Overview on the updated KDIGO Guideline on Glomerular Disease
KDIGO Controversies Conference on Glomerular Diseases...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
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