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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AIDSnephropathy

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

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