KDIGO Controversies Conference on Glomerular...
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1 KDIGO Controversies Conference on Glomerular Diseases November 16-19, 2017 Singapore Kidney Disease: Improving Global Outcomes (KDIGO) is an international organization whose mission is to improve the care and outcomes of kidney disease patients worldwide by promoting coordination, collaboration, and integration of initiatives to develop and implement clinical practice guidelines. Periodically, KDIGO hosts conferences on topics of importance to patients with kidney disease. These conferences are designed to review the state of the art on a focused subject and to ask conference participants to determine what needs to be done in this area to improve patient care and outcomes. Sometimes the recommendations from these conferences lead to KDIGO guideline efforts and other times they highlight areas for which additional research is needed to produce evidence that might lead to guidelines in the future. Background Glomerular diseases, excluding diabetic nephropathy, account for about 25% of the cases of chronic kidney disease worldwide. 1, 2 However this varies considerably between countries from a low of about 10% in Latin America to over 50% in China. 1 In the United States, the prevalence of end-stage kidney disease (ESKD) due to a glomerular disease is about 300 per million population, making glomerular disease the third most important cause of ESKD in the country . 3 Given the magnitude of long-term morbidity from glomerular diseases and in particular its frequent manifestation in younger patients, it is critical that they be diagnosed efficiently and that management be optimized to control disease and prevent progressive renal insufficiency. Traditionally the diagnosis of a glomerular disease rests on the histologic evaluation of a kidney biopsy. The kidney biopsy or the ability to interpret the biopsy is not
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Transcript of KDIGO Controversies Conference on Glomerular...
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KDIGOControversiesConferenceonGlomerularDiseases
November16-19,2017Singapore
KidneyDisease:ImprovingGlobalOutcomes(KDIGO)isaninternationalorganizationwhosemissionistoimprovethecareandoutcomesofkidneydiseasepatientsworldwidebypromotingcoordination,collaboration,andintegrationofinitiativestodevelopandimplementclinicalpracticeguidelines.Periodically,KDIGOhostsconferencesontopicsofimportancetopatientswithkidneydisease.Theseconferencesaredesignedtoreviewthestateoftheartonafocusedsubjectandtoaskconferenceparticipantstodeterminewhatneedstobedoneinthisareatoimprovepatientcareandoutcomes.SometimestherecommendationsfromtheseconferencesleadtoKDIGOguidelineeffortsandothertimestheyhighlightareasforwhichadditionalresearchisneededtoproduceevidencethatmightleadtoguidelinesinthefuture.
BackgroundGlomerulardiseases,excludingdiabeticnephropathy,accountforabout25%ofthecasesofchronickidneydiseaseworldwide.1,2Howeverthisvariesconsiderablybetweencountriesfromalowofabout10%inLatinAmericatoover50%inChina.1IntheUnitedStates,theprevalenceofend-stagekidneydisease(ESKD)duetoaglomerulardiseaseisabout300permillionpopulation,makingglomerulardiseasethethirdmostimportantcauseofESKDinthecountry.3Giventhemagnitudeoflong-termmorbidityfromglomerulardiseasesandinparticularitsfrequentmanifestationinyoungerpatients,itiscriticalthattheybediagnosedefficientlyandthatmanagementbeoptimizedtocontroldiseaseandpreventprogressiverenalinsufficiency.Traditionallythediagnosisofaglomerulardiseaserestsonthehistologicevaluationofakidneybiopsy.Thekidneybiopsyortheabilitytointerpretthebiopsyisnot
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universallyavailablethroughouttheworldandevenwhenavailable,someplatforms,suchaselectronmicroscopymaynotbereadilyaccessible.Thereforeanunmetneedinthenephrologycommunityistheidentificationofserumorurinebiomarkersofrenalpathologytosupplement,orinsomecasessubstituteforthebiopsy,atleastindevelopingnations.Forsomeglomerulardiseases,likemembranousnephropathy,anti-phospholipaseA2receptorantibodytitersbegintoaddressthisneedbuthowtousethisantibodytooptimizeclinicalmanagementisstillcontroversial.4Biomarkersofkidneyhistologyarebeingsoughtinotherglomerulardiseases.5Innationswithmoreaccesstohealthcareresources,thequestionariseswhethersimplehistologyofthekidneyissufficienttoevaluatethekidneybiopsy,oriftheapplicationofmolecularpathologymayaddtoourunderstandingofdiseaseheterogeneitywithintypesofglomerulardiseasethatcouldbeusedtooptimizetreatment.6,7Themanagementofglomerulardiseasedependsonthetypeofglomerulonephritis(GN),butinalmostallcasesreliesonnon-specific,broad-spectrumimmunosuppression.Thisresultsinsuboptimalefficacyandconsiderabledrug-relatedtoxicity.8Anumberofrandomizedclinicaltrialsofnovelimmunomodulatorytherapeuticshavebeenconductedoverthelastfewyearsinseveralglomerulardiseases.Overallmanyofthesetrialshavenotsucceeded,butimportantlessonsmaybetakenfromthefailures.Ontheotherhand,afewnoveldrugshavebeenapprovedandafewphaseIItrialshavebeenverypromising.9Thisincreasingmenuofavailabledrugsaddstotheconfusionofhowtotreatpatientsandraisesthequestionofsortingoutnewerdrugsfromboththesuccessfulandfailedtrials.9-14Theeffectsoftherapyinglomerulardiseasesarefollowedclinicallybychangesinproteinuriaandkidneyfunction(serumcreatinineconcentration[SCr]orestimatedglomerularfiltrationrate[eGFR]).ProteinuriahasnotbeenacceptedbytheUSFoodandDrugAdministrationasasufficientendpointforclinicaltrialsingeneral,buttherenowseemstobeachangeinthisposition,especiallyifspecificlevelsofproteinuriacanpredictspecificlong-termkidneyoutcomesforindividualGNs.15,16
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Proteinuriaisareasonablemarkerearlyindisease,butovertime,andwithscarringoftherenalparenchyma,itbecomesdifficulttodistinguishproteinuriaduetodiseaseactivityfromproteinuriaduetoobliterativenephropathyfromnephronloss.Inaddition,SCrandeGFRarealsopoormarkersofintactnephronmass.Thusthebestwaystofollowpatientswithglomerulardiseasehavenotbeenestablished.Thisisanareawaitingforbiomarkerstobeidentifiedandvalidated,butuntilthattimeguidelinesontheinterpretationandapplicationoftraditionalclinicalparametersmustbereviewed.17ConferenceOverviewTheobjectiveofthisKDIGOconferenceistogatheraglobalpanelofmultidisciplinaryclinicalandscientificexpertise(nephrology,pathology,rheumatology,pediatrics,etc.)toidentifykeyissuesrelevanttotheoptimalmanagementofprimaryandsecondaryglomerulardiseases.ThegoalofthisKDIGOconferenceistodeterminebestpracticetreatmentandareasofuncertaintiesinthetreatmentofglomerulardiseases,reviewkeyrelevantliteraturepublishedsincethe2012KDIGOGNGuideline,identifytopicsorissuesthatwarrantrevisitingforfutureguidelineupdating,andoutlineresearchneededtoimproveGNmanagement.Drs.JürgenFloege(UniversityofAachen,Germany)andBradRovin(OhioStateUniversity,USA)willco-chairthisconference.Theformatoftheconferencewillinvolvetopicalplenarysessionpresentationsfollowedbyfocuseddiscussiongroupsthatwillreportbacktothefullgroupforconsensusbuilding.InvitedparticipantsandspeakersincludeworldwideleadingexpertswhowilladdressclinicalissuesasoutlinedintheAppendix:ScopeofCoveragebelow.TheconferenceoutputwillincludepublicationofapositionstatementtohelpguideKDIGOandothersontherapeuticmanagementandfutureresearchinglomerulardiseases.
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Appendix:ScopeofCoverageGroup1:GeneralPrinciples,MembranoproliferativeGN(MPGN),C3Glomerulonephritis(C3GN)1. Generalprinciples(i):Whatconstitutestheoptimaltargetbloodpressure,lipid
levels,fluidanddietarysodiumintakeinglomerulardisease?Whichotherlifestylemodificationsaregenerallyadvisable?
2. Generalprinciples(ii):AretherespecificindicationswhereRAASblockadeshouldnotbeconsideredforglomerulardisease?RoleofanapparentfallinGFRafterRAASblockade:goodorbad(correctinghyperfiltrationvs.AKI)?ShouldtherebealowGFRcut-offfordiscontinuingRAASblockade?Inpatientswithpersistenthigh-gradeproteinuria,shouldRAASblockersbeincreasedabovethemaximumdailydosethatisrecommendedforhypertension?IsthereanyevidencethatRAASblockademayreduceproteinuriabutmaskongoinginflammationinglomerulardiseaseswhenimmunosuppressioniscontemplatedorbeingused?
3. Nephroticsyndrome:Whentostartprophylacticanticoagulanttherapy,forhowlong,andwhichdrugsshouldbeused?(dose?)Doestheapproachinmembranousnephropathy(MN)differfromotherglomerulardiseasesassociatedwiththenephroticsyndrome?Whatistheoptimalapproachtotreatinghyperlipidemia?Whatshouldbethegoal?
4. MPGN(i):IsthedivisioninthehistologicclassificationofMPGNintoimmunecomplex-mediatedandcomplement-mediatedGNsufficient?Ifso,whatshouldbethesequenceandlimitofdiagnosticinvestigationinclinicalpractice?
5. MPGN(ii):Howshouldparaprotein-associatedMPGN(“monoclonalgammopathyofrenalsignificance”)beevaluated?Whatistheapproachtotherapybasedonthisworkup?Whataremeaningfulclinicalendpointsinthisdisease?
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6. MPGN(iii):WhatistheappropriateworkupforothervariantsofMPGNinparticularso-calledidiopathicMPGN?Whichofthesevariantsrequireimmunosuppressivetherapy,andwhatshouldbeusedasclinicallymeaningfulendpointsfortreatment(e.g.,proteinuria/changeinGFR)?
7. MPGN(iv):Incomplementassociated/mediatedMPGN,howspecificallycandysregulationofthedifferentcomplementpathways(classic,lectin,alternate)bedemonstrated,andcanthisinformtheuseanddevelopmentofcomplementinhibitorsforthesediseases?
Group2:IgANephropathy(IgAN)
Pathogenesis1. Aretherenewinsightsintopathogenesisthatcanguidetreatment?
Biomarkers&predictionofprognosis2. Whichclinical,laboratoryandpathologicparametersshouldformthebasisfor
riskassessment?Shouldmicrohematuria(qualitativeorquantitative?)beincorporatedintheriskassessment?
3. IstherearapidlyprogressivelyGN(RPGN)variantofIgANoristhisseverehypertensiveinjury(withorwithoutthromboticmicroangiopathy)superimposedonIgAN?
4. Shouldpathology,inparticulartheOxford-MEST-Cclassification,guidetreatment?
Treatment5. Whatistheevidencesuggestingrenalbenefitatareasonablecost-benefitratio
ofestablishedimmunosuppressivemono-orcombination-therapy(suchas
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steroids,mycophenolatemofetil,cyclophosphamide,azathioprine)?
6. WhatmaybetheimmunosuppressivestrategyinpatientswithlowerGFRs?
7. Howtotreatrelapsesofproteinuriafollowinganinitialresponsetotherapy(supportiveorimmunosuppressive)?
8. Shouldethnicityinfluencetreatmentdecision?
Futurestudies9. Aretherenovelemergingimmunosuppressiveorotherapproaches(suchas
rituximab,tacrolimus,entericcorticosteroids,BAFFinhibitor,MASP2antibody)toprogressiveIgAN?
10. WhatisthefutureofclinicaltrialsinIgAN?• Howcanclinicaltrialsbefacilitatedinthefuture?• Inclusionofhigh-riskpatientsonly?• Appropriateendpoints?• Determiningoptimaltimeforassessingprimaryendpoint
Durationofclinicaltrial/followup• Patientreportedoutcomemeasures&sideeffects
Group3:MembranousGN(MGN)
Diagnosis1. CanadiagnosisofMNbemadereliablywithoutkidneybiopsy?
2. Isakidneybiopsyneededbeforestartofimmunosuppressivetherapy?
3. IsPLA2R(antibodiesorinbiopsy)sufficienttoruleoutsecondaryMN?
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Biomarkers&predictionofprognosis4. Whichclinicalandlaboratoryparameterspredictspontaneousremission?
5. Doantibodyassays(PLA2R,THSD7A)contributetopredictionofspontaneous
remission?Shouldqualitativeassaysbereplacedbyquantitativeassays?Treatment6. Howshouldremissionbedefined?
a. Arethecurrentdefinitionsofpartialremissionandcompleteremissionappropriate?Couldtheybeimproved?
b. Howshouldanti-PLA2Rbeintegratedintothesedefinitions?c. Shouldothermarkersbeincluded?
7. Whatshouldbethegoaloftherapy?
8. Whenshouldwestartimmunosuppressivetherapy?Whichbiomarkersare
usefulinpredictingresponsetotherapy?
9. Howtomonitorpatientswhohavedevelopedremissionandwhichparametersshouldbeusedtoguiderestartofimmunosuppression?
10. Howtodifferentiatebetweenproteinuriaduetorelapseorsecondaryfocalsegmentalglomerulosclerosis(FSGS)?
11. Howshouldtreatmentresistancebedefined(i.e.,non-responsiveness)?Whataretreatmentoptionsforinitiallynon-responsivepatients?
12. AretherenewtreatmentoptionsdevelopedforuseinMN?ArethererandomizedclinicaltrialsorlargecomparativecohortstudiesinMNpublishedafter2010andhowshouldtheresultschangeKDIGOtreatmentguidelines?
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Futurestudies13. WhatisthefutureofclinicaltrialsinMN?
• Inclusionofhigh-riskpatientsonly?• Appropriateendpoints?• Determiningoptimaltimeforassessingprimaryendpoint
Durationofclinicaltrial/followup• Patientreportedoutcomemeasures&sideeffects• OthermethodologybesidesRCTs.
Group4:Minimal-ChangeDisease(MCD)andFocalSegmentalGlomerulosclerosis(FSGS)Diagnosis,biomarkers&predictionofprognosis1. ShouldFSGSstillbeconsideredasinglediseaseentityorratherafamilyof
diseases?Canparticularsubsetsbeidentified?2. AretherenewinsightsintopathogenesisthatcanguidetreatmentinMCD,in
particularwithrespecttopermeabilityfactors?
3. WhatistheroleofgenetictestinginFSGS?Towhomandwhenshoulditbeapplied?Doesgenetictestinghelpinchoiceoftherapy?
4. Ishistologicalanalysisofrenaltissuesufficientfordiagnosisandmanagement
ofFSGSorshouldmoleculardiagnosisbeincorporatedintotheroutineevaluationofthebiopsytobetterdefinethevariantsthatcomprisethissyndrome?
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Treatment5. WhoshouldreceiveimmunosuppressivetreatmentforFSGSandwhoshould
not?Ifneeded,whatisthemostreasonableimmunosuppressiveapproachwhencorticosteroidshavefailed?
6. Regardingimmunosuppression:
a)WhenshouldtherapywithcalcineurininhibitorsorcytotoxicagentsbeconsideredinMCD?b)Whatabouttherapywithrituximab,mycophenolatemofetil,adrenocorticotropichormone(ACTH)orabatacept?c)Wouldoneofthesetherapiesbeusedasfirstlineinsteadofcorticosteroids?d)WhatistheroleofplasmapheresisinFSGS?
7. Aretherenewinsightsintohowweshouldfollowandmanagetransplanted
patientswithahistoryofFSGS?Howshouldweapproachtreatmentofrecurrentdisease?
Futurestudies
8. WhatisthefutureofclinicaltrialsinMCD/FSGS?
• Doesitstillmakesensetostudy“FSGS”independentofthespecificentity?
• Inclusionofhigh-riskpatientsonly?• Appropriateendpoints?• Determiningoptimaltimeforassessingprimaryendpoint
Durationofclinicaltrial/followup• Patientreportedoutcomemeasures&sideeffects
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Group5:Lupusnephritis(LN)andANCAvasculitis
Diagnosis,biomarkers&predictionofprognosis1. Howshouldwebestusethekidneybiopsyinrelapsingdiseases?Whatisthe
roleofrepeatingthebiopsy,whenshoulditbedone,andhowoften?
2. Issimplehistology(light,immunofluorescence,andelectronmicroscopy)ofrenaltissuesufficientfordiagnosisandmanagementofheterogeneousdiseasesorshouldmoleculardiagnosisbeincorporatedintotheroutineevaluationofthebiopsy?
3. Areproteinuria,urinarysedimentanalysisandSCroreGFRsufficienttodetermineresponsetotherapy?Whatabouttheuseofdrugssuchascalcineurininhibitorsthatmayalterproteinuriabyseveralmechanisms?
4. a)Howcanwebestapplymyeloperoxidase(MPO),proteinase3(PR3)forpredictingrelapseinANCAvasculitis?Arethereotherpredictivebiomarkersthatshouldbeincorporatedintoclinicaluse,includingtherapy-specificbiomarkerssuchasB-cellcountsinpatientstreatedwithanti-Bcelltherapies?b)Howcanwebestapplyanti-DNA,complementandextractablenuclearantigen(ENA)profiletestingforpredictingrelapseinLN?Arethereotherpredictivebiomarkersthatshouldbeincorporatedintoclinicaluse,includingtherapy-specificbiomarkerssuchasB-cellcountsinpatientstreatedwithanti-Bcelltherapies?
5. Arethereanyclinicalsignsorserum/urinebiomarkers/geneticteststhatcanhelpto:a)predictwhomaydevelopLNamongpatientswithsystemiclupuserythematosus(SLE)andwhomaydevelopkidneyinvolvementamongpatientswithsystemicANCA;b)helpdiagnoseanddirecttherapy?
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Treatment
6. AreweusingtoomuchcorticosteroidinLNandANCAvasculitis?Canwereducecumulativedosing?Areshortcourseofintravenouspulsesteroidssuperiortoprolongeduseoforalsteroids?
7. a)Forhowlongshouldmaintenancetherapybecontinuedinvasculitis?Whentoconsidertherapydiscontinuation?ShouldMPOandPR3positivepatientsreceivedifferentmaintenanceregimens?Dopatientswithdrug-inducedANCAvasculitisrequiremaintenance?b)ForhowlongshouldmaintenancetherapybecontinuedinLN?Howcanpatientcharacteristics(responsetotherapy,historyofrelapse,biomarkersofdiseaseactivity)guidelengthofmaintenancetherapy?Whentoconsidertherapydiscontinuation?
8. HowshouldrefractorydiseaseinLNandANCAvasculitisbedefined?Whatstrategiesmaybeusedtotreatrefractorydisease?Whichistheroleofanti-Bcellandotherbiologicaltherapies?WhichistheroleofplasmaexchangeincrescenticANCAvasculitis?Whatistheroleofcomplementinhibition?
9. Whichistheroleofantiphospholipidantibodies(aPL)testinginthecontextofLN?DoaPLandaPL-relatednephropathyhaveanimpactonthemanagementofLN?IfthromboticmicroangiopathyiscoexistentwithLNonkidneybiopsywhatistheappropriateworkupandtreatment(antiphospholipidsyndrome(APS)vs.thromboticthrombocytopenicpurpura(TTP)vs.atypicalhemolyticuremicsyndrome(aHUS)?Whatistheroleofplasmaexchange?Anticoagulation?Anti-complementtherapies?
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Futurestudies
10. WhatisthefutureofclinicaltrialsinSLE/ANCAvasculitis?• Doesitmakesensetostudyparticularsubgroups?• Inclusionofhigh-riskpatientsonly?• Appropriateendpoints?• Determiningoptimaltimeforassessingprimaryendpoint
Durationofclinicaltrial/followup• Patientreportedoutcomemeasures&sideeffects
REFERENCES
1. WebsterAC,NaglerEV,MortonRL,etal.ChronicKidneyDisease.Lancet2017;389:1238-1252.
2. FloegeJ,AmannK.Primaryglomerulonephritides.Lancet2016;387:2036-2048.3. USRenalDataSystem2016AnnualDataReportEpidemiologyofKidneyDiseasein
theUnitedStates.AmJKidneyDis2017;69:S1-S688.4. BeckLH,Jr.,BonegioRG,LambeauG,etal.M-typephospholipaseA2receptoras
targetantigeninidiopathicmembranousnephropathy.NEnglJMed2009;361:11-21.
5. BirminghamDJ,MerchantM,WaikarSS,etal.Biomarkersoflupusnephritis
histologyandflare:decipheringtherelevantamidstthenoise.NephrolDialTransplant2017;32:i71-i79.
6. ParikhSV,MalvarA,SongH,etal.Molecularimagingofthekidneyinlupusnephritis
tocharacterizeresponsetotreatment.TranslRes2017;182:1-13.7. SethiS,TheisJD,VranaJA,etal.Lasermicrodissectionandproteomicanalysisof
amyloidosis,cryoglobulinemicGN,fibrillaryGN,andimmunotactoidglomerulopathy.ClinJAmSocNephrol2013;8:915-921.
8. RauenT,EitnerF,FitznerC,etal.IntensiveSupportiveCareplus
ImmunosuppressioninIgANephropathy.NEnglJMed2015;373:2225-2236.
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9. FellstromBC,BarrattJ,CookH,etal.Targeted-releasebudesonideversusplaceboinpatientswithIgAnephropathy(NEFIGAN):adouble-blind,randomised,placebo-controlledphase2btrial.Lancet2017;389:2117-2127.
10. JayneDR,BruchfeldAN,HarperL,etal.RandomizedTrialofC5aReceptorInhibitor
AvacopaninANCA-AssociatedVasculitis.JAmSocNephrol2017.doi:10.1681/ASN.2016111179.
11. JonesRB,TervaertJW,HauserT,etal.Rituximabversuscyclophosphamidein
ANCA-associatedrenalvasculitis.NEnglJMed2010;363:211-220.
12. StoneJH,MerkelPA,SpieraR,etal.RituximabversuscyclophosphamideforANCA-associatedvasculitis.NEnglJMed2010;363:221-232.
13. ACCESSTrialGroup.Treatmentoflupusnephritiswithabatacept:theAbataceptand
CyclophosphamideCombinationEfficacyandSafetyStudy.ArthritisRheumatol2014;66:3096-3104.
14. RovinBH,FurieR,LatinisK,etal.Efficacyandsafetyofrituximabinpatientswith
activeproliferativelupusnephritis:theLupusNephritisAssessmentwithRituximabstudy.ArthritisRheum2012;64:1215-1226.
15. ThompsonA,CattranDC,BlankM,etal.CompleteandPartialRemissionas
SurrogateEndPointsinMembranousNephropathy.JAmSocNephrol2015;26:2930-2937.
16. InkerLA,MondalH,GreeneT,etal.EarlyChangeinUrineProteinasaSurrogate
EndPointinStudiesofIgANephropathy:AnIndividual-PatientMeta-analysis.AmJKidneyDis2016;68:392-401.
17. AndersHJ,JayneDR,RovinBH.Hurdlestotheintroductionofnewtherapiesfor
immune-mediatedkidneydiseases.NatRevNephrol2016;12:205-216.
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