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Kidney and bone disease in HIV

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

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Kidney and bone disease in HIV

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  1. Kidney and bone disease in HIV Dr Frank Post Clinical Senior Lecturer King’s 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) Associated Focal and Segmental Glomerulosclerosis in the Acquired Immunodeficiency Syndrome T. K. SreepadaRao et al. N Engl J Med 1984; 310:669-673 AIDS 2004; 18: 541-6, Nat Genet. 2008; 40: 1175-84

  4. HIVAN in the UK (1998-2004) • 16,834 patients • 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

  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 • 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

  6. Characteristics of HIVAN patients with late onset ESRF / stable renal function cART CD4>200 VL<50 Clin Infect Dis 2008; 46: 1282-9

  7. 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% Renal Disease in HIV infection • 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)

  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 (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%

  10. Patient characteristics (N=21948) 1 Obtained by Chi-squared and Mann Whitney tests AIDS 2009; 23: 2517-21

  11. Characteristics of those with ESRF by HIVAN status (N=65) AIDS 2009; 23: 2517-21

  12. 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

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

  14. 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

  15. Steroids Proteinuria 2g/d

  16. 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

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

  18. 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

  19. 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

  21. 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

  22. 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

  23. 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

  24. cART and CKD progression Mocroft et al. AIDS 2010

  25. 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

  26. 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) Proteinuria as a marker of chronic kidney disease in HIV JAIDS 32: 203 (2003) Kidney Int 61: 195 (2002)

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

  28. 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

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

  31. 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 8 Non-TDF-containing HAART 6 TDF-containing HAART 6 TDF+3TC+EFV 5 4 d4T+3TC+EFV 2 Phosphate level, mg/dl Mean change, % 4 P = 0.06 0 3 –2 –4 2 –6 –8 1 0 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

  32. 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

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

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

  35. DXA is affected by changes in fat

  36. STEAL: Effects on DEXA of change to Kivexa or Truvada

  37. 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

  38. 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

  39. 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

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