Kidney and bone disease in HIV Dr Frank Post Clinical Senior Lecturer King’s College London

Case 1 (October 2004) 33 yrs old lady – Zimbabwe New HIV diagnosis; CD4 1 and HIV RNA 530,000 Disseminated tuberculosis HBV/HCV negative Creatinine 300; eGFR 20 mL/min; Proteinuria 5 g/24h Normal sized, echogenic kidneys HIVAN on biopsy Commenced cART – current CD4 450, VL<40 Required dialysis for 4 weeks – current eGFR 50 mL/min

HIV-Associated Nephropathy (HIVAN) Black ethnicity CD4 <250 cells/L Large, echogenic kidneys Heavy proteinuria Associated Focal and Segmental Glomerulosclerosis in the Acquired Immunodeficiency Syndrome T. K. Sreepada Rao et al. N Engl J Med 1984; 310:669-673 AIDS 2004; 18: 541-6, Nat Genet. 2008; 40: 1175-84

HIVAN in the UK (1998-2004) 16,834 patients Overall survival HIVAN prevalence in Black patients: 0.93% HIVAN incidence (in patients without renal disease at BL): 0.61/1000 py Overall survival Renal survival Clin Infect Dis 2008; 46: 1282-9

Natural History of HIVAN Cohort of 42 patients with HIVAN and 47 patients with renal diseases other than HIVAN Use of HAART associated with slower progression to RRT Cohort of 36 patients with HIVAN Complete suppression of HIV replication may slow progression to RRT Kidney Int 66: 1145 (2004) Nephrol Dial Transplant 2006; 21: 2809

ESRD>3 months after HIVAN diagnosis (n=20) Characteristics of HIVAN patients with late onset ESRF / stable renal function Baseline ESRD>3 months after HIVAN diagnosis (n=20) Stable RF (n=23) eGFR (mL/min) 28 (12-42) 29 (17-38) Proteinuria (g/24h) 5.9 (3.9-9.2) 4.9 (4.0-7.1) CD4 T-cell count 66 (39-140) 77 (34-197) cART CD4>200 VL<50 Clin Infect Dis 2008; 46: 1282-9

Renal Disease in HIV infection 77 Renal biopsies 1999-2003 (Johns Hopkins, USA) (89% African American) HIVAN 40% FS (non-collapsing) GN 17% Immune complex GN 34% Interstitial nephritis 5% Thrombotic 1% microangiopathy Amyloidosis (AA) 1% Hypertensive nephropathy 1% 99 Renal biopsies 2003-2004 (Baragwanath Hospital, South Africa) HIVAN 27% FS (non-collapsing) GN 3% Immune complex GN 21% Membranous GN 13% Post-infectious/IgA GN 13% Other GN’s 15% Other 10% Haas et al, Kidney Int 67: 1381 (2005) Gerntholtz et al, Kidney Int 69: 1885 (2006)

Case 2 (March 2005) 34 yrs old lady – Finland New HIV diagnosis; CD4 38 and HIV RNA 120,000 Diabetes mellitus (retinopathy) HBV/HCV negative Creatinine 629; eGFR 7 mL/min; Proteinuria 2 g/24h Normal sized kidneys Diabetic nephropathy Commenced cART – current CD4 663, VL<40 Required permanent dialysis – renal transplant 2008 current eGFR 48 mL/min

HIV/ESRF in UK CHIC All patients with permanent RRT in UK CHIC (1998-2007) 68 (0.31%) of 21,948 patients had ESRF AIDS 2009; 23: 2517-21 Black patients (44) HIVAN 36 Vascular/HPT 1 Glomerulonephritis 2 Diabetes 2 Congenital 2 Unknown 1 Confirmed 57% White/other patients (24) Vascular/hypertension 7 Glomerulonephritis 5 Diabetes 4 Amyloid 3 Congenital 2 Unknown 3 Confirmed 63% 9

Patient characteristics (N=21948) ESRF No ESRF P-value1 N 68 21883 Age (years), median (IQR) 36 (31, 41) 34 (30, 40) 0.13 Female, N (%) 20 (29.4) 4707 (21.5) Black ethnicity, N (%) 44 (64.7) 5418 (24.8) <0.0001 Prior AIDS diagnosis, N (%) 25 (38.5) 4902 (22.4) 0.005 CD4 nadir (cells/mm3), median (IQR) 72 (27, 157) 179 (71, 300) HBV+, N (%) 4 (5.9) 1679 (7.7) 0.58 HCV+, N (%) 5 (7.4) 1594 (7.3) 0.98 1 Obtained by Chi-squared and Mann Whitney tests AIDS 2009; 23: 2517-21 10

Characteristics of those with ESRF by HIVAN status (N=65) Other P-value N 35 30 - Age (years), median (IQR) 35 (29, 39) 42 (37, 48) 0.001 Female, N (%) 15 (42.9) 4 (13.3) 0.01 Black ethnicity, N (%) 35 (100.0) 7 (23.3) <0.0001 Prior AIDS diagnosis, N (%) 16 (45.7) 9 (30.0) CD4 nadir (cells/mm3), median (IQR) 70 (29, 144) 72 (25, 190) 0.67 HBV+, N (%) 2 (5.7) 2 (6.7) 0.87 HCV+, N (%) 1 (2.9) 0.11 Baseline eGFR (mL/min), median 11 50 Time HIV-pRRT (days), median (IQR) 196 (0, 1035) 2171 (1574, 3668) AIDS 2009; 23: 2517-21 11

Prevalence of HIV/ESRF and survival on pRRT In the UK The incidence of ESRF was approximately 5-10 fold lower than in the USA Survival of black patients was markedly better than in the USA (97% v 43% at 2 years) AIDS 2009; 23: 2517-21

Black ethnicity and low current CD4 cell count are risk factors for HIV/ESRF AIDS 2009; 23: 2517-21

Case 3 (April 2010) 59 yrs old man – Uganda HIV diagnosis 1995; CD4 354 and HIV RNA 53,000 HBV/HCV negative 1998-1999 d4T/ddI/NVP 1999-2002 AZT/3TC/NVP 2002 onwards: TFV/3TC/NVP TFV/FTC/NVP CD4 500-1000, VL<50 (3 blips, 2 rebounds) 2010: General malaise Severe acute renal failure (dialysis) Interstitial nephritis: response to corticosteroids

Steroids Proteinuria 2g/d

ARF in a multi-ethnic UK HIV cohort Associated aetiology <3 months >3 months Pre-renal state 67% 73% Nephrotoxic agents 73% 73% NSAIDs 15% 27% Mortality 30% Clin Infect Dis 2008; 47: 242-9

Effects of current CD4 cell count and current eGFR on ARF incidence 10 20 30 40 Rate (per 100 person years) 0-50 51-100 101-200 201-350 >350 Current CD4 cell count 10 20 30 <60 61-74 75-89 ≥90 Current eGFR (ml/min/1.73m2) Ibrahim et al, AIDS 2010

Case 4 (April 2006) 28 yrs old man – Portugal HIV diagnosis 1998; CD4 54 and HIV RNA >500,000 HBV/HCV negative 1998-2002 AZT/3TC/EFV d4T/ddI/IDV/r 2002 onwards: TFV/d4T/LPV/r TFV/d4T/ATV/r 2006: Painful ribcage, lumbar spine and metatarsal joints Raised ALP (227), hypophosphatemia (0.47) Normal creatinine / eGFR 3+ glycosuria (no DM), 1+ proteinuria (PCR 14.7) Reduced fractional excretion of P (57%) Normal vitamin D and PTH

Fanconi syndrome Prevalence: 1-2% of patients receiving Tenofovir Bone pain Phosphate wasting Osteomalacia Almost exclusively when tenofovir is co-administered with a (boosted) PI 20

Tenofovir-associated renal toxicity 100% of patients had evidence of reduced phosphate re-absorption HIV8, Glasgow 2006

KTD in HIV infected patients 284 consecutive HIV patients Median creatinine clearance 109-123 mL/min 22% of 154 on TFV 6% of 49 on cART/no TFV 12% of 81 no cART AIDS 2009;23:689-96

Risk factors for KTD while receiving tenofovir Role of polymorphisms in genes encoding drug transporters Curr Opin Infect Dis 2009; 22: 43-48 Clin Infect Dis. 2009;48:e108-16

Effects of cART on renal function AZT/3TC/NVP or AZT/3TC/TFV Clin Inf Dis 2008;46:1271-81 AIDS 2008;22:481-7 Clin Inf Dis 2008;46:1271-81, AIDS 2008;22:481-7, AIDS 2009; 23: 2143-9

cART and CKD progression Mocroft et al. AIDS 2010

Proteinuria in the ALLRT cohort (n=2857) Prevalence 16% (>200 mg/d; 3% > 1 g/d) Little change in the amount of proteinuria over time Associated with: older age, HPT, DM, reduced eGFR reduced CD4, prior ART, HIV viraemia, HCV co-infection Antivir Ther 2009; 14: 543-49

Proteinuria as a marker of chronic kidney disease in HIV Proteinuria in 2057 HIV+ women: Prevalence (2x dipstix 1+): 32% Risk factors for proteinuria (OR): Log HIV RNA 1.05* CD4 <200 1.41* Black ethnicity 2.00* HCV antibody 1.27* * p<0.0001 Proteinuria is a risk factor for Renal failure (doubling serum creatinine) Death (RHadj = 2.9, p<0.0001) JAIDS 32: 203 (2003) Kidney Int 61: 195 (2002)

Reduced eGFR, albuminuria, and (cardiovascular) mortality Lancet 2010; 375: 2073

Reduced eGFR, albuminuria, and cardiovascular events in HIV Case control study (JH cohort) median eGFR: cases 69 mL/min controls 103 mL/min (p<0.001) Increased risk of MI with lower eGFR: OR 1.2 (1.1-1.5), p=0.004 per 10 mL/min reduced AIDS 2010; 24: 387-94 Circulation 2010; 121: 651-658 29

Factors associated with low BMD Osteoporosis: HIV+ v - cART Brown, AIDS 2006; 20:2165-74 Cazanave, AIDS 2008, 22: 395-402

Fractures in HIV patients females males 8525 HIV-infected and 2,208,792 non-HIV-infected patients (1996 – 2008) Triant, J Clin Endocrinol Metab 2008, 93: 3499-504

Tenofovir, hypophosphatemia, and BMD Phosphate levels in patients on TDF versus non-TDF HAART Changes in hip BMD in patients on TDF versus non-TDF HAART 7 Non-TDF-containing HAART 8 6 TDF-containing HAART 6 TDF+3TC+EFV 5 4 d4T+3TC+EFV Phosphate level, mg/dl 2 4 Mean change, % P = 0.06 3 –2 –4 2 –6 1 Preliminary clinical evidence for ARV-specific bone toxicity Some clinical evidence for ARV-specific bone toxicity is presented. A small reduction in serum phosphate over 24 months was seen in one study in patients on TDF-containing HAART versus those on non TDF-containing HAART [1]. A reduction in BMD was seen in HIV patients during the first year of TDF- versus non-TDF-containing HAART [2]. The mean change in BMD remained at –2.7% in patients on TDF after 5 years, therefore no significant decrease was observed after 1 year [3]. The long-term significance of these reductions in serum phosphate and BMD are not yet known. References Buchacz K, et al. HIV Med 2006; 7:451–456. Gallant JE, et al. JAMA 2004; 292:191–201. Cassetti I, et al. for the 903 study team. 8th International Workshop on Adverse Drug Reactions and Lipodystrophy. San Francisco, CA. September 24–26, 2006. Abstract P152. –8 3 6 9 12 15 18 21 24 BL 24 48 72 96 120 144 Months from baseline Weeks Buchacz K, et al. HIV Med 2006; 7:451–456 Gallant JE, et al. JAMA 2004; 292:191–201

Tenofovir, PRTD and BMD In multivariate analysis, neither tenofovir use (OR 1.32 [0.60-2.92]) nor PRTD (OR 1.54 [0.29-8.29]) were associated with reduced BMD JID 2009; 200: 1746-54

Changes in BMD in patients initiating EFV with ABC/3TC or TFV/FTC Changes in markers consistent with other drug-induced fanconi-like syndromes, and can progress to full-blown fanconi’s Tubular Dysfunction β2-microglobulin is a low molecular weight protein synthesised in all nucleated cells. Very little is found in the urine of healthy subjects, but levels can increase substantially following renal tubular damage caused by disease or exposure to toxic chemicals. Under normal conditions resorption of beta-mic by proximal tubular cells is almost complete (>99.9%), so any increase above normal levels is indicative of tubular damage Retinol binding protein transports vitamin A in its alcoholic form (retinol) from the liver to epithelial tissues. Most RBP forms a high molecular weight complex with thyroxin-binding prealbumin, preventing filtration by the glomerulus. After delivering retinol to target tissues RBP loses affinity for prealbumin and is feely filtered by the glomerulus. It is absorbed with an efficiency of >99.9% by the proximal tubular cells and normally very little is found in the urine Tubular Damage N-Acetyl-(D)-Glucosaminidase is a lysosomal enzyme present in kidney tubule cells. With a molecular weight of 130-140 Kd, NAG is not normally filtered at the glomerulus, so its presence in urine is indicative of renal tubular cell injury. It has been shown to be a sensitive indicator of renal injury due to a variety of drugs <100% is a reduction from baseline, >100% is an increase from baseline

ART and changes in BMD Hip LS Hip LS 35 Cooper et al, 16th CROI 2009 * -linear regression No significant interaction of NRTI and NNRTI/PI components (p=0.69) Mallon, Curr Opin Inf Dis 2010 McComsey, G et al. 17th CROI 2010. Abstract 106LB 35

DXA is affected by changes in fat

STEAL: Effects on DEXA of change to Kivexa or Truvada

Vitamin D status in a London cohort: 91.3% <30 g/L (suboptimal) 73.5% <20 g/L (deficient) 34.8% <10 g/L (severely deficient) Mueller, AIDS 2010; 24: 1127-34; Welz, AIDS 2010

Summary Renal dysfunction is common, although severe kidney disease is relatively rare Renal dysfunction may impact on cardiovascular and bone health TFV is associated with progression of CKD and renal tubular dysfunction Vitamin D deficiency and osteopenia are common, but fragility fractures are rare TFV/FTC is associated with greater initial bone loss compared to ABC/3TC

Acknowledgements King's College London: Lucy Campbell, Fowzia Ibrahim, Lisa Hamzah, Emily Wandolo, Bruce Hendry King’s College Hospital: Chris Taylor, Mary Poulton, Claire Naftalin, Emily Cheserem, Jennifer Roe, Tanya Welz, Rashim Salota, Roy Sherwood, Caje Moniz, Paul Donohoe