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Kidney Disease in HIV PatientsKidney Disease in HIV Patients

Christina Wyatt, MDMount Sinai, New York

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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

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Kidney Disease in HIV

Acute Kidney Injuryy j y

Nephrotoxicity End-stage Renalp y

HIV-Associated

End stage Renal Disease (ESRD)

Comorbid Disease

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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

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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

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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

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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

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Tenofovir Toxicity

Risk factors remain controversial– Unrecognized low GFR– Genetic predisposition?– Concomitant medications (ddi, boosted PI)

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Tenofovir Toxicity

OAT1

OAT3Tenofovir

MRP4

Na-KTenofovir

OCTCreatinine

MRP2Ritonavir

(Blood)Ray et al. Antimicrob Agents Chemother 2006

(Urine)

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Tenofovir Toxicity

Co rtes ofCourtesy of Glen Markowitz &

Vivette D’Agati

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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

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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

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HIVAN: Classic Presentation

Rapid progression to ESRDLarge, echogenic kidneysAdvanced HIV diseaseAlmost exclusively in blacks

Rao et al. NEJM 1984Pardo et al. Annals 1984

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HIVAN: Pathology

Wyatt, Klotman, & D’Agati. Seminars in Nephrology 2008

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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

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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

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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

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HIVAN Epidemiology: Impact of ART

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Deaths inAfricanAmericanswith AIDS

HIVAN is an indication for

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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

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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

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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

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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

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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

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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

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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

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HIV & ESRD: Survival

Ahuja et al. JASN 2002Atta et al. CID 2007

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HIV & ESRD: Choice of Dialysis

Ahuja et al. AJKD 2003

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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

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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