 1998

67. Clyne N, Jogestrand T, Lins LE, Pehrsson SK:rogressive decline in renal function induces a gradualecrease in total hemoglobin and exercise capacity. Nephron7:322-326, 199468. Nankivell BJ, Allen RD, O’Connell PJ, Chapman JR:

rythrocytosis after renal transplantation: Risk factors and
elationship with GFR. Clin Transplant 9:375-382, 1995

Gc

Sf5

stA

lt7

tt1

JhD

ep(

rpD

Aa

Ar

ae

tJ

rc2

Kee1

eeA

Cmr

er2

iLp

SrM

tvP

ov1

evoL

Jl9

ve

ol5

P

Ra

rb

tC

Mc

KrA

swat

REFERENCESS134

69. de Klerk G, Wilmink JM, Rosengarten PC, Vet RJ,oudsmit R: Serum erythropoietin (ESF) titers in anemia of

hronic renal failure. J Lab Clin Med 100:720-734, 198270. Urabe A, Saito T, Fukamachi H, Kubota M, Takaku F:

erum erythropoietin titers in the anemia of chronic renalailure and other hematological states. Int J Cell Cloning:202-208, 198771. Silverberg DS, Iaina A, Peer G, et al: Intravenous iron

upplementation for the treatment of the anemia of moderateo severe chronic renal failure patients not receiving dialysis.m J Kidney Dis 27:234-238, 199672. Lin JL, Kou MT, Leu ML: Effect of long-term

ow-dose aluminum-containing agents on hemoglobin syn-hesis in patients with chronic renal insufficiency. Nephron4:33-38, 199673. Clyne N, Jogestrand T: Effect of erythropoietin

reatment on physical exercise capacity and on renal func-ion in predialytic uremic patients. Nephron 60:390-396,99274. Portoles J, Torralbo A, Martin P, Rodrigo J, Herrero

A, Barrientos A: Cardiovascular effects of recombinantuman erythropoietin in predialysis patients. Am J Kidneyis 29:541-548, 199775. Dimitrakov D, Kumchev E, Tllkian E: Study of the

ffect of recombinant erythropoietin on renal anaemia inredialysis patients with chronic renal failure. Folia MedPlovdiv) 36:31-36, 1994

76. Klahr S, Breyer JA, Beck GJ, et al: Dietary proteinestriction, blood pressure control, and the progression ofolycystic kidney disease. Modification of Diet in Renalisease Study Group. J Am Soc Nephrol 5:2037-2047, 199577. Howard AD, Moore J Jr, Welch PG, Gouge SF:

nalysis of the quantitative relationship between anemiand chronic renal failure. Am J Med Sci 297:309-313, 1989

78. Lim VS, Fangman J, Flanigan MJ, DeGowin RL,bels RT: Effect of recombinant human erythropoietin on

enal function in humans. Kidney Int 37:131-136, 199079. Besarab A, Caro J, Jarrell B, et al: Effect of cyclosporine

nd delayed graft function on posttransplantation erythropoi-sis. Transplantation 40:624-631, 1985

80. Brod J, Hornych A: Effect of correction of anemia onhe glomerular filtration rate in chronic renal failure. IsrMed Sci 3:53-59, 196781. Roth D, Smith RD, Schulman G, et al: Effects of

ecombinant human erythropoietin on renal function inhronic renal failure predialysis patients. Am J Kidney Dis4:777-784, 199482. Kuriyama S, Tomonari H, Yoshida H, Hashimoto T,

awaguchi Y, Sakai O: Reversal of anemia by erythropoi-tin therapy retards the progression of chronic renal failure,specially in nondiabetic patients. Nephron 77:176-185,99783. Hayashi T, Suzuki A, Shoji T, et al: Cardiovascular

ffect of normalizing the hematocrit level during erythropoi-tin therapy in predialysis patients with chronic renal failure.m J Kidney Dis 35:250-256, 200084. Schwartz AB, Prior JE, Mintz GS, Kim KE, Kahn SB:

ardiovascular hemodynamic effects of correction of ane-ia of chronic renal failure with recombinant-human eryth-

opoietin. Transplant Proc 23:1827-1830, 1991 a

85. Fehr T, Ammann P, Garzoni D, et al: Interpretation ofrythropoietin levels in patients with various degrees ofenal insufficiency and anemia. Kidney Int 66:1206-1211,00486. Morris MW, Davey FR: Basic examination of blood,

n Henry JB (ed): Clinical Diagnosis and Management byaboratory Methods. Philadelphia, PA, WB Saunders, 1996,p 549-59387. Brittin GM, Brecher G, Johnson CA, Elashoff RM:

tability of blood in commonly used anticoagulants. Use ofefrigerated blood for quality control of the Coulter Counter

odel S. Am J Clin Pathol 52:690-694, 196988. Holt JT, DeWandler MJ, Arvan DA: Spurious eleva-

ion of the electronically determined mean corpuscularolume and hematocrit caused by hyperglycemia. Am J Clinathol 77:561-567, 198289. van Duijnhoven HL, Treskes M: Marked interference

f hyperglycemia in measurements of mean (red) cellolume by Technicon H analyzers. Clin Chem 42:76-80,99690. Paterakis GS, Laoutaris NP, Alexia SV, et al: The

ffect of red cell shape on the measurement of red cellolume. A proposed method for the comparative assessmentf this effect among various haematology analysers. Clinab Haematol 16:235-245, 199491. Fraser CG, Wilkinson SP, Neville RG, Knox JD, King

F, MacWalter RS: Biologic variation of common hemato-ogic laboratory quantities in the elderly. Am J Clin Pathol2:465-470, 198992. Movilli E, Pertica N, Camerini C, et al: Predialysis

ersus postdialysis hematocrit evaluation during erythropoi-tin therapy. Am J Kidney Dis 39:850-853, 2002

93. Bellizzi V, Minutolo R, Terracciano V, et al: Influencef the cyclic variation of hydration status on hemoglobinevels in hemodialysis patients. Am J Kidney Dis 40:549-55, 200294. Hillman RS, Finch CA: Red Cell Manual (ed 7).

hiladelphia, PA, Davis, 199695. Naets JP, Garcia JF, Tousaaint C, Buset M, Waks D:

adioimmunoassay of erythropoietin in chronic uraemia ornephric patients. Scand J Haematol 37:390-394, 1986

96. Ross RP, McCrea JB, Besarab A: Erythropoietinesponse to blood loss in hemodialysis patients in bluntedut preserved. ASAIO J 40:M880-M885, 199497. Fishbane S, Lynn RI: The efficacy of iron dextran for

he treatment of iron deficiency in hemodialysis patients.lin Nephrol 44:238-240, 199598. Fernandez-Rodriguez AM, Guindeo-Casasus MC,olero-Labarta T, et al: Diagnosis of iron deficiency in

hronic renal failure. Am J Kidney Dis 34:508-513, 199999. Kalantar-Zadeh K, Hoffken B, Wunsch H, Fink H,

leiner M, Luft FC: Diagnosis of iron deficiency anemia inenal failure patients during the post-erythropoietin era.m J Kidney Dis 26:292-299, 1995100. Annibale B, Lahner E, Chistolini A, et al: Endo-

copic evaluation of the upper gastrointestinal tract isorthwhile in premenopausal women with iron-deficiency

naemia irrespective of menstrual flow. Scand J Gastroen-erol 38:239-245, 2003

101. Coban E, Timuragaoglu A, Meric M: Iron deficiency
nemia in the elderly: Prevalence and endoscopic evaluation

o1

It

Ps1

to

aw

CpH

pwr

opa

Zpw1

ha

vi

apn

Dd

hr

d

Ao

PtM

rs

Sod1

fierr1

Ri

Gor

Pah1

tS

aer

MeO

Ni6

dp

Wbc

SwF

s1

rdA

hd

REFERENCES S135

f the gastrointestinal tract in outpatients. Acta Haematol10:25-28, 2003102. Ioannou GN, Rockey DC, Bryson CL, Weiss NS:

ron deficiency and gastrointestinal malignancy: A popula-ion-based cohort study. Am J Med 113:276-280, 2002

103. Ioannou GN, Spector J, Scott K, Rockey DC:rospective evaluation of a clinical guideline for the diagno-is and management of iron deficiency anemia. Am J Med13:281-287, 2002104. Goddard AF, McIntyre AS, Scott BB: Guidelines for

he management of iron deficiency anaemia. British Societyf Gastroenterology. Gut 46:SIV1-SIV5, 2000 (suppl 3-4)105. Joosten E, Ghesquiere B, Linthoudt H, et al: Upper

nd lower gastrointestinal evaluation of elderly inpatientsho are iron deficient. Am J Med 107:24-29, 1999106. Ho CH, Chau WK, Hsu HC, Gau JP, You JY, Chen

C: Predictive risk factors and prevalence of malignancy inatients with iron deficiency anemia in Taiwan. Am Jematol 78:108-112, 2005107. Akmal M, Sawelson S, Karubian F, Gadallah M: The

revalence and significance of occult blood loss in patientsith predialysis advanced chronic renal failure (CRF), or

eceiving dialytic therapy. Clin Nephrol 42:198-202, 1994108. Besarab A, Bolton WK, Browne JK, et al: The effects

f normal as compared with low hematocrit values inatients with cardiac disease who are receiving hemodialysisnd epoetin. N Engl J Med 339:584-590, 1998

109. Parfrey PS, Foley RN, Wittreich BH, Sullivan DJ,agari MJ, Frei D: Double-blind comparison of full andartial anemia correction in incident hemodialysis patientsithout symptomatic heart disease. J Am Soc Nephrol6:2180-2189, 2005110. Foley RN, Parfrey PS, Morgan J, et al: Effect of

emoglobin levels in hemodialysis patients with asymptom-tic cardiomyopathy. Kidney Int 58:1325-1335, 2000

111. Lacson E Jr, Ofsthun N, Lazarus JM: Effect ofariability in anemia management on hemoglobin outcomesn ESRD. Am J Kidney Dis 41:111-124, 2003

112. Collins AJ, Brenner RM, Ofman JJ, et al: Epoetinlfa use in patients with ESRD: An analysis of recent USrescribing patterns and hemoglobin outcomes. Am J Kid-ey Dis 46:481-488, 2005113. Berns JS, Elzein H, Lynn RI, Fishbane S, Meisels IS,

eoreo PB: Hemoglobin variability in epoetin-treated hemo-ialysis patients. Kidney Int 64:1514-1521, 2003114. Fishbane S, Berns JS: Hemoglobin cycling in

emodialysis patients treated with recombinant human eryth-opoietin. Kidney Int 68:1337-1343, 2005

115. Eckardt KU: The CREATE trial—Building the evi-ence. Nephrol Dial Transplant 16:S16-S18, 2001 (suppl 2)115A. US National Institutes of Health: CHOIR Trial. 2005.

vailable at: www.clinicaltrials.gov/ct/show/NCT00211120?rder�1. Accessed March 31, 2006116. Man-Son-Hing M, Gage BF, Montgomery AA, et al:

reference-based antithrombotic therapy in atrial fibrilla-ion: Implications for clinical decision making. Med Decis

aking 25:548-559, 2005117. Canadian Erythropoietin Study Group: Effect of

ecombinant human erythropoietin therapy on blood pres-
ure in hemodialysis patients. Am J Nephrol 11:23-26, 1991 1
118. Furuland H, Linde T, Ahlmen J, Christensson A,trombom U, Danielson BG: A randomized controlled trialf haemoglobin normalization with epoetin alfa in pre-ialysis and dialysis patients. Nephrol Dial Transplant8:353-361, 2003119. Suzuki M, Hirasawa Y, Hirashima K, et al: Dose-

nding, double-blind, clinical trial of recombinant humanrythropoietin (Chugai) in Japanese patients with end-stageenal disease. Research Group for Clinical Assessment ofhEPO. Contrib Nephrol 76:179-192; discussion 212-178,989120. Furuland H, Linde T, Wikstrom B, Danielson BG:

educed hemodialysis adequacy after hemoglobin normal-zation with epoetin. J Nephrol 18:80-85, 2005

121. McMahon LP, Mason K, Skinner SL, Burge CM,rigg LE, Becker GJ: Effects of haemoglobin normalizationn quality of life and cardiovascular parameters in end-stageenal failure. Nephrol Dial Transplant 15:1425-1430, 2000

122. McMahon LP, McKenna MJ, Sangkabutra T, et al:hysical performance and associated electrolyte changesfter haemoglobin normalization: A comparative study inaemodialysis patients. Nephrol Dial Transplant 14:1182-187, 1999123. Nissenson AR, Korbet S, Faber M, et al: Multicenter

rial of erythropoietin in patients on peritoneal dialysis. J Amoc Nephrol 5:1517-1529, 1995124. Bahlmann J, Schoter KH, Scigalla P, et al: Morbidity

nd mortality in hemodialysis patients with and withoutrythropoietin treatment: A controlled study. Contrib Neph-ol 88:90-106, 1991

125. Sikole A, Polenakovic M, Spirovska V, Polenakovic B,asin G:Analysis of heart morphology and function following

rythropoietin treatment of anemic dialysis patients. Artifrgans 17:977-984, 1993126. Morris KP, Sharp J, Watson S, Coulthard MG:

on-cardiac benefits of human recombinant erythropoietinn end stage renal failure and anaemia. Arch Dis Child9:580-586, 1993127. Abraham PA, Macres MG: Blood pressure in hemo-

ialysis patients during amelioration of anemia with erythro-oietin. J Am Soc Nephrol 2:927-936, 1991128. Berns JS, Rudnick MR, Cohen RM, Bower JD,ood BC: Effects of normal hematocrit on ambulatory

lood pressure in epoetin-treated hemodialysis patients withardiac disease. Kidney Int 56:253-260, 1999

129. Conlon PJ, Kovalik E, Schumm D, Minda S, SchwabJ: Normalization of hematocrit in hemodialysis patientsith cardiac disease does not increase blood pressure. Renail 22:435-444, 2000130. Levin A: The relationship of haemoglobin level and

urvival: Direct or indirect effects? Nephrol Dial Transplant7:S8-S13, 2002 (suppl 5)130A. Levin A, Djurdjev O, Thompson C, et al: Canadian

andomized trial of hemoglobin maintenance to prevent orelay left ventricular mass growth in patients with CKD.m J Kidney Dis 46:799-811, 2005131. Lim VS, DeGowin RL, Zavala D, et al: Recombinant

uman erythropoietin treatment in pre-dialysis patients. Aouble-blind placebo-controlled trial. Ann Intern Med 110:
08-114, 1989

rep

Kiet

Js8

HfN

dwin

Bwf(

RtD

Sps1

chSN

iad

Bmk

GmN

Rec

AfJ

ec

adN

es

Ftr3

esN

Ma5

JJ

EtflN

iie

ch3

rc2

Fs2

Mct

dcN

pK

s

REFERENCESS136

132. Revicki DA, Brown RE, Feeny DH, et al: Health-elated quality of life associated with recombinant humanrythropoietin therapy for predialysis chronic renal diseaseatients. Am J Kidney Dis 25:548-554, 1995133. Kleinman KS, Schweitzer SU, Perdue ST, Bleifer

H, Abels RI: The use of recombinant human erythropoietinn the correction of anemia in predialysis patients and itsffect on renal function: A double-blind, placebo-controlledrial. Am J Kidney Dis 14:486-495, 1989

134. Watson AJ, Gimenez LF, Cotton S, Walser M, SpivakL: Treatment of the anemia of chronic renal failure withubcutaneous recombinant human erythropoietin. Am J Med9:432-435, 1990135. Abraham PA, Opsahl JA, Rachael KM, Asinger R,

alstenson CE: Renal function during erythropoietin therapyor anemia in predialysis chronic renal failure patients. Am Jephrol 10:128-136, 1990136. Locatelli F, Baldamus CA, Villa G, Ganea A, Martin

e Francisco AL: Once-weekly compared with three-times-eekly subcutaneous epoetin beta: Results from a random-

zed, multicenter, therapeutic-equivalence study. Am J Kid-ey Dis 40:119-125, 2002137. Locatelli F, Canaud B, Giacardy F, Martin-Malo A,

aker N, Wilson J: Treatment of anaemia in dialysis patientsith unit dosing of darbepoetin alfa at a reduced dose

requency relative to recombinant human erythropoietinrHuEpo). Nephrol Dial Transplant 18:362-369, 2003

138. Nissenson AR, Swan SK, Lindberg JS, et al:andomized, controlled trial of darbepoetin alfa for the

reatment of anemia in hemodialysis patients. Am J Kidneyis 40:110-118, 2002139. Tolman C, Richardson D, Bartlett C, Will E:

tructured conversion from thrice weekly to weekly erythro-oietic regimens using a computerized decision-supportystem: A randomized clinical study. J Am Soc Nephrol6:1463-1470, 2005140. Kaufman JS, Reda DJ, Fye CL, et al: Subcutaneous

ompared with intravenous epoetin in patients receivingemodialysis. Department of Veterans Affairs Cooperativetudy Group on Erythropoietin in Hemodialysis Patients.Engl J Med 339:578-583, 1998141. Vanrenterghem Y, Barany P, Mann JF, et al: Random-

zed trial of darbepoetin alfa for treatment of renal anemiat a reduced dose frequency compared with rHuEPO inialysis patients. Kidney Int 62:2167-2175, 2002142. Ling B, Walczyk M, Agarwal A, Carroll W, Liu W,

renner R: Darbepoetin alfa administered once monthlyaintains hemoglobin concentrations in patients with chronicidney disease. Clin Nephrol 63:327-334, 2005143. Jadoul M, Vanrenterghem Y, Foret M, Walker R,

ray SJ: Darbepoetin alfa administered once monthlyaintains haemoglobin levels in stable dialysis patients.ephrol Dial Transplant 19:898-903, 2004144. Eschbach JW, Abdulhadi MH, Browne JK, et al:

ecombinant human erythropoietin in anemic patients withnd-stage renal disease. Results of a phase III multicenterlinical trial. Ann Intern Med 111:992-1000, 1989

145. Eschbach JW, Kelly MR, Haley NR, Abels RI,damson JW: Treatment of the anemia of progressive renal

ailure with recombinant human erythropoietin. N Engl
Med 321:158-163, 1989 d
146. Locatelli F, Olivares J, Walker R, et al: Novelrythropoiesis stimulating protein for treatment of anemia inhronic renal insufficiency. Kidney Int 60:741-747, 2001

147. Toto RD, Pichette V, Navarro J, et al: Darbepoetinlfa effectively treats anemia in patients with chronic kidneyisease with de novo every-other-week administration. Am Jephrol 24:453-460, 2004148. Besarab A, Amin N, Ahsan M, et al: Optimization of

poetin therapy with intravenous iron therapy in hemodialy-is patients. J Am Soc Nephrol 11:530-538, 2000

149. DeVita MV, Frumkin D, Mittal S, Kamran A,ishbane S, Michelis MF: Targeting higher ferritin concen-

rations with intravenous iron dextran lowers erythropoietinequirement in hemodialysis patients. Clin Nephrol 60:335-40, 2003150. Chang CH, Chang CC, Chiang SS: Reduction in

rythropoietin doses by the use of chronic intravenous ironupplementation in iron-replete hemodialysis patients. Clinephrol 57:136-141, 2002151. Fishbane S, Galgano C, Langley RC Jr, Canfield W,aesaka JK: Reticulocyte hemoglobin content in the evalu-

tion of iron status of hemodialysis patients. Kidney Int2:217-222, 1997152. Fishbane S, Kowalski EA, Imbriano LJ, Maesaka

K: The evaluation of iron status in hemodialysis patients.Am Soc Nephrol 7:2654-2657, 1996153. Chuang CL, Liu RS, Wei YH, Huang TP, Tarng DC:

arly prediction of response to intravenous iron supplemen-ation by reticulocyte haemoglobin content and high-uorescence reticulocyte count in haemodialysis patients.ephrol Dial Transplant 18:370-377, 2003154. Tessitore N, Solero GP, Lippi G, et al: The role of

ron status markers in predicting response to intravenousron in haemodialysis patients on maintenance erythropoi-tin. Nephrol Dial Transplant 16:1416-1423, 2001

155. Mittman N, Sreedhara R, Mushnick R, et al: Reticulo-yte hemoglobin content predicts functional iron deficiency inemodialysis patients receiving rHuEPO. Am J Kidney Dis0:912-922, 1997156. Fishbane S, Frei GL, Maesaka J: Reduction in

ecombinant human erythropoietin doses by the use ofhronic intravenous iron supplementation. Am J Kidney Dis6:41-46, 1995157. Fishbane S, Shapiro W, Dutka P, Valenzuela OF,

aubert J: A randomized trial of iron deficiency testingtrategies in hemodialysis patients. Kidney Int 60:2406-411, 2001158. Kaneko Y, Miyazaki S, Hirasawa Y, Gejyo F, Suzuki: Transferrin saturation versus reticulocyte hemoglobin

ontent for iron deficiency in Japanese hemodialysis pa-ients. Kidney Int 63:1086-1093, 2003

159. Mitsuiki K, Harada A, Miyata Y: Assessment of ironeficiency in chronic hemodialysis patients: Investigation ofutoff values for reticulocyte hemoglobin content. Clin Expephrol 7:52-57, 2003160. Besarab A, Kaiser JW, Frinak S: A study of

arenteral iron regimens in hemodialysis patients. Am Jidney Dis 34:21-28, 1999161. Lin JL, Chang MY, Tan DT, Leu ML: Short-term

mall-dose intravenous iron trial to detect functional iron
eficiency in dialysis patients. Am J Nephrol 21:91-97, 2001

smh

op6

ci1

Ah2

BsK

Ll1

et4

RIn

Kib1

swe

iaN

lr

Op2

fr6

dtp

Sd

i1

Ch

it

tp

FP

Cpt

Dnh2

Lth

trp

sm

TrS

iiP

pJ

f(

cf

L

S

e

REFERENCES S137

162. Low CL, Bailie GR, Eisele G: Sensitivity andpecificity of transferrin saturation and serum ferritin asarkers of iron status after intravenous iron dextran in

emodialysis patients. Ren Fail 19:781-788, 1997163. Canavese C, Bergamo D, Ciccone G, et al: Validation

f serum ferritin values by magnetic susceptometry inredicting iron overload in dialysis patients. Kidney Int5:1091-1098, 2004164. Kalantar-Zadeh K, Regidor DL, McAllister CJ, Mi-

hael B, Warnock DG: Time-dependent associations betweenron and mortality in hemodialysis patients. J Am Soc Nephrol6:3070-3080, 2005165. Feldman HI, Joffe M, Robinson B, Knauss J, et al:

dministration of parenteral iron and mortality amongemodialysis patients. J Am Soc Nephrol 15:1623-1632,004166. Macdougall IC, Tucker B, Thompson J, Tomson CR,

aker LR, Raine AE: A randomized controlled study of ironupplementation in patients treated with erythropoietin.idney Int 50:1694-1699, 1996167. Fudin R, Jaichenko J, Shostak A, Bennett M, Gotloib

: Correction of uremic iron deficiency anemia in hemodia-yzed patients: A prospective study. Nephron 79:299-305,998168. Nissenson AR, Berns JS, Sakiewicz P, et al: Clinical

valuation of heme iron polypeptide: Sustaining a responseo rHuEPO in hemodialysis patients. Am J Kidney Dis2:325-330, 2003169. Van Wyck DB, Roppolo M, Martinez CO, Mazey

M, McMurray S: A randomized, controlled trial comparingV iron sucrose to oral iron in anemic patients withondialysis-dependent CKD. Kidney Int 68:2846-2856, 2005170. Aggarwal HK, Nand N, Singh S, Singh M, Hemant,

aushik G: Comparison of oral versus intravenous iron therapyn predialysis patients of chronic renal failure receiving recom-inant human erythropoietin. J Assoc Physicians India 51:170-74, 2003171. Stoves J, Inglis H, Newstead CG: A randomized

tudy of oral vs intravenous iron supplementation in patientsith progressive renal insufficiency treated with erythropoi-

tin. Nephrol Dial Transplant 16:967-974, 2001172. Charytan C, Qunibi W, Bailie GR: Comparison of

ntravenous iron sucrose to oral iron in the treatment ofnemic patients with chronic kidney disease not on dialysis.ephron Clin Pract 100:c55-c62, 2005173. Novey HS, Pahl M, Haydik I, Vaziri ND: Immuno-

ogic studies of anaphylaxis to iron dextran in patients onenal dialysis. Ann Allergy 72:224-228, 1994

174. Agarwal R, Vasavada N, Sachs NG, Chase S:xidative stress and renal injury with intravenous iron inatients with chronic kidney disease. Kidney Int 65:2279-289, 2004175. Michael B, Coyne DW, Fishbane S, et al: Sodium

erric gluconate complex in hemodialysis patients: Adverseeactions compared to placebo and iron dextran. Kidney Int1:1830-1839, 2002176. Walters BA, Van Wyck DB: Benchmarking iron

extran sensitivity: reactions requiring resuscitative medica-ion in incident and prevalent patients. Nephrol Dial Trans-
lant 20:1438-1442, 2005 s
177. Fletes R, Lazarus JM, Gage J, Chertow GM:uspected iron dextran-related adverse drug events in hemo-ialysis patients. Am J Kidney Dis 37:743-749, 2001178. Hamstra RD, Block MH, Schocket AL: Intravenous

ron dextran in clinical medicine. JAMA 243:1726-1731,980179. Fishbane S, Ungureanu VD, Maesaka JK, Kaupke

J, Lim V, Wish J: The safety of intravenous iron dextran inemodialysis patients. Am J Kidney Dis 28:529-534, 1996180. Faich G, Strobos J: Sodium ferric gluconate complex

n sucrose: Safer intravenous iron therapy than iron dex-rans. Am J Kidney Dis 33:464-470, 1999

181. Bailie GR, Clark JA, Lane CE, Lane PL: Hypersensi-ivity reactions and deaths associated with intravenous ironreparations. Nephrol Dial Transplant 20:1443-1449, 2005182. Stang PE, Fox JL: Adverse drug events and the

reedom of Information Act: An apple in Eden. Annharmacother 26:238-243, 1992183. Brimble KS, Rabbat CG, McKenna P, Lambert K,

arlisle EJ: Protocolized anemia management with erythro-oietin in hemodialysis patients: A randomized controlledrial. J Am Soc Nephrol 14:2654-2661, 2003

184. Cervelli MJ, Gray N, McDonald S, Gentgall MG,isney AP: Randomized cross-over comparison of intrave-ous and subcutaneous darbepoetin dosing efficiency inaemodialysis patients. Nephrology (Carlton) 10:129-135,005185. Markowitz GS, Kahn GA, Feingold RE, Coco M,

ynn RI: An evaluation of the effectiveness of oral ironherapy in hemodialysis patients receiving recombinantuman erythropoietin. Clin Nephrol 48:34-40, 1997186. McCarthy JT, Regnier CE, Loebertmann CL, Bergs-

ralh EJ: Adverse events in chronic hemodialysis patientseceiving intravenous iron dextran—A comparison of tworoducts. Am J Nephrol 20:455-462, 2000187. Aronoff GR, Bennett WM, Blumenthal S, et al: Iron

ucrose in hemodialysis patients: Safety of replacement andaintenance regimens. Kidney Int 66:1193-1198, 2004188. Blaustein DA, Schwenk MH, Chattopadhyay J, et al:

he safety and efficacy of an accelerated iron sucrose dosingegimen in patients with chronic kidney disease. Kidney Intuppl 64:S72-S77, 2003189. Charytan C, Schwenk MH, Al-Saloum MM, Spinow-

tz BS: Safety of iron sucrose in hemodialysis patientsntolerant to other parenteral iron products. Nephron Clinract 96:c63-c66, 2004190. Aronoff GR: Safety of intravenous iron in clinical

ractice: Implications for anemia management protocols.Am Soc Nephrol 15:S99-S106, 2004 (suppl 2)191. Hoppel C: The role of carnitine in normal and altered

atty acid metabolism. Am J Kidney Dis 41:S4-S12, 2003suppl 4)

192. Bohmer T, Bergrem H, Eiklid K: Carnitine defi-iency induced during intermittent haemodialysis for renalailure. Lancet 1:126-128, 1978

193. Golper TA, Goral S, Becker BN, Langman CB:-Carnitine treatment of anemia. Am J Kidney Dis 41:S27-34, 2003 (suppl 4)194. Berns JS, Mosenkis A: Pharmacologic adjuvants to

poetin in the treatment of anemia in patients on hemodialy-
is. Hemodial Int 9:7-22, 2005

DB(2

L

wT

dT

hK

CL

t

cot9

RihJ

op7

mcC

tK

aJ

Al

vs

TC

oo

Vecp

iaR

Med

oep2

Ibr

PpN

saN

Pl

eA

Rla

vs

si3

a3

LcA

dJ

Hps

es

REFERENCESS138

195. Levocarnitine for Use in the Treatment of Carnitineeficiency in ESRD Patients (program memorandum).altimore, MD, Department of Health & Human Services

DHHS), Centers for Medicare & Medicaid Services (CMS),003196. Caruso U, Leone L, Cravotto E, Nava D: Effects of

-carnitine on anemia in aged hemodialysis patients treatedith recombinant human erythropoietin: A pilot study. Dialransplant 27:498-506, 1998197. Kletzmayr J, Sunder-Plassmann G, Horl WH: High

ose intravenous iron: A note of caution. Nephrol Dialransplant 17:962-965, 2002198. Labonia WD: L-Carnitine effects on anemia in

emodialyzed patients treated with erythropoietin. Am Jidney Dis 26:757-764, 1995199. Semeniuk J, Shalansky KF, Taylor N, Jastrzebski J,

ameron EC: Evaluation of the effect of intravenous-carnitine on quality of life in chronic hemodialysis pa-ients. Clin Nephrol 54:470-477, 2000

200. Vaux EC, Taylor DJ, Altmann P, et al: Effects ofarnitine supplementation on muscle metabolism by the usef magnetic resonance spectroscopy and near-infrared spec-roscopy in end-stage renal disease. Nephron Clin Pract7:c41-c48, 2004200a. Steiber AL, Davis AT, Spry L, Strong J, Buss AL,

atkiewicz MM, Weatherspoon LJ: Carnitine treatmentmproved quality-of-life measure in a sample of Midwesternemodialysis patients. JPEN J Parenter Enteral Nutr 2006an-Feb; 30(1):10-5.

201. Hurot JM, Cucherat M, Haugh M, Fouque D: Effectsf L-carnitine supplementation in maintenance hemodialysisatients: A systematic review. J Am Soc Nephrol 13:708-14, 2002202. Eknoyan G, Latos DL, Lindberg J: Practice recom-endations for the use of L-carnitine in dialysis-related

arnitine disorder. National Kidney Foundation Carnitineonsensus Conference. Am J Kidney Dis 41:868-876, 2003203. National Kidney Foundation: K/DOQI Clinical Prac-

ice Guidelines for Nutrition in Chronic Renal Failure. Am Jidney Dis 35:S66-S70, 2000 (suppl 2)204. Bridges KR, Hoffman KE: The effects of ascorbic

cid on the intracellular metabolism of iron and ferritin.Biol Chem 261:14273-14277, 1986205. Lipschitz DA, Bothwell TH, Seftel HC, Wapnick

A, Charlton RW: The role of ascorbic acid in the metabo-ism of storage iron. Br J Haematol 20:155-163, 1971

206. Descombes E, Hanck AB, Fellay G: Water solubleitamins in chronic hemodialysis patients and need forupplementation. Kidney Int 43:1319-1328, 1993

207. Sullivan JF, Eisenstein AB, Mottola OM, Mittal AK:he effect of dialysis on plasma and tissue levels of vitamin. Trans Am Soc Artif Intern Organs 18:277-282, 1972208. Costello JF, Sadovnic MJ, Cottington EM: Plasma

xalate levels rise in hemodialysis patients despite increasedxalate removal. J Am Soc Nephrol 1:1289-1298, 1991209. Gastaldello K, Vereerstraeten A, Nzame-Nze T,

anherweghem JL, Tielemans C: Resistance to erythropoi-tin in iron-overloaded haemodialysis patients can be over-ome by ascorbic acid administration. Nephrol Dial Trans-
lant 10:S44-S47, 1995 (suppl 6) M
210. Lin CL, Hsu PY, Yang HY, Huang CC: Low dosentravenous ascorbic acid for erythropoietin-hyporesponsivenemia in diabetic hemodialysis patients with iron overload.en Fail 25:445-453, 2003211. Sezer S, Ozdemir FN, Yakupoglu U, Arat Z, Turan, Haberal M: Intravenous ascorbic acid administration for

rythropoietin-hyporesponsive anemia in iron loaded hemo-ialysis patients. Artif Organs 26:366-370, 2002212. Tarng DC, Huang TP: A parallel, comparative study

f intravenous iron versus intravenous ascorbic acid forrythropoietin-hyporesponsive anaemia in haemodialysisatients with iron overload. Nephrol Dial Transplant 13:2867-872, 1998213. Tarng DC, Wei YH, Huang TP, Kuo BI, Yang WC:

ntravenous ascorbic acid as an adjuvant therapy for recom-inant erythropoietin in hemodialysis patients with hyperfer-itinemia. Kidney Int 55:2477-2486, 1999

214. Giancaspro V, Nuzziello M, Pallotta G, Sacchetti A,etrarulo F: Intravenous ascorbic acid in hemodialysisatients with functional iron deficiency: A clinical trial. Jephrol 13:444-449, 2000215. Deira J, Diego J, Martinez R, et al: Comparative

tudy of intravenous ascorbic acid versus low-dose desferrox-mine in patients on hemodialysis with hyperferritinemia. Jephrol 16:703-709, 2003216. Mydlik M, Derzsiova K, Boldizsar J, Hribikova M,

etrovicova J: Oral use of iron with vitamin C in hemodia-yzed patients. J Ren Nutr 13:47-51, 2003

217. Nguyen TV: Oral ascorbic acid as adjuvant topoetin alfa in hemodialysis patients with hyperferritinemia.m J Health Syst Pharm 61:2007-2008, 2004218. Tovbin D, Markowitz A, Mostoslavsky M, Landver

: Effectiveness of erythropoiesis on supervised intradia-ytic oral iron and vitamin C therapy is correlated with Kt/Vnd patient weight. Clin Nephrol 53:276-282, 2000

219. Chan D, Irish A, Dogra G: Efficacy and safety of oralersus intravenous ascorbic acid for anaemia in haemodialy-is patients. Nephrology (Carlton) 10:336-340, 2005

220. Balcke P, Schmidt P, Zazgornik J, Kopsa H, Hauben-tock A: Ascorbic acid aggravates secondary hyperoxalemian patients on chronic hemodialysis.Ann Intern Med 101:344-45, 1984221. Pru C, Eaton J, Kjellstrand C: Vitamin C intoxication

nd hyperoxalemia in chronic hemodialysis patients. Nephron9:112-116, 1985222. Canavese C, Petrarulo M, Massarenti P, et al:

ong-term, low-dose, intravenous vitamin C leads to plasmaalcium oxalate supersaturation in hemodialysis patients.m J Kidney Dis 45:540-549, 2005223. Berger TM, Polidori MC, Dabbagh A, et al: Antioxi-

ant activity of vitamin C in iron-overloaded human plasma.Biol Chem 272:15656-15660, 1997224. Chen WT, Lin YF, Yu FC, Kao WY, Huang WH, Yan

C: Effect of ascorbic acid administration in hemodialysisatients on in vitro oxidative stress parameters: Influence oferum ferritin levels. Am J Kidney Dis 42:158-166, 2003

225. Sirken G, Kung SC, Raja R: Decreased erythropoi-tin requirements in maintenance hemodialysis patients withtatin therapy. ASAIO J 49:422-425, 2003

226. Cooper A, Mikhail A, Lethbridge MW, Kemeny DM,
acdougall IC: Pentoxifylline improves hemoglobin levels

if

tt8

h

hN

twb

rdA

hw1

dt

hp

r1m2

SduN

Ewc

evA

4

a3

WuN

ics

r8

cep

hA

SaJ

ht2

ct

H

Zpa

RA

Sae

bK

Cis

pt1

ChS

Kpp

RE4

Up

REFERENCES S139

n patients with erythropoietin-resistant anemia in renalailure. J Am Soc Nephrol 15:1877-1882, 2004

227. Weissgarten J, Modai D, Oz D, et al: Vitamin B(6)herapy does not improve hematocrit in hemodialysis pa-ients supplemented with iron and erythropoietin. Nephron7:328-332, 2001228. Ayli D, Ayli M, Azak A, et al: The effect of high-flux

emodialysis on renal anemia. J Nephrol 17:701-706, 2004229. Locatelli F, Andrulli S, Pecchini F, et al: Effect of

igh-flux dialysis on the anaemia of haemodialysis patients.ephrol Dial Transplant 15:1399-1409, 2000230. Opatrny K Jr, Reischig T, Vienken J, et al: Does

reatment modality have an impact on anemia in patientsith chronic renal failure? Effect of low- and high-fluxiocompatible dialysis. Artif Organs 26:181-188, 2002231. Richardson D, Lindley EJ, Bartlett C, Will EJ: A

andomized, controlled study of the consequences of hemo-ialysis membrane composition on erythropoietic response.m J Kidney Dis 42:551-560, 2003232. Ifudu O, Feldman J, Friedman EA: The intensity of

emodialysis and the response to erythropoietin in patientsith end-stage renal disease. N Engl J Med 334:420-425,996233. Ifudu O, Uribarri J, Rajwani I, et al: Adequacy of

ialysis and differences in hematocrit among dialysis facili-ies. Am J Kidney Dis 36:1166-1174, 2000

234. Madore F, Lowrie EG, Brugnara C, et al: Anemia inemodialysis patients: Variables affecting this outcomeredictor. J Am Soc Nephrol 8:1921-1929, 1997235. Movilli E, Cancarini GC, Vizzardi V, et al: Epoetin

equirement does not depend on dialysis dose when Kt/V �.33 in patients on regular dialysis treatment with cellulosicembranes and adequate iron stores. J Nephrol 16:546-551,

003236. Movilli E, Cancarini GC, Zani R, Camerini C,

andrini M, Maiorca R: Adequacy of dialysis reduces theoses of recombinant erythropoietin independently from these of biocompatible membranes in haemodialysis patients.ephrol Dial Transplant 16:111-114, 2001237. Kobayashi S, Moriya H, Aso K, Ohtake T: Vitamin

-bonded hemodialyzer improves atherosclerosis associatedith a rheological improvement of circulating red blood

ells. Kidney Int 63:1881-1887, 2003238. Miller ER III, Pastor-Barriuso R, Dalal D, Riem-

rsma RA, Appel LJ, Guallar E: Meta-analysis: High-dosageitamin E supplementation may increase all-cause mortality.nn Intern Med 142:37-46, 2005239. Ward RA: Ultrapure dialysate. Semin Dial 17:489-

97, 2004240. Ward RA: Ultrapure dialysate: A desirable and

chievable goal for routine hemodialysis. Semin Dial 13:378-80, 2000241. Kleophas W, Haastert B, Backus G, Hilgers P,esthoff A, van Endert G: Long-term experience with an

ltrapure individual dialysis fluid with a batch type machine.ephrol Dial Transplant 13:3118-3125, 1998242. Hsu PY, Lin CL, Yu CC, et al: Ultrapure dialysate

mproves iron utilization and erythropoietin response inhronic hemodialysis patients—A prospective cross-over
tudy. J Nephrol 17:693-700, 2004 h
243. Schiffl H, Lang SM, Bergner A: Ultrapure dialysateeduces dose of recombinant human erythropoietin. Nephron3:278-279, 1999244. Sitter T, Bergner A, Schiffl H: Dialysate related

ytokine induction and response to recombinant humanrythropoietin in haemodialysis patients. Nephrol Dial Trans-lant 15:1207-1211, 2000245. Eiselt J, Racek J, Opatrny K Jr: The effect of

emodialysis and acetate-free biofiltration on anemia. Int Jrtif Organs 23:173-180, 2000246. Ward RA, Schmidt B, Hullin J, Hillebrand GF,

amtleben W: A comparison of on-line hemodiafiltrationnd high-flux hemodialysis: A prospective clinical study.Am Soc Nephrol 11:2344-2350, 2000247. Wizemann V, Lotz C, Techert F, Uthoff S: On-line

aemodiafiltration versus low-flux haemodialysis.Aprospec-ive randomized study. Nephrol Dial Transplant 15:S43-S48,000 (suppl 1)248. Maduell F, del Pozo C, Garcia H, et al: Change from

onventional haemodiafiltration to on-line haemodiafiltra-ion. Nephrol Dial Transplant 14:1202-1207, 1999

249. Lindsay RM: The London, Ontario, Daily/Nocturnalemodialysis Study. Semin Dial 17:85-91, 2004250. Ting GO, Kjellstrand C, Freitas T, Carrie BJ,

arghamee S: Long-term study of high-comorbidity ESRDatients converted from conventional to short daily hemodi-lysis. Am J Kidney Dis 42:1020-1035, 2003

251. Rao M, Muirhead N, Klarenbach S, Moist L, LindsayM: Management of anemia with quotidian hemodialysis.m J Kidney Dis 42:18-23, 2003252. Schwartz DI, Pierratos A, Richardson RM, Fenton

S, Chan CT: Impact of nocturnal home hemodialysis onnemia management in patients with end-stage renal dis-ase. Clin Nephrol 63:202-208, 2005

253. Woods JD, Port FK, Orzol S, et al: Clinical andiochemical correlates of starting “daily” hemodialysis.idney Int 55:2467-2476, 1999254. Yuen D, Richardson RM, Fenton SS, McGrath-

hong ME, Chan CT: Quotidian nocturnal hemodialysismproves cytokine profile and enhances erythropoietin re-ponsiveness. ASAIO J 51:236-241, 2005

255. Coronel F, Herrero JA, Montenegro J, et al: Erythro-oietin requirements: A comparative multicenter study be-ween peritoneal dialysis and hemodialysis. J Nephrol6:697-702, 2003256. Snyder JJ, Foley RN, Gilbertson DT, Vonesh EF,

ollins AJ: Hemoglobin levels and erythropoietin doses inemodialysis and peritoneal dialysis patients in the Unitedtates. J Am Soc Nephrol 15:174-179, 2004257. Taji Y, Morimoto T, Okada K, Fukuhara S, Fukui T,

uwahara T: Effects of intravenous ascorbic acid on erythro-oiesis and quality of life in unselected hemodialysisatients. J Nephrol 17:537-543, 2004258. Keven K, Kutlay S, Nergizoglu G, Erturk S:

andomized, crossover study of the effect of vitamin C onPO response in hemodialysis patients. Am J Kidney Dis1:1233-1239, 2003259. Sheashaa H, Abdel-Razek W, El-Husseini A, et al:se of nandrolone decanoate as an adjuvant for erythro-oietin dose reduction in treating anemia in patients on
emodialysis. Nephron Clin Pract 99:c102-c106, 2005

saa3

oah

aiM

f

oa

rt1

rp1

Pe

p2

sM

f1

LpS

ba

aw4

eN

ii2

t1

m

e7

r1

AaRN

WoK

LrN

bht

nK

em

clb

aN

Kmd

pp

Fea

LbJ

TtE

Kpc1

REFERENCESS140

260. Gaughan WJ, Liss KA, Dunn SR, et al: A 6-monthtudy of low-dose recombinant human erythropoietin alonend in combination with androgens for the treatment ofnemia in chronic hemodialysis patients. Am J Kidney Dis0:495-500, 1997261. Berns JS, Rudnick MR, Cohen RM: A controlled trial

f recombinant human erythropoietin and nandrolone decano-te in the treatment of anemia in patients on chronicemodialysis. Clin Nephrol 37:264-267, 1992262. McCullough PA, Lepor NE: The deadly triangle of

nemia, renal insufficiency, and cardiovascular disease:mplications for prognosis and treatment. Rev Cardiovasc

ed 6:1-10, 2005263. Linman JW: Physiologic and pathophysiologic ef-

ects of anemia. N Engl J Med 279:812-818, 1968264. Rao SV, Jollis JG, Harrington RA, et al: Relationship

f blood transfusion and clinical outcomes in patients withcute coronary syndromes. JAMA 292:1555-1562, 2004

265. House AA, Pham B, Page DE: Transfusion andecombinant human erythropoietin requirements differ be-ween dialysis modalities. Nephrol Dial Transplant 13:1763-769, 1998266. Popovsky MA, Ransil BJ: Long-term impact of

ecombinant human erythropoietin on transfusion support inatients with chronic renal failure. Immunohematology2:1-3, 1996267. Eschbach JW: The anemia of chronic renal failure:

athophysiology and the effects of recombinant erythropoi-tin. Kidney Int 35:134-148, 1989

268. European Best Practice Guidelines for Renal Trans-lantation (part 1). Nephrol Dial Transplant 15:S1-S85,000 (suppl 7)269. Welch HG, Meehan KR, Goodnough LT: Prudent

trategies for elective red blood cell transfusion. Ann Interned 116:393-402, 1992270. American College of Physicians: Practice strategies

or elective red blood cell transfusion. Ann Intern Med16:403-406, 1992271. Crosby E, Ferguson D, Hume HA, Kronick JB,

arke B, LeBlond P, et al: Guidelines for red blood cell andlasma transfusion for adults and children. CMAJ 156:S1-24, 1997 (suppl 11)272. Ifudu O, Macey LJ, Friedman EA: Resurgence of

lood transfusion therapy in erythropoietin treated hemodi-lysis patients. ASAIO J 41:M426-M430, 1995

273. Casadevall N, Nataf J, Viron B, et al: Pure red-cellplasia and antierythropoietin antibodies in patients treatedith recombinant erythropoietin. N Engl J Med 346:469-75, 2002274. Rossert J, Casadevall N, Eckardt KU: Anti-

rythropoietin antibodies and pure red cell aplasia. J Am Socephrol 15:398-406, 2004275. Boven K, Stryker S, Knight J, et al: The increased

ncidence of pure red cell aplasia with an Eprex formulationn uncoated rubber stopper syringes. Kidney Int 67:2346-353, 2005276. Eckardt KU, Casadevall N: Pure red-cell aplasia due

o anti-erythropoietin antibodies. Nephrol Dial Transplant8:865-869, 2003277. Casadevall N, Cournoyer D, Marsh J, et al: Recom-
endations on haematological criteria for the diagnosis of E
poetin-induced pure red cell aplasia. Eur J Haematol3:389-396, 2004278. Bennett CL, Luminari S, Nissenson AR, et al: Pure

ed-cell aplasia and epoetin therapy. N Engl J Med 351:1403-408, 2004279. Cournoyer D, Toffelmire EB, Wells GA, et al:

nti-erythropoietin antibody-mediated pure red cell aplasiafter treatment with recombinant erythropoietin products:ecommendations for minimization of risk. J Am Socephrol 15:2728-2734, 2004280. Kausz AT, Solid C, Pereira BJ, Collins AJ, St Peter: Intractable anemia among hemodialysis patients: A sign

f suboptimal management or a marker of disease? Am Jidney Dis 45:136-147, 2005281. Cheng IK, Lu HB, Wei DC, Cheng SW, Chan CY,

ee FC: Influence of thalassemia on the response toecombinant human erythropoietin in dialysis patients. Am Jephrol 13:142-148, 1993282. Di Iorio B, Guastaferro P, Bellizzi V: Relationship

etween resistance to erythropoietin and high anomalousemoglobin levels in hemodialysis patients with beta-halassemia minor. Blood Purif 21:376-380, 2003

283. Lai KN, Wong KC, Li PK, Lui SF: Use of recombi-ant erythropoietin in thalassemic patients on dialysis. Am Jidney Dis 19:239-245, 1992284. Di Iorio B, De Nicola L, Bellizzi V, et al: Efficacy of

rythropoietin on dialysis in patients with beta thalassemiainor. Blood Purif 22:453-460, 2004285. Paritpokee N, Wiwanitkit V, Bhokaisawan N, Boon-

halermvichian C, Preechakas P: Serum erythropoietinevels in pediatric patients with beta-thalassemia/hemoglo-in E. Clin Lab 48:631-634, 2002286. Katopodis KP, Elisaf MS, Pappas HA, et al: Renal

bnormalities in patients with sickle cell-beta thalassemia. Jephrol 10:163-167, 1997287. Papassotiriou I, Traeger-Synodinos J, Kanavakis E,

aragiorga M, Stamoulakatou A, Kattamis C: Erythroidarrow activity and hemoglobin H levels in hemoglobin H

isease. J Pediatr Hematol Oncol 20:539-544, 1998288. Powe NR, Griffiths RI, Greer JW, et al: Early dosing

ractices and effectiveness of recombinant human erythro-oietin. Kidney Int 43:1125-1133, 1993289. Tomson CR, Edmunds ME, Chambers K, Bricknell S,

eehally J, Walls J: Effect of recombinant human erythropoi-tin on erythropoiesis in homozygous sickle-cell anaemiand renal failure. Nephrol Dial Transplant 7:817-821, 1992

290. Papassotiriou I, Voskaridou E, Stamoulakatou A,oukopoulos D: Increased erythropoietin level inducedy hydroxyurea treatment of sickle cell patients. Hematol1:295-300, 2000291. Dammacco F, Luccarelli G, Prete M, Silvestris F:

he role of recombinant human erythropoietin alpha in thereatment of chronic anemia in multiple myeloma. Rev Clinxp Hematol Suppl 1:S32-S38, 2002292. Weber G, Gross J, Kromminga A, Loew HH, Eckardt

U: Allergic skin and systemic reactions in a patient withure red cell aplasia and anti-erythropoietin antibodieshallenged with different epoetins. J Am Soc Nephrol3:2381-2383, 2002293. Verhelst D, Rossert J, Casadevall N, Kruger A,

ckardt KU, Macdougall IC: Treatment of erythropoietin-

i3

mr2

ep

rhD

rS

c

r

Tci

NN

EdC

hGHP

t6

fh

cr

RiN

Ic

Rcr

Zwd

foI

hk

Bef3

ht1

PaS

elP

e1

rc7

Sc

rM

cp

Spc

su1

n1

tN

hdP

M

REFERENCES S141

nduced pure red cell aplasia: A retrospective study. Lancet63:1768-1771, 2004294. Rossert J, Macdougall I, Casadevall N: Antibody-ediated pure red cell aplasia (PRCA) treatment and

e-treatment: Multiple options. Nephrol Dial Transplant0:Siv23-Siv26, 2005 (suppl 4)295. Asari A, Gokal R: Pure red cell aplasia secondary to

poetin alpha responding to darbepoetin alpha in a patient oneritoneal dialysis. J Am Soc Nephrol 15:2204-2207, 2004296. Tarng DC, Chang JG, Huang TP: Resistance to

ecombinant erythropoietin in a hemodialysis patient witheterozygous hemoglobinopathy J-Meinung. Am J Kidneyis 29:769-772, 1997297. Drueke TB: Resistance to recombinant human eryth-

opoietin in hemodialysis patients. Am J Nephrol 10:S34-39, 1990 (suppl 2)298. Ataga KI, Orringer EP: Renal abnormalities in sickle

ell disease. Am J Hematol 63:205-211, 2000299. Drueke TB: Modulating factors in the hematopoietic

esponse to erythropoietin. Am J Kidney Dis 18:87-92, 1991300. Yorgin PD, Belson A, Al-Uzri AY, Alexander SR:

he clinical efficacy of higher hematocrit levels inhildren with chronic renal insufficiency and those undergo-ng dialysis. Semin Nephrol 21:451-462, 2001

301. Greenbaum LA: Anemia management in children, inissenson AR, Fine RN (eds): Clinical Dialysis. New York,Y, McGraw Hill, 2005, pp 1111-1134302. McGonigle RJ, Boineau FG, Beckman B, et al:

rythropoietin and inhibitors of in vitro erythropoiesis in theevelopment of anemia in children with renal disease. J Lablin Med 105:449-458, 1985303. Nathan DG, Orkin SH: Appendix 11. Normal

ematologic values in children, in Nathan DG, Orkin SH,insburg D, Look AT, Oski FA (eds): Nathan and Oski’sematology of Infancy and Childhood (ed 6). Philadelphia,A, Saunders, 2003, p 1841304. Warady BA, Kausz A, Lerner G, et al: Iron therapy in

he pediatric hemodialysis population. Pediatr Nephrol 19:55-661, 2004305. Warady BA, Zobrist RH, Wu J, Finan E: Sodium

erric gluconate complex therapy in anemic children onemodialysis. Pediatr Nephrol 20:1320-1327, 2005306. Warady BA, Ho M: Morbidity and mortality in

hildren with anemia at initiation of dialysis. Pediatr Neph-ol 18:1055-1062, 2003

307. Mitsnefes MM, Daniels SR, Schwartz SM, MeyerA, Khoury P, Strife CF: Severe left ventricular hypertrophy

n pediatric dialysis: Prevalence and predictors. Pediatrephrol 14:898-902, 2000308. Mitsnefes MM, Kimball TR, Border WL, et al:

mpaired left ventricular diastolic function in children withhronic renal failure. Kidney Int 65:1461-1466, 2004

309. Martin GR, Ongkingo JR, Turner ME, Skurow ES,uley EJ: Recombinant erythropoietin (Epogen) improvesardiac exercise performance in children with end-stageenal disease. Pediatr Nephrol 7:276-280, 1993

310. Baraldi E, Montini G, Zanconato S, Zacchello G,acchello F: Exercise tolerance after anaemia correctionith recombinant human erythropoietin in end-stage renal
isease. Pediatr Nephrol 4:623-626, 1990 m
311. Bassi S, Montini G, Edefonti A, et al: Cardiovascularunction in a chronic peritoneal dialysis pediatric populationn recombinant human erythropoietin treatment. Perit Dialnt 13:S267-S269, 1993 (suppl 2)

312. Gerson A, Hwang W, Fiorenza J, et al: Anemia andealth-related quality of life in adolescents with chronicidney disease. Am J Kidney Dis 44:1017-1023, 2004313. Van Damme-Lombaerts R, Broyer M, Businger J,

aldauf C, Stocker H: A study of recombinant humanrythropoietin in the treatment of anaemia of chronic renalailure in children on haemodialysis. Pediatr Nephrol 8:338-42, 1994314. Kurtin PS, Landgraf JM, Abetz L: Patient-based

ealth status measurements in pediatric dialysis: Expandinghe assessment of outcome. Am J Kidney Dis 24:376-382,994315. Halterman JS, Kaczorowski JM, Aligne CA, Auinger

, Szilagyi PG: Iron deficiency and cognitive achievementmong school-aged children and adolescents in the Unitedtates. Pediatrics 107:1381-1386, 2001316. Burke JR: Low-dose subcutaneous recombinant

rythropoietin in children with chronic renal failure. Austra-ian and New Zealand Paediatric Nephrology Association.ediatr Nephrol 9:558-561, 1995317. Jabs K: The effects of recombinant human erythropoi-

tin on growth and nutritional status. Pediatr Nephrol0:324-327, 1996318. Scigalla P, Bonzel KE, Bulla M, et al: Therapy of

enal anemia with recombinant human erythropoietin inhildren with end-stage renal disease. Contrib Nephrol6:227-240; discussion 240-221, 1989319. Brandt JR, Avner ED, Hickman RO, Watkins SL:

afety and efficacy of erythropoietin in children withhronic renal failure. Pediatr Nephrol 13:143-147, 1999

320. Burghard R, Gordjani N, Leititis JU: [Treatment ofenal anemia with recombinant human erythropoietin].onatsschr Kinderheilkd 137:174-177, 1989321. Campos A, Garin EH: Therapy of renal anemia in

hildren and adolescents with recombinant human erythro-oietin (rHuEPO). Clin Pediatr (Phila) 31:94-99, 1992322. Offner G, Hoyer PF, Latta K, Winkler L, Brodehl J,

cigalla P: One year’s experience with recombinant erythro-oietin in children undergoing continuous ambulatory orycling peritoneal dialysis. Pediatr Nephrol 4:498-500, 1990

323. Sinai-Trieman L, Salusky IB, Fine RN: Use ofubcutaneous recombinant human erythropoietin in childrenndergoing continuous cycling peritoneal dialysis. J Pediatr14:550-554, 1989324. Eschbach JW, Adamson JW: Guidelines for recombi-

ant human erythropoietin therapy. Am J Kidney Dis 14:2-8,989325. North American Pediatric Renal Transplant Coopera-

ive Study (NAPRTCS) 2004 Annual Report. Boston, MA,APRTCS Administrative Office, 2004326. Sieniawska M, Roszkowska-Blaim M: Recombinant

uman erythropoietin dosage in children undergoing hemo-ialysis and continuous ambulatory peritoneal dialysis.ediatr Nephrol 11:628-630, 1997327. Port RE, Kiepe D, Van Guilder M, Jelliffe RW,ehls O: Recombinant human erythropoietin for the treat-
ent of renal anaemia in children: no justification for

b2

t

eg

nk

Hc1

op(

TiP

Lc1

rE

t1

Gp

ah7

Pc7

Lid

Ic2

Hf

pN

iP

BL

Ina

rIh8

Kp9

JpM

fc

Ccm

Pd

t3

Sf

k1

sdS

if

df

KcK

Oid

up

REFERENCESS142

odyweight-adjusted dosage. Clin Pharmacokinet 43:57-70,004328. Juul SE: Nonerythropoietic roles of erythropoietin in

he fetus and neonate. Clin Perinatol 27:527-541, 2000329. De Palo T, Giordano M, Palumbo F, et al: Clinical

xperience with darbepoietin alfa (NESP) in children under-oing hemodialysis. Pediatr Nephrol 19:337-340, 2004330. Lerner G, Kale AS, Warady BA, et al: Pharmacoki-

etics of darbepoetin alfa in pediatric patients with chronicidney disease. Pediatr Nephrol 17:933-937, 2002331. Geary DF, Keating LE, Vigneux A, Stephens D,

ebert D, Harvey EA: Darbepoetin alfa (Aranesp) inhildren with chronic renal failure. Kidney Int 68:1759-765, 2005332. Bald M, Holder M, Leichter HE: Improved therapy

f renal anemia after switching to darbepoietin (NESP) ineritoneal dialysis patients. Pediatr Nephrol 9:249A, 2002abstr)

333. Scharer K, Klare B, Braun A, Dressel P, Gretz N:reatment of renal anemia by subcutaneous erythropoietin

n children with preterminal chronic renal failure. Actaaediatr 82:953-958, 1993334. Yalcinkaya F, Tumer N, Cakar N, Ozkaya N:

ow-dose erythropoietin is effective and safe in children onontinuous ambulatory peritoneal dialysis. Pediatr Nephrol1:350-352, 1997335. Schroder CH: The management of anemia in pediat-

ic peritoneal dialysis patients. Guidelines by an ad hocuropean committee. Pediatr Nephrol 18:805-809, 2003336. Van Damme-Lombaerts R, Herman J: Erythropoietin

reatment in children with renal failure. Pediatr Nephrol3:148-152, 1999337. Gershanik J, Boecler B, Ensley H, McCloskey S,

eorge W: The gasping syndrome and benzyl alcoholoisoning. N Engl J Med 307:1384-1388, 1982338. Hiller JL, Benda GI, Rahatzad M, et al: Benzyl

lcohol toxicity: impact on mortality and intraventricularemorrhage among very low birth weight infants. Pediatrics7:500-506, 1986339. Evans JH, Brocklebank JT, Bowmer CJ, Ng PC:

harmacokinetics of recombinant human erythropoietin inhildren with renal failure. Nephrol Dial Transplant 6:709-14, 1991340. Reddingius RE, Schroder CH, Koster AM, Monnens

A: Pharmacokinetics of recombinant human erythropoietinn children treated with continuous ambulatory peritonealialysis. Eur J Pediatr 153:850-854, 1994341. Seeherunvong W, Rubio L, Abitbol CL, et al:

dentification of poor responders to erythropoietin amonghildren undergoing hemodialysis. J Pediatr 138:710-714,001342. Muller-Wiefel DE, Sinn H, Gilli G, Scharer K:

emolysis and blood loss in children with chronic renalailure. Clin Nephrol 8:481-486, 1977

343. Gillespie RS, Wolf FM: Intravenous iron therapy inediatric hemodialysis patients: A meta-analysis. Pediatrephrol 19:662-666, 2004344. Morgan HE, Gautam M, Geary DF: Maintenance

ntravenous iron therapy in pediatric hemodialysis patients.
ediatr Nephrol 16:779-783, 2001 t
345. Cook JD, Carriaga M, Kahn SG, Schalch W, SkikneS: Gastric delivery system for iron supplementation.ancet 335:1136-1139, 1990346. Goch J, Birgegard G, Danielson BG, Wikstrom B:

ron absorption in patients with chronic uremia on mainte-ance hemodialysis and in healthy volunteers measured withsimple oral iron load test. Nephron 73:403-406, 1996347. Ruiz-Jaramillo Mde L, Guizar-Mendoza JM, Gutier-

ez-Navarro Mde J, Dubey-Ortega LA, Amador-Licona N:ntermittent versus maintenance iron therapy in children onemodialysis: A randomized study. Pediatr Nephrol 19:77-1, 2004348. Greenbaum LA, Pan CG, Caley C, Nelson T, Sheth

J: Intravenous iron dextran and erythropoietin use inediatric hemodialysis patients. Pediatr Nephrol 14:908-11, 2000349. Frankenfield DL, Neu AM, Warady BA, Fivush BA,

ohnson CA, Brem AS: Anemia in pediatric hemodialysisatients: Results from the 2001 ESRD Clinical Performanceeasures Project. Kidney Int 64:1120-1124, 2003350. Tenbrock K, Muller-Berghaus J, Michalk D, Quer-

eld U: Intravenous iron treatment of renal anemia inhildren on hemodialysis. Pediatr Nephrol 13:580-582, 1999

351. Morris KP, Watson S, Reid MM, Hamilton PJ,oulthard MG: Assessing iron status in children withhronic renal failure on erythropoietin: Which measure-ents should we use? Pediatr Nephrol 8:51-56, 1994352. Brugnara C, Zurakowski D, DiCanzio J, Boyd T,

latt O: Reticulocyte hemoglobin content to diagnose ironeficiency in children. JAMA 281:2225-2230, 1999353. Bothwell TH, Pirzio-Biroli G, Finch CA: Iron absorp-

ion. I. Factors influencing absorption. J Lab Clin Med 51:24-6, 1958354. Yorgin PD, Belson A, Sarwal M, Alexander SR:

odium ferric gluconate therapy in renal transplant and renalailure patients. Pediatr Nephrol 15:171-175, 2000

355. Danielson BG: Structure, chemistry, and pharmaco-inetics of intravenous iron agents. J Am Soc Nephrol5:S93-S98, 2004 (suppl 2)356. Ahsan N: Intravenous infusion of total dose iron is

uperior to oral iron in treatment of anemia in peritonealialysis patients: A single center comparative study. J Amoc Nephrol 9:664-668, 1998357. Anuradha S, Singh NP, Agarwal SK: Total dose

nfusion iron dextran therapy in predialysis chronic renalailure patients. Ren Fail 24:307-313, 2002

358. Dahdah K, Patrie JT, Bolton WK: Intravenous ironextran treatment in predialysis patients with chronic renalailure. Am J Kidney Dis 36:775-782, 2000

359. Domrongkitchaiporn S, Jirakranont B, Atamasrikul, Ungkanont A, Bunyaratvej A: Indices of iron status in

ontinuous ambulatory peritoneal dialysis patients. Am Jidney Dis 34:29-35, 1999360. Prakash S, Walele A, Dimkovic N, Bargman J, Vas S,

reopoulos D: Experience with a large dose (500 mg) ofntravenous iron dextran and iron saccharate in peritonealialysis patients. Perit Dial Int 21:290-295, 2001361. Folkert VW, Michael B, Agarwal R, et al: Chronic

se of sodium ferric gluconate complex in hemodialysisatients: safety of higher-dose (� or �250 mg) administra-
ion. Am J Kidney Dis 41:651-657, 2003

i1

M

e

f2

sh1

Pc

aP

cce

Eo1

L

p6

Se1

PJ

s2

Mcr

ir

rt2

DpO

DK

Wf1

Ji1

GcT

Nt

At

Dk

e6

Kte1

Lar1

iP

t(

Kf2

aK

t

Aal

hy4

Pr

REFERENCES S143

362. Leijn E, Monnens LA, Cornelissen EA: Intravenousron supplementation in children on hemodialysis. J Nephrol7:423-426, 2004363. Puntarulo S: Iron, oxidative stress and human health.ol Aspects Med 26:299-312, 2005364. Erdemoglu AK, Ozbakir S: Serum ferritin levels and

arly prognosis of stroke. Eur J Neurol 9:633-637, 2002365. Gulcelik NE, Kayatas M: Importance of serum

erritin levels in patients with renal failure. Nephron 92:230-31, 2002366. Gloggler A, Bulla M, Furst P: Effect of low dose

upplementation of L-carnitine on lipid metabolism inemodialyzed children. Kidney Int Suppl 27:S256-S258,989367. Gloggler A, Bulla M, Puchstein C, Gulotta F, Furst P:

lasma and muscle carnitine in healthy and hemodialyzedhildren. Child Nephrol Urol 9:277-282, 1988

368. Zachwieja J, Duran M, Joles JA, et al: Amino acidnd carnitine supplementation in haemodialysed children.ediatr Nephrol 8:739-743, 1994369. Murakami R, Momota T, Yoshiya K, et al: Serum

arnitine and nutritional status in children treated withontinuous ambulatory peritoneal dialysis. J Pediatr Gastro-nterol Nutr 11:371-374, 1990

370. Warady BA, Borum P, Stall C, Millspaugh J, Taggart, Lum G: Carnitine status of pediatric patients on continu-us ambulatory peritoneal dialysis. Am J Nephrol 10:109-14, 1990371. Berard E, Iordache A: Effect of low doses of

-carnitine on the response to recombinant human erythro-oietin in hemodialyzed children: About two cases. Nephron2:368-369, 1992372. Lilien MR, Duran M, Quak JM, Frankhuisen JJ,

chroder CH: Oral L-carnitine does not decrease erythropoi-tin requirement in pediatric dialysis. Pediatr Nephrol5:17-20, 2000373. Goodman AM, Pollack MM, Patel KM, Luban NL:

ediatric red blood cell transfusions increase resource use.Pediatr 142:123-127, 2003374. Hume HA, Limoges P: Perioperative blood transfu-

ion therapy in pediatric patients. Am J Ther 9:396-405,002375. Niaudet P, Dudley J, Charbit M, Gagnadoux MF,acleay K, Broyer M: Pretransplant blood transfusions with

yclosporine in pediatric renal transplantation. Pediatr Neph-ol 14:451-456, 2000

376. Gill JS, Tonelli M, Mix CH, Pereira BJ: The changen allograft function among long-term kidney transplantecipients. J Am Soc Nephrol 14:1636-1642, 2003

377. Gill JS, Mix CH, Pereira BJ: Glomerular filtrationate and the prevalence of chronic kidney disease amongransplant recipients in the United States. Am J Transplant:358A, 2002 (abstr)377A. Levey AS, Eckardt KU, Tsukamoto Y, et al:

efinition and classification of chronic kidney disease: Aosition statement from Kidney Disease: Improving Globalutcomes (KDIGO). Kidney Int 67:2089-2100, 2005378. Besarab A, Caro J, Jarrell BE, Francos G, Erslev AJ:

ynamics of erythropoiesis following renal transplantation.
idney Int 32:526-536, 1987 2
379. Beshara S, Birgegard G, Goch J, Wahlberg J,ikstrom B, Danielson BG: Assessment of erythropoiesis

ollowing renal transplantation. Eur J Haematol 58:167-173,997380. Brown JH, Lappin TR, Elder GE, Taylor TN, Bridges

M, McGeown MG: The initiation of erythropoiesis follow-ng renal transplantation. Nephrol Dial Transplant 4:1076-079, 1989381. Moore LW, Smith SO, Winsett RP, Acchiardo SR,

aber AO: Factors affecting erythropoietin production andorrection of anemia in kidney transplant recipients. Clinransplant 8:358-364, 1994382. Sun CH, Ward HJ, Paul WL, Koyle MA, Yanagawa

, Lee DB: Serum erythropoietin levels after renal transplan-ation. N Engl J Med 321:151-157, 1989

383. Tornero F, Prats D,Alvarez-Sala JL, Coronel F, Sanchez, Barrientos A: Iron deficiency anemia after successful renal

ransplantation. J Urol 149:1398-1400, 1993384. Goch J, Birgegard G, Wikstrom B, Tufveson G,

anielson BG: Serum erythropoietin levels in the immediateidney-posttransplant period. Nephron 60:30-34, 1992385. Wolff M, Jelkmann W: Erythropoiesis and erythropoi-

tin levels in renal transplant recipients. Klin Wochenschr9:53-58, 1991386. Nampoory MR, Johny KV, al-Hilali N, Seshadri MS,

anagasabhapathy AS: Erythropoietin deficiency and rela-ive resistance cause anaemia in post-renal transplant recipi-nts with normal renal function. Nephrol Dial Transplant1:177-181, 1996387. Van Loo A, Vanholder R, Bernaert P, De Roose J,

ameire N: Recombinant human erythropoietin correctsnaemia during the first weeks after renal transplantation: Aandomized prospective study. Nephrol Dial Transplant1:1815-1821, 1996388. Arbeiter K, Greenbaum L, Balzar E, et al: Reproduc-

ble erythroid aplasia caused by mycophenolate mofetil.ediatr Nephrol 14:195-197, 2000389. Kessler M: Erythropoietin and erythropoiesis in renal

ransplantation. Nephrol Dial Transplant 10:S114-S116, 1995suppl 6)

390. Eckardt KU, Frei U, Kliem V, Bauer C, Koch KM,urtz A: Role of excretory graft function for erythropoietin

ormation after renal transplantation. Eur J Clin Invest0:563-572, 1990391. Lee DB: Interrelationship between erythropoietin

nd erythropoiesis: Insights from renal transplantation. Am Jidney Dis 18:54-56, 1991392. Muirhead N: Erythropoietin and renal transplanta-

ion. Kidney Int Suppl 69:S86-S92, 1999393. Yorgin PD, Scandling JD, Belson A, Sanchez J,

lexander SR, Andreoni KA: Late post-transplant anemia indult renal transplant recipients. An under-recognized prob-em? Am J Transplant 2:429-435, 2002

394. Yorgin PD, Belson A, Sanchez J, et al: Unexpectedlyigh prevalence of posttransplant anemia in pediatric andoung adult renal transplant recipients. Am J Kidney Dis0:1306-1318, 2002395. Vanrenterghem Y, Ponticelli C, Morales JM, et al:

revalence and management of anemia in renal transplantecipients: A European survey. Am J Transplant 3:835-845,
003

mp2

N3

N3

cT

WaN

GoN

kc

p5

be

fi

a4

eA

Mr2

HJ

GD

Hs

taD

aK

J

tT

Bo

CrD

l9

icrt

oU3

Smp

tm2

NauN

afK

rt1

BMrr

sa

Lhi7

Tir

REFERENCESS144

395A. Gill JS, Solid C, Pereira BJG, Collins AJ: Anemiaanagement prior to kidney transplantation and the risk of

ost-transplant blood transfusion. Am J Transplant 4:S484,004 (suppl 8) (abstr 1191)396. Saito S, Fujiwara T, Sakagami K, Matsuno T, Tanaka

: Anemia following renal transplantation. Transplant Proc0:3025-3026, 1998397. Saito S, Fujiwara T, Sakagami K, Matsuno T, Tanaka

: Anemia following renal transplantation. Transplant Proc0:3025-3026., 1998398. Mix TC, Kazmi W, Khan S, et al: Anemia: A

ontinuing problem following kidney transplantation. Am Jransplant 3:1426-1433, 2003399. Lorenz M, Kletzmayr J, Perschl A, Furrer A, HorlH, Sunder-Plassmann G: Anemia and iron deficiencies

mong long-term renal transplant recipients. J Am Socephrol 13:794-797, 2002400. Winkelmayer WC, Kewalramani R, Rutstein M,

abardi S, Vonvisger T, Chandraker A: Pharmacoepidemiol-gy of anemia in kidney transplant recipients. J Am Socephrol 15:1347-1352, 2004401. Shibagaki Y, Shetty A: Anaemia is common after

idney transplantation, especially among African Ameri-ans. Nephrol Dial Transplant 19:2368-2373, 2004

402. Kausman JY, Powell HR, Jones CL: Anemia inediatric renal transplant recipients. Pediatr Nephrol 19:526-30, 2004403. Karthikeyan V, Karpinski J, Nair RC, Knoll G: The

urden of chronic kidney disease in renal transplant recipi-nts. Am J Transplant 4:262-269, 2004

404. Miles AM, Markell MS, Daskalakis P, et al: Anemiaollowing renal transplantation: Erythropoietin response andron deficiency. Clin Transplant 11:313-315, 1997

405. Teruel JL, Lamas S, Vila T, et al: Serum ferritin levelsfter renal transplantation: A prospective study. Nephron 51:62-465, 1989406. Moulin B, Ollier J, George F, et al: Serum erythropoi-

tin and reticulocyte maturity index after renal transplantation:prospective longitudinal study. Nephron 69:259-266, 1995407. Chua MS, Barry C, Chen X, Salvatierra O, SarwalM: Molecular profiling of anemia in acute renal allograft

ejection using DNA microarrays. Am J Transplant 3:17-22,003408. Creemers GJ, van Boven WP, Lowenberg B, van der

eul C: Azathioprine-associated pure red cell aplasia.Intern Med 233:85-87, 1993409. Pruijt JF, Haanen JB, Hollander AA, den Ottolander

J: Azathioprine-induced pure red-cell aplasia. Nephrolial Transplant 11:1371-1373, 1996410. Abraham KA, Little MA, Dorman AM, Walshe JJ:

emolytic-uremic syndrome in association with both cyclo-porine and tacrolimus. Transpl Int 13:443-447, 2000

411. Epstein M, Landsberg D: Cyclosporine-inducedhrombotic microangiopathy resulting in renal allograft lossnd its successful reuse: A report of two cases. Am J Kidneyis 17:346-348, 1991412. Pham PT, Peng A, Wilkinson AH, et al: Cyclosporine

nd tacrolimus-associated thrombotic microangiopathy.Am Jidney Dis 36:844-850, 2000413. Trimarchi HM, Truong LD, Brennan S, Gonzalez

M, Suki WN: FK506-associated thrombotic microangiopa- 8

hy: Report of two cases and review of the literature.ransplantation 67:539-544, 1999414. Zarifian A, Meleg-Smith S, O’Donovan R, Tesi RJ,

atuman V: Cyclosporine-associated thrombotic microangi-pathy in renal allografts. Kidney Int 55:2457-2466, 1999415. Dussol B, Brunet P, Vacher-Coponat H, Saingra Y,

asanova P, Berland Y: Haemolytic uraemic syndrome in aenal transplant recipient during OKT3 therapy. Nephrolial Transplant 9:1191-1193, 1994416. Morris-Stiff G, Evans M, Baboolal K, et al: Haemo-

ytic uraemic syndrome associated with OKT3. Transpl Int:522-523, 1996417. MacDonald AS: A worldwide, phase III, random-

zed, controlled, safety and efficacy study of a sirolimus/yclosporine regimen for prevention of acute rejection inecipients of primary mismatched renal allografts. Transplan-ation 71:271-280, 2001

418. Kahan BD, Knight R, Schoenberg L, et al: Ten yearsf sirolimus therapy for human renal transplantation: Theniversity of Texas at Houston experience. Transplant Proc5:S25-S34, 2003 (suppl 3)419. Augustine JJ, Knauss TC, Schulak JA, Bodziak KA,

iegel C, Hricik DE: Comparative effects of sirolimus andycophenolate mofetil on erythropoiesis in kidney trans-

lant patients. Am J Transplant 4:2001-2006, 2004420. Crew RJ, Radhakrishnan J, Cohen DJ, et al: De novo

hrombotic microangiopathy following treatment with siroli-us: Report of two cases. Nephrol Dial Transplant 20:203-

09, 2005421. Naito M, Kawashima A, Akiba T, Takanashi M,

ihei H: Effects of an angiotensin II receptor antagonist andngiotensin-converting enzyme inhibitors on burst formingnits-erythroid in chronic hemodialysis patients. Am Jephrol 23:287-293, 2003422. Le Meur Y, Lorgeot V, Comte L, et al: Plasma levels

nd metabolism of AcSDKP in patients with chronic renalailure: Relationship with erythropoietin requirements. Am Jidney Dis 38:510-517, 2001423. So BJ, Chae KM, Lee KK, Lee YJ, Jeong BH: Pure

ed cell aplasia due to parvovirus B19 infection in a renalransplant patient: A case report. Transplant Proc 32:1954-956, 2000424. Vales-Albertos LJ, Garcia-Cardenas M, Chavez-

ecerra S, Gomez-Navarro B, Monteon-Ramos F, Cueto-anzano AM: Pure red cell aplasia associated with parvovi-

us B19 infection in renal transplantation: The first caseeport in Mexico. Transplantation 79:739, 2005 (abstr)

425. Karras A, Thervet E, Legendre C: Hemophagocyticyndrome in renal transplant recipients: Report of 17 casesnd review of literature. Transplantation 77:238-243, 2004

426. Artz MA, Steenbergen EJ, Hoitsma AJ, MonnensA, Wetzels JF: Renal transplantation in patients withemolytic uremic syndrome: High rate of recurrence andncreased incidence of acute rejections. Transplantation6:821-826, 2003427. Asaka M, Ishikawa I, Nakazawa T, Tomosugi N, Yuri

, Suzuki K: Hemolytic uremic syndrome associated withnfluenza A virus infection in an adult renal allograftecipient: Case report and review of the literature. Nephron
4:258-266, 2000

mt3

Jitl

ScU

eP

rp

Hc

a

anN

Pep

Jeh

Prb2

Sct

Pr

MgT

et

RoT

L

tT

me

ef

NT

Hi6

ei

pJ

p

es

Lo1

aid

hr

rt4

Er1

bt

g

Bk

Pha2

e

REFERENCES S145

428. Waiser J, Budde K, Rudolph B, Ortner MA, Neu-ayer HH: De novo hemolytic uremic syndrome postrenal

ransplant after cytomegalovirus infection. Am J Kidney Dis4:556-559, 1999429. Laurence J, Mitra D, Steiner M, Staiano-Coico L,

affe E: Plasma from patients with idiopathic and humanmmunodeficiency virus-associated thrombotic thrombocy-openic purpura induces apoptosis in microvascular endothe-ial cells. Blood 87:3245-3254, 1996

430. Anagnostou A, Lee ES, Kessimian N, Levinson R,teiner M: Erythropoietin has a mitogenic and positivehemotactic effect on endothelial cells. Proc Natl Acad SciSA 87:5978-5982, 1990431. Anagnostou A, Liu Z, Steiner M, et al: Erythropoi-

tin receptor mRNA expression in human endothelial cells.roc Natl Acad Sci U S A 91:3974-3978, 1994432. Carlini RG, Alonzo EJ, Dominguez J, et al: Effect of

ecombinant human erythropoietin on endothelial cell apo-tosis. Kidney Int 55:546-553, 1999433. Debska-Slizien A, Chamienia A, Krol E, et al:

emolytic anemia after renal transplantation: Analysis ofase reports. Transplant Proc 35:2233-2237, 2003

434. Li FK, Chan TM, Lai KN: Alloimmune hemolysisfter renal transplantation. Am J Nephrol 20:473-475, 2000

435. Peces R, Diaz Corte C, Navascues RA: [Hemolyticnemia caused by graft-versus-host reaction in ABO-onidentical renal transplants from blood group O donors].efrologia 21:395-401, 2001436. Djamali A, Becker YT, Simmons WD, Johnson CA,

remasathian N, Becker BN: Increasing hematocrit reducesarly posttransplant cardiovascular risk in diabetic trans-lant recipients. Transplantation 76:816-820, 2003437. Rigatto C, Parfrey P, Foley R, Negrijn C, Tribula C,

effery J: Congestive heart failure in renal transplant recipi-nts: Risk factors, outcomes, and relationship with ischemiceart disease. J Am Soc Nephrol 13:1084-1090, 2002438. Rigatto C, Foley R, Jeffery J, Negrijn C, Tribula C,

arfrey P: Electrocardiographic left ventricular hypertrophy inenal transplant recipients: Prognostic value and impact oflood pressure and anemia. J Am Soc Nephrol 14:462-468,003439. Winkelmayer WC, Lorenz M, Kramar R, Horl WH,

under-Plassmann G: Percentage of hypochromic red bloodells is an independent risk factor for mortality in kidneyransplant recipients. Am J Transplant 4:2075-2081, 2004

440. Khan S, Tighiouart H, Kalra A, Raman G, Rohrer RJ,ereira BJ: Resource utilization among kidney transplantecipients. Kidney Int 64:657-664, 2003

441. Schmidt R, Kupin W, Dumler F, Venkat KK, Mozes: Influence of the pretransplant hematocrit level on early

raft function in primary cadaveric renal transplantation.ransplantation 55:1034-1040, 1993442. Vasquez EM, Pollak R: Effect of pretransplant

rythropoietin therapy on renal allograft outcome. Transplan-ation 62:1026-1028, 1996

443. Paganini EP, Braun WE, Latham D, Abdulhadi MH:enal transplantation: results in hemodialysis patients previ-usly treated with recombinant human erythropoietin.ASAIOrans 35:535-538, 1989444. Van Biesen W, Vanholder R, Veys N, Verbeke F,

ameire N: Efficacy of erythropoietin administration in the 1

reatment of anemia immediately after renal transplantation.ransplantation 79:367-368, 2005444A. Nagarajan S, Vidhun J, Mansfield E, et al: Molecularechanisms of transplant renal artery stenosis from early use of

rythropoietin.Am J Transplant 4:S568-S569, 2004 (suppl 8)445. Bagnis C, Beaufils H, Jacquiaud C, et al: Erythropoi-

tin enhances recovery after cisplatin-induced acute renalailure in the rat. Nephrol Dial Transplant 16:932-938, 2001

446. Cerami A, Brines M, Ghezzi P, Cerami C, Itri LM:europrotective properties of epoetin alfa. Nephrol Dialransplant 17:S8-S12, 2002 (suppl 1)447. Fishbane S, Ragolia L, Palaia T, Johnson B, Elzein

, Maesaka JK: Cytoprotection by darbepoetin/epoetin alfan pig tubular and mouse mesangial cells. Kidney Int5:452-458, 2004448. Grimm C, Wenzel A, Groszer M, et al: HIF-1-induced

rythropoietin in the hypoxic retina protects against light-nduced retinal degeneration. Nat Med 8:718-724, 2002

449. Parsa CJ, Matsumoto A, Kim J, et al: A novelrotective effect of erythropoietin in the infarcted heart.Clin Invest 112:999-1007, 2003450. Westenfelder C: Unexpected renal actions of erythro-

oietin. Exp Nephrol 10:294-298, 2002451. Yang CW, Li C, Jung JY, et al: Preconditioning with

rythropoietin protects against subsequent ischemia-reperfu-ion injury in rat kidney. FASEB J 17:1754-1755, 2003

452. Jindal KK, Hirsch DJ, Belitsky P, Whalen MA:ow-dose subcutaneous erythropoietin corrects the anaemiaf renal transplant failure. Nephrol Dial Transplant 7:143-46, 1992453. Muirhead N, Cattran DC, Zaltzman J, et al: Safety

nd efficacy of recombinant human erythropoietin in correct-ng the anemia of patients with chronic renal allograftysfunction. J Am Soc Nephrol 5:1216-1222, 1994454. Traindl O, Barnas U, Franz M, et al: Recombinant

uman erythropoietin in renal transplant recipients withenal anemia. Clin Transplant 8:45-48, 1994

455. Yoshimura N, Oka T, Ohmori Y, Aikawa I: Effects ofecombinant human erythropoietin on the anemia of renalransplant recipients with chronic rejection. Transplantation8:527-529, 1989456. Becker BN, Becker YT, Leverson GE, Heisey DM:

rythropoietin therapy may retard progression in chronicenal transplant dysfunction. Nephrol Dial Transplant 17:667-1673, 2002457. Lezaic V, Djukanovic L, Pavlovic-Kentera V: Recom-

inant human erythropoietin treatment of anemia in renalransplant patients. Ren Fail 17:705-714, 1995

458. Page B, Zingraff J: Resistance to rHuEpo and kidneyraft rejection. Nephrol Dial Transplant 9:1696-1697, 1994459. Gill JS, Abichandani R, Khan S, Kausz AT, Pereira

J: Opportunities to improve the care of patients withidney transplant failure. Kidney Int 61:2193-2200, 2002460. Lopez-Gomez JM, Perez-Flores I, Jofre R, et al:

resence of a failed kidney transplant in patients who are onemodialysis is associated with chronic inflammatory statend erythropoietin resistance. J Am Soc Nephrol 15:2494-501, 2004461. Atkins D, Best D, Briss PA, et al: Grading quality of

vidence and strength of recommendations. BMJ 328:1490-
494, 2004

American Journal ofKidney Diseases

W . B . S a u n d e r s , a n I m p r i n t o f E l s e v i e r

VOL 47, NO 5, SUPPL 3, MAY 2006Supplement to

Vol 47, N

o 5, Suppl 3, May 2006 pp S1-S146

Am

erican Journal of Kidney D

iseases

KDOQI Clinical Practice Guidelines and ClinicalPractice Recommendations for Anemia

in Chronic Kidney Disease

zkd1050600spc1 4/28/06 2:17 PM Page 1

creo

Anemia in Ckd

Documents

Transcript of Anemia in Ckd