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KDIGOControversiesConferenceonGlomerularDiseasesBreakoutGroupQuestions

November16-19,2017

SingaporeGroup1:GeneralPrinciples,MembranoproliferativeGN(MPGN),C3Glomerulonephritis(C3GN)1. Generalprinciples(I)

• Whatconstitutestheoptimaltargetbloodpressure,lipidlevels,fluidanddietarysodiumintakeinglomerulardisease?IsthereabestwaytochoosethetypeofRASblockade(ACEinhibitororARB,orincombination),diureticsandtheirdosageinpatientswithglomerulardisease?Howarethesedrugsbestadjustedinthepresenceofnephroticsyndromeand/orprogressivedeclineinGFR?IsthereanorderthatispreferableintermsoftheintroductionofantihypertensiveagentsbeyondRASblockadeanddiuretics?

• AretherespecificindicationswhereRAASblockadeshouldnotbeconsideredforglomerulardisease?RoleofanapparentfallinGFRafterRAASblockade:goodorbad(correctinghyperfiltrationvs.AKI)?Whenandhowshouldweintroducethe“sickday“concepttowithholdingRASblockade?ShouldtherebealowGFRcut-offfordiscontinuingRAASblockade?ShouldRAASblockadebestartedandup-titratedinpatientswhohaveordevelophypotensionduringtreatment?Inpatientswithpersistenthigh-gradeproteinuria,shouldRAASblockersbeincreasedabovethemaximumdailydosethatisrecommendedforhypertension?IsthereanyevidencethatRAASblockademayreduceproteinuriabutmaskongoinginflammationinglomerulardiseaseswhenimmunosuppressioniscontemplatedorbeingused?(discussionsonRAASblockadeshouldincludeagentssuchasdirectrenin

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inhibitors,mineralocorticoidblockers,andepithelialsodiumchannelblockade)

• Whatotherlifestylemodifications(e.g.,diet,exercise,sleephealth,tobacco

use)aregenerallyadvisable?WhatisthepotentialmechanismbywhichobesitycontributestoCKDandinparticularglomerulardiseasepathogenesisandprogression?Whatmedicationsshouldbeconsidered(e.g.,vitaminD,statinsandSGLTinhibitors)beyondRASblockers?Whatshouldbeavoided(e.g.,non-dihydropyridinecalciumchannelblockers)?

• Whatareclinicallyrelevantendpointsforglomerulardiseases?(should

address/commentonbiomarkersingeneralincludingmarkersoftubulardamage)Whataretheimportantaspectsofstudydesigninglomerulardiseasewithrespecttotheregulatoryapprovaldecision-makingprocess?Whichmethodofmonitoringproteinuriashouldbeusedintherapeuticdecisionmakinginclinicalpractice?Shouldhematuriabeusedasamarkerofdiseaseactivityand/orasurrogateendpoint?Ifsoinwhichspecificdiseasesshoulditbemeasuredandhow(i.e.,morphologyexamination;semiquantitativevs.quantitative)?

• Whatistheevidencethatthereisacontributionofbirthweightand/ornephronmasstothepathogenesisandprogressionofglomerulardisease?

• Isthereastandardapproachwhichcouldorshouldbeappliedtobothdevelopedanddevelopingcountriesdespiteresourcelimitationsinthediagnosisandtreatmentofglomerulardisease?

2. Nephroticsyndrome

• Isthereatimetointroduceprophylacticanticoagulanttherapyandifsofor

howlong,andwhichdrugsshouldbeused?(doseadjustmentnecessaryby

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GFR?)Doestheapproachinmembranousnephropathy(MN)differfromotherglomerulardiseasesassociatedwiththenephroticsyndrome?

• Whatistheoptimalapproachtotreatinghyperlipidemia?Whatshouldbethegoal?Whataretherecommendationsoftheuseofprophylaxis(e.g.,forinfections,gastrointestinalbleeding,osteoporosis)inpatientsbeingtreatedwithimmunosuppression?Whataretherecommendationsinregardstothetimingandtypeofvaccinationsinpatientswithglomerulardisease?

3. MPGN(i):ExplainthatMPGNisapatternofinjuryratherthanadiseaseentity.

IsthedivisioninthehistologicclassificationofMPGNintoimmunecomplex-mediatedandcomplement-mediatedGNsufficient?Whatisthelikelihoodofoverlapandisthisdependentontiming(trajectory)orpresumedetiologicaltype?Ifso,whatshouldbethesequenceandlimitofdiagnosticinvestigationinclinicalpractice?Aretherearespecificmonitoringtoolsandifso,inwhichspecificvariants?Inwhichcasesshouldpronaseimmunofluorescenceofkidneybiopsytissuebeperformed?

4. MPGN(ii):Howshouldparaprotein-associatedMPGN(“monoclonalgammopathyofrenalsignificance”)beevaluated?Whatistheapproachtotherapybasedonthisworkup?Whataremeaningfulclinicalendpointsinthisdisease?

5. MPGN(iii):WhatistheappropriateworkupforothervariantsofMPGN,particularinso-calledidiopathicMPGN,andshouldothertypesofdepositiondiseasesuchasfibrillaryandimmunotactoidGNbeincluded?Whichofthesevariantsrequireimmunosuppressivetherapy,andwhatshouldbeusedasclinicallymeaningfulendpointsfortreatment(e.g.,proteinuria/changeinGFR)?Whatistheevidencetosupportimmunosuppressivetherapyhere?Whatistheapproachtothediagnosis,treatmentandmonitoringofhepatitisC-associatedglomerulonephritis?

6. MPGN(iv):Incomplementassociated/mediatedMPGN,howspecificallycandysregulationofthedifferentcomplementpathways(classic,lectin,alternate)bedemonstrated,andcanthisinformtheuseanddevelopmentofcomplement

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inhibitorsforthesediseases?WhatistheroleofeculizumabinC3G?Whereareweinthedevelopmentofadditionalcomplementinhibitorstoday?Wheredotheyactinthecomplementcascadeandistherelikelytobespecificityofthesedrugsinrelationshiptospecificcomplementassociated/MPGNvariants?WhatisthedistinctioninC3dominantinfection-associatedGN?Aretherespecialconsiderationsinthepre-andpost-transplantmanagementofpatientswithESKDduetoMPGN/C3glomerulopathy?

Group2:IgANephropathy(IgAN)

Pathogenesis1. Aretherenewinsightsintopathogenesisthatcanguidetreatment?

Biomarkers&predictionofprognosis2. Whichclinical,laboratoryandpathologicparametersshouldformthebasisfor

riskassessment?Shouldmicrohematuria(qualitativeorquantitative?)beincorporatedintheriskassessment?

3. Whatistheroleofnewbiomarkers,suchassCD89andtransferrinreceptor?4. IstherearapidlyprogressivelyGN(RPGN)variantofIgANoristhissevere

hypertensiveinjury(withorwithoutthromboticmicroangiopathy)superimposedonIgAN?

5. Shouldpathology,inparticulartheOxford-MEST-Cclassification,guide

treatment?Howdocrescentsaffecttreatmentdecisions?Aretherehistologicalthresholdsthatcanguidetreatment?

6. InIgAvasculitis,aretherebiomarkersofrenalinvolvementandprognosis?

Shouldaseparatehistologicalclassificationbeconsidered?

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Treatment7. Whatistheevidencesuggestingrenalbenefitatareasonablecost-benefitratio

ofestablishedimmunosuppressivemono-orcombination-therapy(suchassteroids,mycophenolatemofetil,cyclophosphamide,azathioprine)?Andwhatistheoptimumdosage,dosingintervals,durationoftreatmentanddrugformulationforsteroiduseinIgAN?

8. WhatmaybetheimmunosuppressivestrategyinpatientswithlowerGFRs?Is

therea"pointofnoreturn"forIgAN?Ifso,whatisitintermsofeGFR?9. Howshouldonetreatrelapsesofproteinuriafollowinganinitialresponseto

therapy(i.e.,supportiveorimmunosuppressive)?10. HowshouldonemanagenephroticpatientswithIgANwithoutfeaturesof

minimalchangedisease(MCD)inthekidneybiopsy?11. Shouldethnicityinfluencetreatmentdecision?12. Istherearolefortonsillectomy?Futurestudies13. Aretherenovelemergingimmunosuppressiveorotherapproaches(suchas

rituximab,tacrolimus,entericcorticosteroids,BAFFinhibitor,MASP2antibodyandACTH)toprogressiveIgAN?

14. WhatisthefutureofclinicaltrialsinIgAN?

• Howcanclinicaltrialsbefacilitatedinthefuture?• Inclusionofhigh-riskpatientsonly?• Appropriateendpoints?• Determiningoptimaltimeforassessingprimaryendpoint

Durationofclinicaltrial/follow-up

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• Patientreportedoutcomemeasures&sideeffects

Optionalquestionstoaddress(subjecttoavailabilityoftimesinceevidencefromtheliteratureforthesetopicsistooscarcetowarrantincorporationintoaguideline)

1. WhatistheroleofcomplementinhibitioninIgAN?

2. WhatistheroleofthegutmicrobiomeinIgAN,andhowmaydietaryorothertherapiesaffectthisrelationship?Whatistheroleofgluten-freedietinlightofanRCTofgluten-freedietbeingplannedinItaly?

3. HowshouldonemanageIgANinthepediatricpopulation?

4. HowshouldonemanagerecurrentIgANinthekidneytransplantrecipient?

5. HowshouldonemanagepregnancyinpatientswithIgAN?

6. Canweformulaterecommendationsthatshouldbe“standard-of-care”(SOC)inallregionsandhighlightalternativeapproachesthatmaybeexchangedforSOCinresource-limitedcountries?

Group3:MembranousGN(MGN)

Diagnosis1. CanadiagnosisofMNbemadereliablywithoutkidneybiopsy?

2. Isakidneybiopsyneededbeforestartofimmunosuppressivetherapy?

3. IsPLA2R(antibodiesorinbiopsy)sufficienttoruleoutsecondaryMN?What

shouldbethealgorithmforcancerscreening?

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Biomarkers&predictionofprognosis4. Whichclinicalandlaboratoryparameterspredictspontaneousremission?

5. Doantibodyassays(PLA2R,THSD7A)contributetopredictionofspontaneous

remission?Shouldqualitativeassaysbereplacedbyquantitativeassays?Areepitope-specificassayspreferable?

Treatment6. Howshouldremissionbedefined?

a. Arethecurrentdefinitionsofpartialremissionandcompleteremissionappropriate?Couldtheybeimproved?

b. Howshouldanti-PLA2Rbeintegratedintothesedefinitions?c. Shouldothermarkersbeincluded?

7. Whatshouldbethegoaloftherapy?

8. Whenshouldwestartimmunosuppressivetherapy?Whichbiomarkersare

usefulinpredictingresponsetotherapy?Iskidneybiopsyusefulaspredictor?

9. Howshouldonemonitorpatientswhohavedevelopedremissionandwhichparametersshouldbeusedtoguiderestartofimmunosuppression?

10. Howshouldonedifferentiatebetweenproteinuriaduetorelapseorsecondaryfocalsegmentalglomerulosclerosis(FSGS)?

11. Howshouldtreatmentresistancebedefined(i.e.,non-responsiveness)?Whataretreatmentoptionsforinitiallynon-responsivepatients?Istherearoleforplasmaexchange(PLEX)?

12. AretherenewtreatmentoptionsdevelopedforuseinMN?ArethererandomizedclinicaltrialsorlargecomparativecohortstudiesinMNpublished

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after2010andhowshouldtheresultschangeKDIGOtreatmentguideline?WhatwillbetheimpactoftheMENTORandSTARMENstudies?

13. ShouldtreatmentbedifferentinpatientswithMNandimpairedkidneyfunction?Whatarepotentialthresholds?

14. Howshouldtreatmentbeadaptedinspecialpopulationssuchasinchildrenandpregnantwomen?

15. HowshouldwemanageMNpatientswhoreceiveakidneytransplant?WhatistheroleofaPLA2Rabbeforeandaftertransplantation?

Futurestudies16. WhatisthefutureofclinicaltrialsinMN?

• Inclusionofhigh-riskpatientsonly?• Appropriateendpoints?• Determiningoptimaltimeforassessingprimaryendpoint

Durationofclinicaltrial/follow-up• Patientreportedoutcomemeasures&sideeffects• OthermethodologybesidesRCTs.

Group4:Minimal-ChangeDisease(MCD)andFocalSegmentalGlomerulosclerosis(FSGS)Diagnosis,biomarkers&predictionofprognosis1. ShouldFSGSstillbeconsideredasinglediseaseentityorratherafamilyof

diseases?Canparticularsubsetsbeidentified?a. Shouldweabandon“Primary”and“Secondary”FSGSterminology?b. ArethetermsSSNSandSRNSstillrelevant?

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2. AretherenewinsightsintopathogenesisthatcanguidetreatmentinMCD,inparticularwithrespecttopermeabilityfactors?

3. WhatistheroleofgenetictestinginFSGS?Towhomandwhenshoulditbeapplied?Doesgenetictestinghelpinchoiceoftherapy?

4. Ishistologicalanalysisofrenaltissuesufficientfordiagnosisandmanagement

ofFSGSorshouldmoleculardiagnosisbeincorporatedintotheroutineevaluationofthebiopsytobetterdefinethevariantsthatcomprisethissyndrome?a. DothemorphologicalpatternsofFSGSbylightmicroscopyhavearolein

patientcare?b. ShouldwerecommendbiopsystandardsforFSGS?(i.e.,minimumnumberof

glomerulitoexcludeFSGSandwhoshouldbere-biopsied?)

Treatment5. WhoshouldreceiveimmunosuppressivetreatmentforFSGSandwhoshould

not?Ifneeded,whatisthemostreasonableimmunosuppressiveapproachwhencorticosteroidshavefailed?

6. Regardingimmunosuppression:a.WhenshouldtherapywithcalcineurininhibitorsorcytotoxicagentsbeconsideredinMCD?

b.Whatabouttherapywithrituximab,mycophenolatemofetil,adrenocorticotropichormone(ACTH)orabatacept?

c.Wouldoneofthesetherapiesbeusedasfirstlineinsteadofcorticosteroids?

d.WhatistheroleofplasmapheresisinFSGS?

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7. Regardinganti-proteinuricagents:a. Howdoweorshouldwedistinguishimmunosuppressivefromanti-proteinuriceffectsoftherapies(e.g.,steroids,cyclosporine,rituximab,ACTH)

b.WhatistheroleofangiotensinII/endothelinantagonisminallformsofFSGS?

8. Aretherenewinsightsintohowweshouldfollowandmanagetransplanted

patientswithahistoryofFSGS?Howshouldweapproachtreatmentofrecurrentdisease?

9. Whatarespecificaspectsregardingthecareforpediatricpatients?10. Whatarespecificaspectsregardingthecareforpregnantpatients?Futurestudies

11.WhatisthefutureofclinicaltrialsinMCD/FSGS?

• Doesitstillmakesensetostudy“FSGS”independentofthespecificentity?

• Inclusionofhigh-riskpatientsonly?• Appropriateendpoints?• Determiningoptimaltimeforassessingprimaryendpoint

Durationofclinicaltrial/follow-up• Patientreportedoutcomemeasures&sideeffects

Group5:Lupusnephritis(LN)andANCAvasculitis

Diagnosis,biomarkers&predictionofprognosis1. Whatistheroleofrepeatingthebiopsy,whenshoulditbedone,andhowoften?

IstherearoleforprotocolbiopsiesinthemanagementofLN?Howshouldwe

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bestusethekidneybiopsyinrelapsingdiseases?

2. Issimplehistology(light,immunofluorescence,andelectronmicroscopy)ofrenaltissuesufficientfordiagnosisandmanagementofheterogeneousdiseasesorshouldmoleculardiagnosisbeincorporatedintotheroutineevaluationofthebiopsy?IsthecurrentISN/RPSclassificationofLNsufficient?

3. Areproteinuria,urinarysedimentanalysisandSCroreGFRsufficienttodetermineresponsetotherapy?Whichcriteriashouldweusetodefineresponsetotreatment?Whatabouttheuseofdrugssuchascalcineurininhibitorsthatmayalterproteinuriabyseveralmechanisms?

4. a)Howcanwebestapplymyeloperoxidase(MPO),proteinase3(PR3)forpredictingrelapseinANCAvasculitis?Areimmune-enzymaticmethodsequivalenttoIFmethodswhentestingforANCA?Arethereotherpredictivebiomarkersthatshouldbeincorporatedintoclinicaluse,includingtherapy-specificbiomarkerssuchasB-cellcountsinpatientstreatedwithanti-Bcelltherapies?b)Howcanwebestapplyanti-DNA,complementandextractablenuclearantigen(ENA)profiletestingforpredictingrelapseinLN?Arethereotherpredictivebiomarkersthatshouldbeincorporatedintoclinicaluse,includingtherapy-specificbiomarkerssuchasB-cellcountsinpatientstreatedwithanti-Bcelltherapies?Whichapproachtoconsiderinserologicalactive(lowcomplementand/orpositiveanti-DNA)butclinicalsilentLNpatients?

5. Arethereanyclinicalsignsorserum/urinebiomarkers/geneticteststhatcanhelpto:a.predictwhomaydevelopkidneyinvolvementamongpatientswithsystemicANCAand/orhelpdiagnoseanddirecttherapy?b.predictwhomaydevelopLNamongpatientswithsystemiclupuserythematosus(SLE)and/orhelpdiagnoseanddirecttherapy?

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Treatment

6. AreweusingtoomuchcorticosteroidinLNandANCAvasculitis?Canwereducecumulativedosing?Areshortcourseofintravenouspulsesteroidssuperiortoprolongeduseoforalsteroids?

7. a.Forhowlongshouldmaintenancetherapybecontinuedinvasculitis?Whenshouldoneconsidertherapydiscontinuation?ShouldMPOandPR3positivepatientsreceivedifferentmaintenanceregimens?Dopatientswithdrug-inducedANCAvasculitisrequiremaintenance?b.ForhowlongshouldmaintenancetherapybecontinuedinLN?Howcanpatientcharacteristics(e.g.,responsetotherapy,historyofrelapse,biomarkersofdiseaseactivity)guidelengthofmaintenancetherapy?Whenshouldoneconsidertherapydiscontinuation?

8. HowshouldrefractorydiseaseinLNandANCAvasculitisbedefined?Whatstrategiesmaybeusedtotreatrefractorydisease?DoesinductiontherapydifferinpatientswithANCAvasculitiswhendiffusealveolarhemorrhageispresentand/ rapidlyprogressiverenalinsufficiency?

9. Whichistheroleofanti-BcellandotherbiologicaltherapiesinANCAvasculitisandLN?Whentoconsideranti-BcelltherapyinclassVLN?WhatistheroleofplasmaexchangeincrescenticANCAvasculitis?WhatistheroleofcomplementinhibitioninANCAvasculitisandLN?

10. Whichistheroleofantiphospholipidantibodies(aPL)testinginthecontextofLN?DoaPLandaPL-relatednephropathyhaveanimpactonthemanagementofLN?IfthromboticmicroangiopathyiscoexistentwithLNonkidneybiopsy,whatistheappropriateworkupandtreatment?Whatistheroleofplasmaexchange?Anticoagulation?Anti-complementtherapies?

11. WhatistheroleofCNIor“multi-targettherapy”inthetreatmentofLN?WhentoconsidertostopCNI?

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12. HowshouldLNbemanagedduringpregnancy? Whentoconsideranti-plateletagents?

13. HowshoulddiseaserecurrenceforLN/ANCAvasculitisbemanagedpost-transplant?

Futurestudies

14.WhatisthefutureofclinicaltrialsinSLE/ANCAvasculitis?

• Doesitmakesensetostudyparticularsubgroups?(e.g.,separatingMPOfromPR3;separatingclassVfromClassIII/IVLN)?

• Inclusionofhigh-riskpatientsonly?• Appropriateendpoints?• Determiningoptimaltimeforassessingprimaryendpoint• InclusionofpediatricpatientsinLNtrials• Durationofclinicaltrial/follow-up• Patientreportedoutcomemeasures&sideeffects