1

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

2

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

3

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.

4

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?

5

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

6

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?

7

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?

8

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?

9

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

10

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?

11

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?

12

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.

13

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.