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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?