Slide #1 Kidney Disease in HIV Patients Kidney Disease in HIV Patients Christina Wyatt, MD Mount Sinai, New York
Slide #1
Kidney Disease in HIV PatientsKidney Disease in HIV Patients
Christina Wyatt, MDMount Sinai, New York
Slide #2
Non-AIDS Complications in HIV
Contributing causes of deathg
SMART TrialMore serious non-AIDS events than
i OIEl Sadr et al. NEJM 2006
serious OI
Selik et al. JAIDS 2002
Slide #3
Kidney Disease in HIV
Acute Kidney Injuryy j y
Nephrotoxicity End-stage Renalp y
HIV-Associated
End stage Renal Disease (ESRD)
Comorbid Disease
Slide #4
Acute Kidney Injury (AKI) in HIV
More common in HIV patients– OR 2.8 in hospitalized patients*
Associated with increased mortality– OR 5.8 in hospitalized patients*
Risk factors: chronic kidney disease (CKD), advanced HIV, hepatitis C co-infection
Franceschini et al. KI 2005Wyatt et al. AIDS 2006*Roe et al. CID 2008
Slide #5
Common Causes of AKI in HIV
Infection (52%)76% AIDS d fi i– 76% AIDS-defining
Drugs (32%)A tibi ti– Antibiotics
– ARV (indinavir & tenofovir)NSAIDS radiocontrast lithium– NSAIDS, radiocontrast, lithium
Liver Failure (10%)90% Hepatitis C– 90% Hepatitis C
Franceschini et al. KI 2005
Slide #6
Antiretroviral Nephrotoxicity
Tenofovir (Viread®, Truvada®, Atripla®)Indinavir (Crixivan®)Atazanavir (Reyataz®) ?Boosted PI ?Rare case reports with other agents
Kirk et al. for EuroSIDA, CROI 2010
Slide #7
Tenofovir Toxicity
Classic presentation: proximal tubulopathy– Phosphate wasting– Metabolic acidosis– Euglycemic glycosuria– Elevated creatinine
1-2% of patients develop significant toxicity– More frequent sub-clinical abnormalitiesq
Slide #8
Tenofovir Toxicity
Risk factors remain controversial– Unrecognized low GFR– Genetic predisposition?– Concomitant medications (ddi, boosted PI)
Slide #9
Tenofovir Toxicity
OAT1
OAT3Tenofovir
MRP4
Na-KTenofovir
OCTCreatinine
MRP2Ritonavir
(Blood)Ray et al. Antimicrob Agents Chemother 2006
(Urine)
Slide #10
Tenofovir Toxicity
•
Co rtes ofCourtesy of Glen Markowitz &
Vivette D’Agati
Slide #11
Indinavir Toxicity
Classic presentation: crystalluria, obstruction, & interstitial nephritis& interstitial nephritisPoorly soluble at physiologic urine pH
Crystalluria in up to 2/3 of patients– Crystalluria in up to 2/3 of patientsRarely used in the US– May inform toxicity of other agents– May inform toxicity of other agents
Atazanavir ?– Still used in resource-poor settingsp g
Slide #12
HIV-Associated Kidney Disease
May present with either AKI or CKD– Glomerular disease excluded from AKI studies
HIV-associated nephropathy (HIVAN)p p y ( )Immune complex kidney disease (“HIVICK”)Thrombotic microangiopathy g p y
Slide #13
HIVAN: Classic Presentation
Rapid progression to ESRDLarge, echogenic kidneysAdvanced HIV diseaseAlmost exclusively in blacks
Rao et al. NEJM 1984Pardo et al. Annals 1984
Slide #14
HIVAN: Pathology
Wyatt, Klotman, & D’Agati. Seminars in Nephrology 2008
Slide #15
HIVAN Pathogenesis: Mouse Model
“Tg26” HIV-1 transgenic mouseg g– Gag/pol deleted HIV construct – Expressed in most tissues, including kidneyExpressed in most tissues, including kidney– Kidney disease indistinguishable from
human HIVAN
Dickie et al. Virology 1991Ross et al. JASN 2001
Slide #16
HIVAN Pathogenesis: Mouse Model
HIV gene expression in kidney → HIVANg p y– Reciprocal transplantation– Podocyte-specific expressionPodocyte specific expression
HIV gene expression in lymphoid tissue →interstitial inflammation
Bruggeman et al. JCI 1997Zhong et al. KI 2005Hanna et al. J Virology 1998
Slide #17
HIVAN Pathogenesis: Human Data
HIV sequences detected• HIV sequences detected•Cluster separately from PBMC•Mechanism of entry is unknown
Bruggeman et al. JASN 2000Marras et al. Nat Med 2002
•Mechanism of entry is unknown
Slide #18
HIVAN Epidemiology: Impact of ART
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ith A
IDS
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HIVAN i300
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AIDSnephropathy
Deaths inAfricanAmericanswith AIDS
HIVAN is an indication for
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eath
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• Decline in ESRD attributed to HIVAN• Case reports of HIVAN regression
Ross & Klotman JASN 2002Winston et al. NEJM 2001
p g
Slide #19
HIVAN Pathogenesis: Genetics
Strong racial disparity in HIVAN & ESRD– ~90% of ESRD attributed to HIVAN– 4-30 fold increased risk of ESRD
Genetic strain also influences mouse model
Lucas et al. JID 2008Choi et al. JASN 2007Gharavi et al. PNAS 2004
Slide #20
HIVAN Pathogenesis: Genetics
Mapping by admixture linkage dysequilibrium (MALD) id tifi d MYH9 i k(MALD) identified MYH9 as a risk geneMutations in MYH9 cause kidney diseasePolymorphisms in MYH9 may account for racial disparity in HIVAN
F ti i k– Function is unknown– Cofactors are required for disease
Kopp et al. Nature Gen 2008
Slide #21
Changing Spectrum of CKD in HIV
Decline in biopsies with classic HIVANRecognition of other HIV-related diseasesMore comorbid kidney diseasey– Hepatitis co-infection– Diabetes & hypertensionyp
Szczech Szczech et al.et al. Kidney Int 2004Kidney Int 2004Berliner Berliner et alet al. Am J Nephrol 2008. Am J Nephrol 2008
Slide #22
CKD & Hepatitis Co-infection
10 studies of CKD in HIVPooled RR associated with
HCV 1.49 (1.08-2.06)
Wyatt et al. AIDS 2008
Slide #23
CKD Screening in HIV
Screen all newly diagnosed individuals– Urinalysis – Creatinine-based GFR estimate
Annual screening for “high risk” patients– Black race– Advanced HIV disease– Diabetes, hypertension, or hepatitis C, yp , p
Gupta et al. CID 2005
Slide #24
CKD Management in HIV
Consider nephrology referralDi i– Diagnosis
– ESRD preparationAggressive management of comorbiditiesAggressive management of comorbidities– DM– HTN– Hepatitis ?
Cardiovascular risk reduction*Gupta et al. CID 2005Choi et al. Circulation 2010George et al. AIDS 2010
Slide #25
HIV & ESRD: Survival
Ahuja et al. JASN 2002Atta et al. CID 2007
Slide #26
HIV & ESRD: Choice of Dialysis
Ahuja et al. AJKD 2003
Slide #27
HIV & Kidney Transplant
Observational dataProspective studies– Good outcomes in selected patients– No increase in OI– High incidence of rejection
D i t ti ( i ll PI NNRTI)– Drug interactions (especially PI, NNRTI)
Roland et al. Am J Transplant 2008Kumar et al. Transplantation 2005
Slide #28
Kidney Disease in HIV
AKI & CKD are more common in HIVG id li d i f CKD– Guidelines recommend screening for CKD
Spectrum of disease has changed with ARTHIV i t d di– HIV-associated disease
– Medication toxicity Comorbid CKD– Comorbid CKD
Survival of HIV+ ESRD patients has improvedTransplant is an option in selected patients– Transplant is an option in selected patients