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KDIGOControversiesConferenceonHIV-RelatedKidneyDiseases
March17-20,2017Yaoundé,Cameroon
KidneyDisease:ImprovingGlobalOutcomes(KDIGO)isaninternationalorganization
whosemissionistoimprovethecareandoutcomesofkidneydiseasepatients
worldwidebypromotingcoordination,collaboration,andintegrationofinitiativesto
developandimplementclinicalpracticeguidelines.Periodically,KDIGOhosts
conferencesontopicsofimportancetopatientswithkidneydisease.Theseconferences
aredesignedtoreviewthestateoftheartonafocusedsubjectandtoaskconference
participantstodeterminewhatneedstobedoneinthisareatoimprovepatientcare
andoutcomes.Sometimestherecommendationsfromtheseconferencesleadto
KDIGOguidelineeffortsandothertimestheyhighlightareasforwhichadditional
researchisneededtoproduceevidencethatmightleadtoguidelinesinthefuture.
Background
HIV-positiveindividualsareatincreasedriskforbothacuteandchronickidneydisease
(CKD).TheclassickidneydiseaseofHIVinfection,HIV-associatednephropathy(HIVAN),
islesscommonwiththewidespreaduseofearlyantiretroviraltherapy;however,there
hasbeenasimultaneousincreaseintheprevalenceofnon-collapsingFSGS.Thereis
alsogrowingevidencethatHIV-positiveindividualsareatriskforimmune-complex
kidneydiseasesandformorerapidprogressionofcomorbidCKD.Inaddition,patients
withHIVinfectionareexposedtolife-longantiretroviraltherapy,withthepotentialto
causeorexacerbatekidneyinjury.Newerguidelinesrecommendingearlyinitiationof
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antiretroviraltherapyarelikelytoreducetheincidenceofHIVAN,buttheoverallrisk-
benefitforkidneyhealthisnotknown.
DecadesoflaboratorystudieshaveestablishedthatbothdirectHIVinfectionofthe
kidneyandhostgeneticsusceptibilityarecentraltothepathogenesisofHIVAN.1,2
Nonetheless,availableevidencesuggeststhatAfricanancestryoreventhepresenceof
theAPOL1riskallelesisinsufficienttomakeadefinitivediagnosisofHIVAN,whichstill
requireskidneybiopsy.3Theroleandutilityofgenetictestinginthediagnosisand
prognosisofHIV-relatedkidneydiseasehasnotbeendefined.Thereisalsoalackof
consensusonthespecifichistologicfeaturesrequiredtodistinguishHIVANfrom
idiopathicFSGSonkidneybiopsy,andthereisnoconsensusonwhichimmune-
mediatedkidneydiseasesshouldbeclassifiedunderthetermHIV-immunecomplex
kidneydisease(HIVICK).4Thislackofconsensusispartiallydrivenbythelimited
understandingofdiseasepathogenesisandbytheheterogeneityofdiseasesthathave
beencategorizedasHIVICK.ThediagnosisofkidneydiseaseinHIV-positiveindividuals
isalsoconfoundedbythepotentialnephrotoxicityofsomeARTagents,inparticular
tenofovirandtheproteaseinhibitors,andkidneybiopsymaybehelpfultodistinguish
betweenintrinsicandmedication-relatedkidneyinjury.5
InadditiontoHIV-relateddiseases,HIV-positiveindividualsarealsoatriskforcomorbid
kidneydiseaseunrelatedtoHIVinfectionoritstreatment.6Basicandepidemiologic
studieshavesuggestedanadditiveeffectofHIVinfectionandtraditionalCKDrisk
factorsinpromotingCKDprogression.7,8Nonetheless,clinicalguidelinesforCKD
preventionandtreatmentarelargelyextrapolatedfromstudiesinthegeneral
population,andcurrenttherapiesdonottargetuniqueHIV-relatedpathwaysthatmay
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contributetoCKDprogressioninthispopulation.9Recentlydevelopedprediction
modelsforCKDprogressionincorporatemarkersofHIVdiseaseseverity,buttheserisk
scoresmustbevalidatedinmorediversepatientpopulationsbeforetheyareadopted
forclinicaluse.10Finally,althoughobservationalstudiessupportthesafetyofdialysis
andkidneytransplantationinpatientswithwell-controlledHIVinfection,thereisalsoa
lackofconsensusontheoptimalmanagementofend-stagekidneydiseaseinthis
population.11
CONFERENCEOVERVIEW
Tothisend,thisKDIGOconferencewillgatheramultidisciplinary,internationalpanelof
clinicalandscientificexperts(e.g.,nephrology,infectiousdiseases,renalpathology,
pharmacology,etc.)toidentifyanddiscusskeyissuesrelevanttotheoptimaldiagnosis
andmanagementofHIV-relatedkidneydiseases.ThespecificgoalsofthisKDIGO
conferencearetodefinethepathologyofHIV-relatedkidneydisease;describetherole
ofgeneticsinthenaturalhistory,diagnosis,andtreatmentofHIV-associated
nephropathy;characterizetherenalrisk-benefitofantiretroviraltherapyinHIV
treatmentandprevention;anddefinebestpracticestodelaytheprogressionofkidney
diseaseandtotreatend-stagekidneydiseaseinHIV-positiveindividuals.The
conferencewillalsoidentifyknowledgegapsandareasforfutureresearch.
Drs.CharlesSwanepoel,MBChB(UCT),MRCP(UK),FRCP(Edin)(GrooteSchuurHospital
andUniversityofCapeTown,SouthAfrica)andChristinaM.Wyatt,MD,MS(Icahn
SchoolofMedicineatMountSinai,NY,USA)willco-chairthisconference.Theformatof
theconferencewillinvolvetopicalplenarysessionpresentationsfollowedbyfocused
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discussiongroupsthatwillreportbacktothefullgroupforconsensusbuilding.Invited
participantsandspeakerswillincludeworldwideleadingexpertswhowilladdresskey
clinicalissuesasoutlinedintheAppendix:ScopeofCoverage.Theconferenceoutput
willincludepublicationofapositionstatementthatwillhelpguideKDIGOandotherson
therapeuticmanagementandfutureresearchinthisarea.
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References
1. BruggemanLA,DikmanS,MengC,etal.Nephropathyinhumanimmunodeficiencyvirus-1transgenicmiceisduetorenaltransgeneexpression.JClinInvest.1997;100:84-92.
2. GenoveseG,FriedmanDJ,RossMDetal.AssociationoftrypanolyticApoL1variantswithkidneydiseaseinAfricanAmericans.Science.2010;329:841-845.
3. AttaMG,EstrellaMM,KupermanMetal.HIV-associatednephropathypatientswithandwithoutapolipoproteinL1genevariantshavesimilarclinicalandpathologicalcharacteristics.KidneyInt.2012;82:338-343.
4. WearneN,SwanepoelC,BoulleA,etal.ThespectrumofrenalhistologiesseeninHIVwithoutcomes,prognosticindicatorsandclinicalcorrelations.NephrolDialTransplant.2012;27:4109-4118.
5. HerlitzLC,MohanS,StokesMB,etal.Tenofovirnephrotoxicity:acutetubularnecrosiswithdistinctiveclinical,pathological,andmitochondrialabnormalities.KidneyInt.2010;78:1171-1177
6. WyattCM,MorgelloS,Katz-MalamedRetal.ThespectrumofkidneydiseaseinpatientswithAIDSintheeraofantiretroviraltherapy.KidneyInt.2009;75:428-434.
7. MedapalliRK,ParikhCR,GordonKetal.ComorbiddiabetesandtheriskofprogressivechronickidneydiseaseinHIV-infectedadults:datafromtheVeteransAgingCohortStudy.JAcquirImmuneDeficSyndr.2012;60:393-399.
8. MallipattuSK,LiuR,ZhongYetal.ExpressionofHIVtransgeneaggravateskidneyinjuryindiabeticmice.KidneyInt.2013;83:626-634.
9. LucasGM,RossMJ,StockPGetal.ClinicalpracticeguidelineforthemanagementofchronickidneydiseaseinpatientsinfectedwithHIV:2014updatebytheHIVMedicineAssociationoftheInfectiousDiseasesSocietyofAmerica.ClinInfectDis.2014;59:e96-138.
10. MocroftA,LundgrenJD,RossMetal.DevelopmentandvalidationofariskscoreforchronickidneydiseaseinHIVinfectionusingprospectivecohortdatafromtheD:A:Dstudy.PLoSMed.2015;12:e1001809.
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11. StockPG,BarinB,MurphyBetal.OutcomesofkidneytransplantationinHIV-infectedrecipients.NEnglJMed.2010;363:2004-2014.
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APPENDIX:SCOPEOFCOVERAGE
GROUP1:GENETICS&HIVAN
• GeneticsofkidneydiseasewithHIVinfectionintheAfricangeneticmilieuo CaneffectsizesandpopulationattributableriskfromstudiesinSouth
AfricaandamongAfricanAmericansbeextrapolatedtootherAfricanpopulations?
o ArethereadditionalsusceptibilityandresistancegeneticfactorsremainingtobediscoveredinAfricanpopulations?
o WhatarethegeneticandenvironmentalfactorswhichaffectpenetranceofAPOL1anddoesthisdifferbyethnicityorrace?
o DoweneedmoregranulardataforepidemiologyofHIVandprevalenceofkidneydiseaseinAfricaforpublichealthpolicydecisions?
o WhatistheroleofAPOL1inchildrenwithHIV-1infection?ShouldcohortsbeassembledtoassesstheroleofAPOL1riskvariantsonCKDinchildrenandadolescentswithHIVinfection?
o WhatstudiesarewarrantedtoassessutilityofgeneticscreeningforAPOL1riskfactorsversustestingformicroalbuminuria,proteinuria,andestimatedeGFR?
o WillknowledgeofAPOL1genotypechangeclinicalmanagement?o Istherearoleforaggressiveblockadeoftherenin-angiotensin
aldosterone(RAAS)pathway(i.e.,withACEplusaldosteronereceptorinhibitors)inpatientscarryingAPOL1riskalleles?
• APOL1interactionswithHIVincausingkidneydisease;APOL1structureandfunctionalroleinHIVkidneydisease
o DoesAPOL1interactwithtenofovirtopromotetubularandglomerularinjury?
o Sinceabout10-20%ofpeoplewithHIVANcarryonly1ornoAPOL1riskallele,arethereothergeneticvariantsinAfricanancestrychromosomesthatincreasesusceptibilitytoHIVANorincreasepenetranceforcarriersofone-riskallele?
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o IsAPOL1aninitiatorofHIV-associatedkidneydiseaseoraprogressionfactor?
• CorrelationsofHIVkidneydiseasewithgenetics:RapiddeclineineGFR,
prematureaging,collapsingGN,immunecomplexdisease/IgANo Shouldcross-sectionalorlongitudinalcohortstudiesbeassembledto
determinethegeneticcorrelatesofprematureaging,declineofkidneyfunction,andspecificetiologiesintheHIVpopulation?
o Willdurableviralsuppressionmitigateorpreventrenalinjurydifferentiallyinpersonscarryingrenalriskvariants,includingAPOL1?
o HowmuchofHIV-associatedkidneydiseaseisattributabletoknowngeneticfactors?
• Geneticmodifiersforkidneyfunctiondeclineorpathology(e.g.,MYH9,APOL1)o Whatisthebestmethodtoidentifyadditionalgeneticfactorsthat
modifypenetranceofAPOL1—admixturelinkagestudies,wholegenome/exomestudies,geneexpression?
• BiomarkersforkidneydysfunctionorsystemicinflammationinHIVo Whatarethebestbiomarkersforpredictingdeclineinkidneyfunction?
§ Pro-inflammatorycytokines,d-dimer,cystatinC,INF-gamma§ Geneticmarkers§ Geneexpressionprofiles§ ACR,PCR,andalbumin-to-totalproteinratio(uAPR)§ DocirculatinglevelsofIFNpredictACR,PCRoreGFR?Istherea
positivecorrelationbetweenIFNlevelsandHIVburden?
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GROUP2:RENALPATHOLOGY:HIVAN&HIVICK
ClassificationofHIV-relatedkidneydiseases• HowcanweclassifyHIV-relatedkidneydiseasesingeneral?• HowcanwediagnoseHIV-relatedkidneydiseasesdirectlycausedbyintrarenal
HIVtranscriptexpressionversusothers?• HowcanweclassifyHIV-relatedpodocytediseases?
o HowdowedefineclassicHIVANandshoulditbedifferentiatedfromotherformsofpodocytopathy?
• HowcanweclassifyHIV-relatedimmunecomplexdiseases?o Lupus-likeo Relatedtoco-infectionso Others
• HowcanweclassifyHIV-relatedtubulointerstitiallesions?o Viral-mediatedo Cytokine-mediated/DILS/Immunereconstitutionsyndromeo Drugeffects(tenofovirandproteaseinhibitors)o OthercausesofATN/AKI
• Potentialforoverlap?
Knowledgegapsforabove
Utilityofancillarystudies(e.g.,specialstains,etc.)forresearchandclinicalpractice
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GROUP3:HIVANDCKDPROGRESSION&END-STAGEKIDNEYDISEASE
WhatfactorsinfluencethenaturalhistoryofCKDprogressioninHIV-infectedindividuals?
o Timingandcomponentsofcombinationantiretroviraltherapy(cART)o EffectivenessoftreatmentsotherthancART(e.g.,steroids,RAASantagonists)in
themanagementofCKDinHIV-infectedpatientso Co-infectionsandtheirtreatment:HBV,HCV,TBo Non-infectiouscomorbidconditions:Diabetes,hypertension,obesityo Co-existenthistopathologicaldiseases:Primaryandsecondary
glomerulonephritides
AmongHIV-infectedpatientswhohaveadvancedCKDandareco-infectedwiththehepatitisBorCvirus,whataretheoptimalantiviraltreatmentstrategies?
o Subsetofpatientswhoshouldreceiveantiviraltreatmento Earlyversuslateinitiationandpre-vs.post-transplantantiviraltreatmento Risksandbenefitsamongantiviraltreatmentregimensinthecontextof
advancedCKD/ESKDandpotentialdrug-druginteractions
Whatarecost-effective,feasiblestrategiesforscreening,monitoringandmanagingCKDinHIV-positiveindividuals?
o Strategiesindevelopedcountriesvs.resource-limitedsettingso Strategiesinurbanvs.ruralareas
CanexistingCKDriskscoresforincidentCKDandCKDprogressionbegeneralizedtoHIV-infectedpopulationstoinformCKDscreeningandmonitoringandHIVcarestrategies?
o CurrentstatusofuseinclinicalpracticeinHIVcareindevelopedanddevelopingcountries
o ClinicalcontextinwhichserumcystatinCshouldbeusedinsteadoforinadditiontoserumcreatininetoassesskidneyfunction
o UtilityofurinebiomarkersofkidneyinjuryinprognosticationofCKDprogression
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ForkidneytransplantationamongHIV-infectedpersonswithadvancedCKDorESKD,
o WhoaretheoptimalcandidatesforHIV+toHIV+transplantation?o Howdoesco-infectionwiththeHBVorHCVinfluencekidneytransplantlisting?o Whatarethelong-termoutcomesamongHIV-infectedpatientsfollowingkidney
transplantation?(e.g.,recurrenceofHIVAN,riskforacuteandchroniccellularorantibody-mediatedrejection,allograftfailure)
o WhataretheoptimalcART,immunosuppressiveandantimicrobialprophylaxisregimensamongHIV+patientswhoundergotransplantation?
TowhatextentdoestheexcessriskofacutekidneyinjuryamongHIV-infectedpersonscontributetoincidentCKDandCKDprogressioninthispatientpopulation?WhatfactorscontributetothisexcessriskofAKIamongHIV-infectedpersons?
HowaretheoutcomesamongHIV-infectedpatientswithCKDorESKDcomparedtotheirHIV-uninfectedcounterparts?Consider:
o Riskofcardiovasculardiseaseevents,includingheartfailure,andgeneralizabilityofexistingguidelinesoncardiovasculardiseasepreventionandmanagement
o Ratesofvascularaccessfailureandcatheter-relatedinfectioninHIV-infectedvs.uninfectedindividualsreceivingchronichemodialysis
o Ratesofcatheter-relatedinfectionandperitonitisinHIV-infectedvs.uninfectedindividualsreceivingperitonealdialysis
o DoesthenatureofbonemineraldiseasedifferbetweenHIV-infectedvs.uninfectedindividuals?CancurrentguidelinesbegeneralizedtotheHIV-infectedpopulation?
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GROUP4:ANTIRETROVIRALTHERAPY(ART)NEPHROTOXICITY
Whatantiretroviraldrugshavenephrotoxicity?Howcankidneytoxicitybeassessed?• Drugsandknown/hypothesizedmechanisms,pharmacokineticstudies• Trials,cohortdata,caseseriesforthefollowingoutcomesofinterest:
o AKIo CKDo Interstitialnephritiso Proximaltubulartoxicityo Nephrolithiasis/urolithiasiso Kidneyinjuryfollowingkidneytransplantationo KidneyinjuryassociatedwithHIVpre-exposureprophylaxis
• ImplicationsWhatistheoptimalstrategyfordeterminingandmonitoringkidneyfunctioninHIV-positivepatientsonART?
• GFRestimatingequations• Urinalysis• WhataboutnewerARTagentsthatinterferewithcreatinineorcystatinC?• WhataboutinCKD?
HowcanweminimizeARTtoxicity?Consider:
• StrategiesforavoidingnephrotoxicARTinpopulationsathighriskofCKD• Drugadjustmentsduringspecificclinicalpracticesettingsandconditionsin
outpatientclinicsettingvshospitalizationsetting• Drug-druginteractions
WhatconsiderationsareimportantinselectingARTinHIV-infectedpatientswithCKD?
• TDFvs.TAFvs.ABCvs.NRTI-sparingregimensforpatientswithdecreasedGFR• SpecialconsiderationsforHIV-positivechildren
WhatistheoptimalARTinkidneytransplantrecipients?
• WhataretheARTagentstoavoid?• Whatdruginteractionsareimportantinmanagingkidneytransplantrecipientsin
HIV-positiveindividuals?