Kidney Disease in HIV PatientsKidney Disease in HIV Patients › assets › 2387 › Wyatt 2010...
Transcript of Kidney Disease in HIV PatientsKidney Disease in HIV Patients › assets › 2387 › Wyatt 2010...
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Slide #1
Kidney Disease in HIV PatientsKidney Disease in HIV Patients
Christina Wyatt, MDMount Sinai, New York
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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
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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
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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
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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
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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
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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
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Slide #8
Tenofovir Toxicity
Risk factors remain controversial– Unrecognized low GFR– Genetic predisposition?– Concomitant medications (ddi, boosted PI)
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Slide #9
Tenofovir Toxicity
OAT1
OAT3Tenofovir
MRP4
Na-KTenofovir
OCTCreatinine
MRP2Ritonavir
(Blood)Ray et al. Antimicrob Agents Chemother 2006
(Urine)
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Slide #10
Tenofovir Toxicity
•
Co rtes ofCourtesy of Glen Markowitz &
Vivette D’Agati
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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
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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
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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
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Slide #14
HIVAN: Pathology
Wyatt, Klotman, & D’Agati. Seminars in Nephrology 2008
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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
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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
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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
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Slide #18
HIVAN Epidemiology: Impact of ART
800
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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
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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
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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
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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
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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
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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
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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
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Slide #25
HIV & ESRD: Survival
Ahuja et al. JASN 2002Atta et al. CID 2007
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Slide #26
HIV & ESRD: Choice of Dialysis
Ahuja et al. AJKD 2003
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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
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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