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Kidney and bone disease in HIV Dr Frank Post Clinical Senior Lecturer Kings College London.

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Presentation on theme: "Kidney and bone disease in HIV Dr Frank Post Clinical Senior Lecturer Kings College London."— Presentation transcript:

1 Kidney and bone disease in HIV Dr Frank Post Clinical Senior Lecturer Kings College London

2 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

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

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

5 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 Kidney Int 66: 1145 (2004) Cohort of 36 patients with HIVAN Complete suppression of HIV replication may slow progression to RRT Nephrol Dial Transplant 2006; 21: 2809

6 Characteristics of HIVAN patients with late onset ESRF / stable renal function BaselineESRD>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 ( )4.9 ( ) CD4 T-cell count66 (39-140)77 (34-197) Clin Infect Dis 2008; 46: cART CD4>200 VL<50

7 Renal Disease in HIV infection 77 Renal biopsies (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% Haas et al, Kidney Int 67: 1381 (2005) 99 Renal biopsies (Baragwanath Hospital, South Africa) HIVAN 27% FS (non-collapsing) GN 3% Immune complex GN 21% Membranous GN 13% Post-infectious/IgA GN 13% Other GNs 15% Other 10% Gerntholtz et al, Kidney Int 69: 1885 (2006)

8 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

9 HIV/ESRF in UK CHIC All patients with permanent RRT in UK CHIC ( ) 68 (0.31%) of 21,948 patients had ESRF Black patients (44) –HIVAN 36 –Vascular/HPT 1 –Glomerulonephritis 2 –Diabetes 2 –Congenital 2 –Unknown 1 –Confirmed 57% White/other patients (24) –Vascular/hypertension7 –Glomerulonephritis5 –Diabetes4 –Amyloid3 –Congenital2 –Unknown 3 –Confirmed 63% AIDS 2009; 23:

10 Patient characteristics (N=21948) ESRFNo ESRFP-value 1 N Age (years), median (IQR)36 (31, 41)34 (30, 40)0.13 Female, N (%)20 (29.4)4707 (21.5)0.13 Black ethnicity, N (%)44 (64.7)5418 (24.8)< Prior AIDS diagnosis, N (%)25 (38.5)4902 (22.4)0.005 CD4 nadir (cells/mm 3 ), 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) Obtained by Chi-squared and Mann Whitney tests AIDS 2009; 23:

11 Characteristics of those with ESRF by HIVAN status (N=65) HIVANOtherP-value N3530- 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)< Prior AIDS diagnosis, N (%)16 (45.7)9 (30.0)< CD4 nadir (cells/mm 3 ), 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)4 (13.3)0.11 Baseline eGFR (mL/min), median Time HIV-pRRT (days), median (IQR)196 (0, 1035)2171 (1574, 3668)< AIDS 2009; 23:

12 Prevalence of HIV/ESRF and survival on pRRT AIDS 2009; 23: 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)

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

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

15 Proteinuria 2g/d Steroids

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

17 Effects of current CD4 cell count and current eGFR on ARF incidence Rate (per 100 person years) >350 Current CD4 cell count < Current eGFR (ml/min/1.73m 2 ) Ibrahim et al, AIDS 2010

18

19 Case 4 (April 2006) 28 yrs old man – Portugal HIV diagnosis 1998; CD4 54 and HIV RNA >500,000 HBV/HCV negative – AZT/3TC/EFV d4T/ddI/IDV/r –2002 onwards: TFV/d4T/LPV/rTFV/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

20 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

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

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

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

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

25 cART and CKD progression Mocroft et al. AIDS 2010

26 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:

27 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 RNA1.05* CD4 < * Black ethnicity2.00* HCV antibody1.27* * p< Proteinuria is a risk factor for –Renal failure (doubling serum creatinine) –Death (RH adj = 2.9, p<0.0001) JAIDS 32: 203 (2003) Kidney Int 61: 195 (2002)

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

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

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

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

32 Changes in hip BMD in patients on TDF versus non-TDF HAART Gallant JE, et al. JAMA 2004; 292:191– Months from baseline Phosphate level, mg/dl Non-TDF-containing HAART TDF-containing HAART BL –8 –6 –4 –2– Weeks P = 0.06 TDF+3TC+EFV d4T+3TC+EFV Mean change, % Tenofovir, hypophosphatemia, and BMD Phosphate levels in patients on TDF versus non-TDF HAART Buchacz K, et al. HIV Med 2006; 7:451–456

33 JID 2009; 200: In multivariate analysis, neither tenofovir use (OR 1.32 [ ]) nor PRTD (OR 1.54 [ ]) were associated with reduced BMD Tenofovir, PRTD and BMD

34 Changes in BMD in patients initiating EFV with ABC/3TC or TFV/FTC

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

36 DXA is affected by changes in fat

37 STEAL: Effects on DEXA of change to Kivexa or Truvada

38 Mueller, AIDS 2010; 24: ; Welz, AIDS 2010 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)

39 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

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


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