KDIGO Controversies Conference on HIV-Related Kidney Diseases · clinical and scientific experts...
12
1 KDIGO Controversies Conference on HIV-Related Kidney Diseases March 17-20, 2017 Yaoundé, Cameroon Kidney Disease: Improving Global Outcomes (KDIGO) is an international organization whose mission is to improve the care and outcomes of kidney disease patients worldwide by promoting coordination, collaboration, and integration of initiatives to develop and implement clinical practice guidelines. Periodically, KDIGO hosts conferences on topics of importance to patients with kidney disease. These conferences are designed to review the state of the art on a focused subject and to ask conference participants to determine what needs to be done in this area to improve patient care and outcomes. Sometimes the recommendations from these conferences lead to KDIGO guideline efforts and other times they highlight areas for which additional research is needed to produce evidence that might lead to guidelines in the future. Background HIV-positive individuals are at increased risk for both acute and chronic kidney disease (CKD). The classic kidney disease of HIV infection, HIV-associated nephropathy (HIVAN), is less common with the widespread use of early antiretroviral therapy; however, there has been a simultaneous increase in the prevalence of non-collapsing FSGS. There is also growing evidence that HIV-positive individuals are at risk for immune-complex kidney diseases and for more rapid progression of comorbid CKD. In addition, patients with HIV infection are exposed to life-long antiretroviral therapy, with the potential to cause or exacerbate kidney injury. Newer guidelines recommending early initiation of
Transcript of KDIGO Controversies Conference on HIV-Related Kidney Diseases · clinical and scientific experts...
1
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
2
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
3
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
4
discussiongroupsthatwillreportbacktothefullgroupforconsensusbuilding.Invited
participantsandspeakerswillincludeworldwideleadingexpertswhowilladdresskey
clinicalissuesasoutlinedintheAppendix:ScopeofCoverage.Theconferenceoutput
willincludepublicationofapositionstatementthatwillhelpguideKDIGOandotherson
therapeuticmanagementandfutureresearchinthisarea.
5
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.
6
11. StockPG,BarinB,MurphyBetal.OutcomesofkidneytransplantationinHIV-infectedrecipients.NEnglJMed.2010;363:2004-2014.
7
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?
8
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?
9
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
10
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
11
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?
12
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?
