Kidney Disease in HIV: An Update for Ryan White Providers Christina M. Wyatt, MD Assistant Professor Mount Sinai School of Medicine New York, New York FORMATTED: 11/16/2015 Learning Objectives After attending this presentation, participants will be able to: Identify HIV-infected patients at risk of acute or chronic kidney disease Describe the impact of antiretroviral therapy on the risk of kidney disease Slide 3 of 41 Kidney Disease in HIV Slide 4 of 41 Acute Kidney Injury (AKI) HIV-Associated CKD/ ESRD Comorbid CKD Treatment Toxicity 1
Slide 5 of 41 Caveats for Diagnosis in HIV GFR estimates are not well validated CKD-EPI appears to be the best Cystatin C should not be used alone Several antiretrovirals & co-meds interfere with creatinine secretion Don t forget about creatine Inker et al JAIDS 2012 Gagneux-Brunon AIDS 2013 Bhasin et al PLoS ONE 2013 Etiology of AKI in HIV Slide 10 of 41 Detailed data on etiology are outdated Newer data suggest sepsis remains a common risk factor for severe AKI Other associated factors reflect aging of the HIV population: DM, HTN, CKD, liver disease Nadkarni et al, JAIDS 2015 Kidney Disease in HIV Slide 11 of 41 Acute Kidney Injury (AKI) HIV-Associated CKD/ ESRD Comorbid CKD Treatment Toxicity 2
HIV-Associated Disease Slide 12 of 41 May present with either AKI or CKD HIV-associated nephropathy (HIVAN) Immune complex kidney disease (HIVICK) Thrombotic microangiopathy Slide 13 of 41 HIVAN: Classic Presentation Rapid progression to ESRD Large, echogenic kidneys Advanced HIV disease Almost exclusively in blacks ~90% of ESRD cases attributed to HIVAN Rao et al. NEJM 1984 Pardo et al. Annals 1984 Slide 14 of 41 HIVAN: Distinctive Histology Wyatt, Klotman, & D Agati. Seminars in Nephrology 2008 3
HIVAN: Pathogenesis Slide 15 of 41 HIV transgenic ( Tg26 ) mouse HIVAN requires local HIV infection Human tissue HIV infects kidney epithelial cells Dickie et al. Virology 1991 Ross et al. JASN 2001 HIVAN & Host Genetics Slide 16 of 41 Strong racial disparity in HIVAN & ESRD Phenotype varies by murine strain Strong linkage to SNPs in the APOL1 gene Mechanism is not known Gharavi et al. PNAS 2004 Genovese et al. Science 2010 Kopp et al. Nature Gen 2008 Treatment of HIVAN Slide 17 of 41 ART is first-line therapy Low level of evidence for commonly used adjunctive therapies ACE inhibitor/ angiotensin receptor blocker Corticosteroids 4
HIVICK Slide 18 of 41 Immune complex disease (without HCV/ HBV) Causal relationship to HIV is less clear Most data for IgA nephropathy Role of ART is less clear More indolent course than HIVAN Gerntholtz et al. KI 2006 Kimmel et al. NEJM 1992 Foy et al. CJASN 2013 Kidney Disease in HIV Slide 19 of 41 Acute Kidney Injury (AKI) HIV-Associated CKD/ ESRD Comorbid CKD Treatment Toxicity Slide 20 of 41 Changing Spectrum of CKD Decline in biopsies with classic HIVAN Recognition of other HIV-related diseases More comorbid kidney disease Potential for treatment toxicity Berliner et al. Am J Nephrol 2008 5
What Do We See Now? Slide 21 of 41 Non-collapsing FSGS Diabetic nephropathy Arterionephrosclerosis Immune complex disease (+/- hepatitis) Drug toxicity Data from P01 consortium: Mount Sinai/ Johns Hopkins Comorbid CKD in HIV CKD risk factors are overrepresented Black race Diabetes/ hypertension Hepatitis C virus (HCV) Difficult to distinguish contribution of HIV from that of comorbid risk factors Slide 22 of 41 Diabetes & CKD in HIV Slide 24 of 41 Increased risk of progression persists after adjustment for disease severity HIV-RNA, CD4 & ART use HbA1c & cumulative ACE/ ARB use Consistent findings in HIV-Tg mouse model Medapalli et al JAIDS 2012 Mallipattu et al, KI 2013 6
Slide 26 of 41 Hepatitis Co-infection & CKD Strong association between HCV viremia and CKD in two HIV treatment trials In NA ACCORD, HCV was associated with CKD regardless of HCV RNA Unclear impact of widespread HCV therapy Mocroft et al. PLoS ONE 2012 Peters et al AIDS 2012 Lucas et al CROI 2013 Kidney Disease in HIV Slide 27 of 41 Acute Kidney Injury (AKI) HIV-Associated CKD/ ESRD Comorbid CKD Treatment Toxicity Indinavir Slide 28 of 41 Courtesy of Glen Markowitz & Vivette D Agati 7
Tenofovir & Tubular Injury Slide 29 of 41 Usually a clinical diagnosis, but biopsy can be helpful: Atypical presentation/ comorbidities Compelling reasons to continue TDF Tenofovir Toxicity Slide 30 of 41 Courtesy of Glen Markowitz & Vivette D Agati Tenofovir Toxicity Slide 31 of 41 Courtesy of Glen Markowitz & Vivette D Agati 8
Tenofovir in 2016 Slide 35 of 41 Combination with drugs that inhibit tubular creatinine secretion Dolutegravir Cobicistat Rilpivirine Ritonavir (coformulations) Trimethoprim Tenofovir in 2016 Slide 36 of 41 Combination with new anti-hcv drugs Ledipasvir/ sofosbuvir tenofovir levels in patients with or without concomitant PI/r Use for pre-exposure prophylaxis Tenofovir alafenamide (TAF) Median (Q1, Q3) change from baseline egfr Cockroft-Gault (ml/min) 20 E/C/F/TAF STB 10 0-10 -20-30 0 12 24 Time (Weeks) Slide 37 of 41 Tenofovir Alafenamide Fumarate Similar results out to 96 weeks Zolopa et al. CROI 2013* Sax et al. Lancet 2014 9
Tenofovir Alafenamide Fumarate Slide 38 of 41 Switch studies also show improvement in proteinuria and tubular biomarkers Limited data on hard clinical outcomes Approved as E/C/F/TAF on November 5 Approved for CrCl > 30 ml/min Kidney Disease in HIV Slide 39 of 41 Acute Kidney Injury (AKI) HIV-Associated CKD/ ESRD Comorbid CKD Treatment Toxicity HIV & ESRD in 2016 Slide 40 of 41 Candidates for HD, PD, and transplant Early planning to avoid HD catheter use Upcoming study will evaluate the use of HIV+ donor kidneys in HIV+ recipients Stock et al, NEJM 2010 Muller et al, NEJM 2015 10
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