Post on 18-Jun-2020
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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