X H I V / A I D S J o h n s H o p k i n s / B r a z i l April 11-13, 2012 Sofitel Rio de Janeiro Copacabana, Brazil

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1 HIV and the Kidney Mohamed G. Atta, MD, MPH X H I V / A I D S J o h n s H o p k i n s / B r a z i l April 11-13, 2012 Sofitel Rio de Janeiro Copacabana, Brazil

2 Objectives

3 Multivariate hazard ratios for primary outcome in HOPE CV death, MI, and stroke Mann JFE, et al. Ann Intern Med. 2001;134:

4 Current markers of kidney disease Glomerular injury biomarkers: albuminuria/proteinuria Renal tubular injury biomarkers: proteinuria/phosphaturia/glycosuria Estimating equations of kidney function

5 Estimating equations Cockcroft-Gault CrCl (ml/min) = (140-age) * weight * (0.85 if F) scr x 72 MDRD GFR (ml/min per 1.73 m2) = 186 * scr * Age * (0.742 if female) * (1.210 if black) Cockcroft DW and Gault MH. Nephron. 1976;16:31-41 Levey AS, et al. J Am Soc Nephrol. 2000;11:A0828

6 A new equation to estimate glomerular filtration rate (CKD-EPI) Race and sex Black Female Male White or other Female Male Serum creatinine level, µmol/l (mg/dl) 62 ( 0.7) >62 (>0.7) 80 ( 0.9) >80 (>0.9) 62 ( 0.7) >62 (>0.7) 80 ( 0.9) >80 (>0.9) Equation GFR = 166 x (Scr/0.7) x (0.993) Age GFR = 166 x (Scr/0.7) x (0.993) Age GFR = 163 x (Scr/0.9) x (0.993) Age GFR = 163 x (Scr/0.9) x (0.993) Age GFR = 144 x (Scr/0.7) x (0.993) Age GFR = 144 x (Scr/0.7) x (0.993) Age GFR = 141 x (Scr/0.9) x (0.993) Age GFR = 141 x (Scr/0.9) x (0.993) Age Levey et al. Ann Intern Med. 2009;150:

7 Kidney function and the risk of cardiovascular events in HIV-1 infected patients Nested, matched, case-control study 315 HIV-infected patients (63 cases who had cardiovascular events and 252 controls) egfr (CKD-EPI formula/mdrd), and proteinuria were the primary exposures of interest George et. al AIDS, January 2010

8 Kidney function and the risk of cardiovascular events in HIV-1 infected patients egfr of <60: unadjusted OR 15 9 for cardiovascular event (p<0 001) Adjusted OR (egfr 10 ml/min ): 1.2 (95% CI ) for cardiovascular event Prevalence of proteinuria: 51% in cases vs. 25% in control, p<0 001) Proteinuria: unadjusted OR 3 6 (95% CI ) and adjusted OR 2 2 (95% CI ) George et. al AIDS, January 2010

9 Relationship between egfr and cardiovascular event status HIV-1 infected patients Cardiovascular event status No event Event Mean egfr: 68 4 (cases) vs ml/min (control) p < Estimated GFR (CKD-EPI method) George E. AIDS 2010;24:387 94

10 Microalbuminuria is associated with all-cause mortality in women 1547 HIV-infected women (WIHS) 100 Time to all-cause death % survival function No albuminuria Unconfirmed albuminuria Confirmed albuminuria 70 Confirmed proteinuria Wyatt et al. JAIDS 2010

11 Kidney Disease in HIV-Infected Individuals

12 Kidney disease in HIV-infected individuals

14 HIVAN: Classic clinical characteristics Exclusive disease of Africans Proteinuria (often nephrotic range) Atta et al. Am J Med, 2005 Detectable viremia or detectable Proviral DNA Estrella et al. Clin Infect Dis 2006 Izzedine et al. NDT (July, 2010) Normal size echogenic kidneys on ultrasound Atta et al. J Ultrasound Med, 2004 Progressive renal failure (weeks to months)

15 Why AA? Genome wide search

t tttctccatttgtcgtgacacctttgttgacaccttcatttctgcattctcaattctatttcactggtctatggcagagaacacaaaatatgg c ccagtggcctaaatccagcctactaccttttttttttttttgtaacattttactaacatagccattcccatgtgtttccatgtgtctgggctgc Some

gccaactcctgatttatgaacttatcattatgtcaataccatactgtctttattactgtagttttataagtcatgacatcagataatgtaaat 3 million differences between individuals

ctctgtattcgtgggggattggttccacaacaacacccaccccccactcggcaacccctgaaacccccacatcccccagcttttttc ccctgctaccaaaatccatggatgctcaagtccatataaaatgccatactatttgcatataacctctgcaatcctcccctatagtttaga g ~95% of these

tttgtttgtttgtattttaagagatggtgtcttgctttgttgcccaggctggagtgcagtggtgagatcatagcttactgcagcctcaaact phenotypic effects

16 t tttctccatttgtcgtgacacctttgttgacaccttcatttctgcattctcaattctatttcactggtctatggcagagaacacaaaatatgg c ccagtggcctaaatccagcctactaccttttttttttttttgtaacattttactaacatagccattcccatgtgtttccatgtgtctgggctgc Some 15 million SNPs total: g ttttgcactctaatggcagagttaagaaattgtagcagagaccacaatgcctcaaatatttactctacagccctttataaaaacagtgt g t a t a c c gccaactcctgatttatgaacttatcattatgtcaataccatactgtctttattactgtagttttataagtcatgacatcagataatgtaaat 3 million differences between individuals cctccaactttgtttttaatcaaaagtgttttggccatcctagatatactttgtattgccacataaatttgaagatcagcctgtcagtgtcta g caaaatagcatgctaggattttgatagggattgtgtagaatctatagattaattagaggagaatgactatcttgacaatactgctgccc c g a ctctgtattcgtgggggattggttccacaacaacacccaccccccactcggcaacccctgaaacccccacatcccccagcttttttc ccctgctaccaaaatccatggatgctcaagtccatataaaatgccatactatttgcatataacctctgcaatcctcccctatagtttaga g ~95% of these differences have t no c tcatctctagattacttataatactaataaaatctaaatgctatgtaaatagttgctatactgtgttgagggttttttgttttgttttgttttatttg a tttgtttgtttgtattttaagagatggtgtcttgctttgttgcccaggctggagtgcagtggtgagatcatagcttactgcagcctcaaact phenotypic effects cctggactcaaacagtcctcccacctcagcctcccaaagtgctgggatacaggtgtgacccactgtgcccagttattattttttatttg t t t c g c c tattattttactgttgtattatttttaattattttttctgaatattttccatctatagttggttgaatcatggatgtggaacaggcaaatatggag a ggctaactgtattgcatcttccagttcatgagtatgcagtctctctgtttatttaaagttttagtttttctcaaccatgtttacttttcagtatac aagactttgacgttttttgttaaatgtatttgtaagtattttattatttgtgatgttatttaaaaagaaattgttgactgggcacagtggctcac gcctgtaatcccagcactttgggaggctgaggcgggcagatcacgaggtcaggagatcaagaccatcctggctaacatggtaaa Influenced just by demography accccgtctctactaaaaatagaaaaaaattagccaggcgtggtggcgagtgcctgtagtcccagctactcgggaggctgaggc g t g a c a aggagaatggtgtgaacctgggaggcggagcttgcagtgagctgagatcgtgccactgcattccagcctgcgtgacagagcga gactctgtcaaaaaaataaataaaatttaaaaaaagaagaagaaattattttcttaatttcattttcaggttttttatttatttctactatatgg t g atacatgattgatttttgtatattgatcatgtatcctgcaaactagctaacatagtttattatttctctttttttgtggattttaaaggattttctac c a atagataaataaacacacataaacagttttacttctttcttttcaacctagactggatgcattttttgtttttgtttgtttgtttgctttttaacttg g gsmaller Useful percentages to infer encode human phenotypic origins ctgcagtgactagagaatgtattgaagaatatattgttgaacaaaagcagtgagagtggacatccctgctttccccctgattttaggg a g c differences and c ggaatgttttcagtctttcactatttaatatgattttagctataggtttatcctagatccctgttatcatgttgaggaaattcccttctatttcta migrations and also in gene mapping gtttgttgagattttttaattcatgtgattgcgctatctggctttgctctca An even smaller percentage cause or predispose g to t a c disease or variable drug response g a g c g a

17 Non-diabetic ESKD in African Americans: Admixture scan Smith panel (Kao et al.) Chromosome 22 Smith panel (Kopp et al.)

18 Admixture peak: centered on MYH9; >30 other genes were found in the 2 mb 95% interval MYH9 encoding non-muscle myosin heavy chain was chosen: Known Giant Platelet Syndromes caused by rare mutations with dominant Mendelian inheritance pattern sometimes cause ESKD Center of the peak OR statistic for each SNP African ancestry >90% in cases (Mb) African ancestry in controls RAXLX LOC RP5 1119A7.4 Adapted from Kopp et al 2008 and NIDDK 2010, Kao et al 2008 LL22NC01 81G9.2

19 Frequencies of risk (E-1), protective (E-2), and neutral MYH9 haplotypes (E-3-E-5) in the HapMap and HGDP Oleksyk et al. PLoS One, 2010

20 Genovese et al.

21 Genetic hitchhiking Genes 350 kbp around MYH9 Arg182Cys APOL3 APOL4 APOL2 APOL1 MYH9 TXN2 FOXRED2 APOL3 Q58X MYH9 gene, 110kbp Contains dozens of ESKD associated INTRONIC SNPs FOXRED2 R71C APOL1 (15kbp) S342G and I384M LD 279/280 Chromosomes del.n388/y389 Corresponds to Genovese et al. G1 missense risk haplotype Corresponds to Genovese et al. G2 nonsense deletion

22 HIVAN prevention and treatment Presumed HIV-associated nephropathy incidence stratified by AIDS status and antiretroviral use Hopkins Nephrology HIV Cohort ARV treatment of HIVAN: 100 Cases per 1000 person-years 45 No Antiretroviral 40 Therapy Nucleoside Reverse Transcriptase Inhibitor Therapy Highly Active Antiretroviral Therapy 5 No AIDS AIDS Dialysis-free Survival (%) ARV Treatment (n=26) No (n=10) ARV P = (0.025) Time (days) Lucas GM, et al. AIDS. 2004;20:18(3): ; Atta et al., Nephrol Dial Transpl, 2006

23 Recommendations for initiating ART in the USA Clinical condition and/ or CD4+ cell count History of AIDS-defining illness Pregnant women HIV-associated nephropathy (HIVAN) Hepatitis B co-infection requiring treatment CD4+ cell count <350 cells/mm 3 CD4+ cell count cells/mm 3 CD4+ cell count >500 cells/mm 3 Recommendation Treat Treat Treat Treat Treat Treatment recommended* Expert opinions differ: 50% recommend treatment 50% view therapy as optional at this CD4+ cell count *Panel was divided on the strength of this recommendation: 55% of panel members for strong recommendation and 45% for moderate recommendation DHHS. Guidelines for the use of antiretroviral agents in HIV-1-Infected adults and adolescents. Washington, DC: January 10, 2011

24 HIV-immune complex GN Lupus like GN Post infectious GN IgA GN MPGN and MN Non-specific ICGN Nochy et al. Nephrol Dial Transplant 1993;8:11

25 Cumulative Incidence of ESRD 83 with HIVICK 37 with HIVAN 19 with HIVICK + HIVAN p = * Unpublished data

26 HIV-associated TMA 150 ADAMTS13 activity N=45 HIV- patients (n=62) N=17 HIV+ patients (n=29) Malak S. et al. Scandinavian Journal of Immunology 2008;68:

27 HIV-associated TMA ADAMTS13 <5% HIV+ patients: Lower AIDS-related complications (23.5% versus 91.6%, respectively, P = ) Higher median CD4+ T cell count (P = 0.05) Lower mortality (11.7% Vs. 50%, P = 0.04) Malak S. et al. Scandinavian Journal of Immunology 2008;68:

28 Drugs and Mechanism of Renal Injury in HIV

29 HAART-associated kidney disease Renal syndrome Acute kidney injury Toxic acute tubular necrosis Acute interstitial nephritis Crystal nephropathy Tubular Fanconi's syndrome Renal tubular acidosis Nephrogenic diabetes insipidus Chronic kidney disease Drug TDF, DDI, Ritonavir ATZ, IDV, ABC IDV, ATZ TDF, DDI, ATZ, ritonavir Lamivudine, STV TDF, DDI, IDV TDF, IDV, ATZ

30 Crystalluria and stone formation Indinavir a b a: Kopp, J. Ann Intern Med 1997 Atazanavir b: Courtesy of Perazella M, Yale University c, d: Couzigou et al. CID 2007 c d

31 Urolithiasis in HIV positive patients treated with atazanavir Prevalence: 0.97% (11/1134) patients who were treated with ATZ from March 2004 through February 2007 Risk factors: Alkaline ph: 6 Duration on treatment Couzigou et al. CID 2007:45 (15 October)

32 Tenofovir renal toxicity Acute renal failure Fanconi syndrome Nephrogenic diabetes insipidus... Chronic kidney disease Atta M. et al. Seminars in Nephrology 2008;6 Izzedine et.al. AJKD 2005;45 Winston, et.al. HIV Med 20067

33 Model of organic anion transporters in kidney proximal tubule interstitium lumen Na + Dicarboxylates OA - OA -? SDCT2 OAT1 α-kg 2- OAT3? MRP6? OA - OATP1 GSH OAT-K1/(K2) NPT1 OAT4? MRP2 MRP4 PEPT1/2 OA - OA - OA - Cl - (?) OA - OA - OA - H + peptides Russel FG. Annu Rev Physiol 2002;64:563 94

35 Factors influencing elimination Risk Factors Low body weight Underlying kidney disease Use of DDI Use of nephrotoxic drugs Low CD4 count Co-infection with HCV Diabetes Old age SNPs in transporter proteins drugs Adapted from Expert Opin. Drug Saf. 2010;9:

37 Increased risk of abnormal proximal renal tubular function with HIV infection and antiretroviral therapy PRTD was defined on the basis of the presence of at least 2/5 criteria (399 patients): in FE phos, with low sr. phos. <0.80 mmol/l Non-diabetic glucosuria Metabolic acidosis (ph<7.34 and sr. bicarb. <22 mmol/l) Ratio B2-microglobulinuria/ur. cr. >40.3 mg/l Low sr. uric acid with FE uric acid >15% Dauchy et al. Kidney International 2011;80:

38 Increased risk of abnormal proximal renal tubular function with HIV infection and antiretroviral therapy Prevalence: 6.5% Final model OR (95% CI) P-value Age 1.28 ( ) TDF 1.23 ( ) ATZ 1.28 ( ) Dauchy et al. Kidney International 2011;80:

39 Chronic kidney disease and antiretroviral drug use in HIV-positive patients 3.3% over a median follow-up of 3.7 % progressed Months from baseline N= Mocroft et al. AIDS 2010, EuroSIDA Study Group

40 Hazard of CKD incidence Mocroft et al. AIDS 2010, EuroSIDA Study Group

41 Tenofovir exposure and risk of outcomes 10,841 HIV-infected VA patients Median follow-up ranged from 3.9 years (proteinuria) to 5.5 years (CKD) Proteinuria (n=3400 events) Hazard ratio (95% CI) Rapid decline (n=3078 events) Cumulative exposure to tenofovir (per year) CKD (n=1712 events) 1.34 ( )*** 1.11 ( )* 1.23 ( )*** Ever exposure to tenofovir (versus never) 1.68 ( )*** 1.36 ( )*** 1.38 ( )*** *** p<0.0001, ** p<0.001, * p<0.01 Scherzer et al. AIDS, Feb 4, 2012 Epub ahead of print

42 Risk of renal dysfunction in an HIV-infected patient HIV infection HAART Risk of renal dysfunction Age Ethnicity Family history HIV RNA CD4 cells HIVAN/ HIVIC/TMA Non HIV Kidney disease Nephrotoxic ARV Metabolic disturbances (diabetes, hypertension, bone disease) Un-modifiable Time

43 Suggested recommendations In treated or untreated HIV Screen all patients with GFR/urine protein/albumin For high risk patients, monitor kidney disease regularly Every 3 months is optimal For those with CKD Address CV risk Patients on certain ART Close monitoring for renal/tubular abnormalities Be aware of PI/NRTI interactions Avoid in high renal risk patients

44 Acknowledgments Hopkins Nephrology D. Fine M. Estrella M. Foy Pathology M. Kuperman L. Racusen ID G. Lucas J. Gallant R. Moore NIH J. Kopp C. Winkler G. Nelson A. Warner Pitie-Salpetiere Hospital, Paris, France Nephrology G. Deray H. Izzedine All India Institute of Medical Sciences, New Delhi, India E. George

45 Thank you

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BHIVA AUTUMN CONFERENCE 2012 Including CHIVA Parallel Sessions Dr Ian Williams University College London Medical School COMPETING INTEREST OF FINANCIAL VALUE > 1,000: Speaker Name Statement Ian Williams