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HIV Nephropathy

HIV Nephropathy. Tuesday Morning Disease Review December 5, 2006 Edmund Huang, M.D. Objectives. Overview of HIV-associated renal diseases Discuss the nephrotoxicity of antiretroviral therapy agents

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HIV Nephropathy

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  1. HIV Nephropathy Tuesday Morning Disease Review December 5, 2006 Edmund Huang, M.D.

  2. Objectives • Overview of HIV-associated renal diseases • Discuss the nephrotoxicity of antiretroviral therapy agents • Review therapeutic options for patients with HIV-associated renal disease, including the effect of HAART on the incidence of HIV-associated renal diseases • Understand the risks, benefits, and ethical issues associated with kidney transplantation in HIV-positive patients

  3. HIV-Associated Renal Diseases • Acute Renal Failure • Nephrotoxic drugs (aminoglycosides, amphotericin B, foscarnet, trimethoprim-sulfamethoxazole, adefovir, tenofovir, indinavir, acyclovir) • TTP/HUS • Chronic Renal Failure • HIVAN (HIV-associated nephropathy) • Immune complex-mediated glomerulonephritis (IgA nephritis, MPGN, membranous, fibrillary, immunotactoid glomerulopathy)

  4. Nephrotoxicity of Antiretroviral Agents • Protease Inhibitors • Indinavir: nephrolithiasis, crystalluria, dysuria, papillary necrosis, and acute renal failure related to interstitial nephritis • Ritonavir: case reports of reversible renal failure; most reports had concomitant administration of nephrotoxic agents or underlying renal pathology • Saquinavir and nelfinavir: single case reports suggesting possible etiologic role in inducing renal calculi (analysis of a urinary stone revealed 99% composition of nelfinavir) • Atazanavir: single case report of interstitial nephritis and reversible acute renal failure; renal biopsy showed HIVAN and patient was receiving concomitant nephrotoxic drugs

  5. Nephrotoxicity of Antiretroviral Agents • Nucleotide Reverse-Transcriptase Inhibitors • Tenofovir: Fanconi’s syndrome, mild elevation in creatinine • Adefovir: ARF less frequent with lower dosages (30 mg/day) and reversible with dose reduction or cessation of medication; hematuria • Cidofovir: dose-dependent renal toxicity; Fanconi’s syndrome

  6. Nephrotoxicity of Antiretroviral Agents • Nucleoside Reverse Transcriptase Inhibitors • Didanosine and Lamivudine-Stavudine treatment associated with tubular dysfunction and Fanconi-like syndrome • Abacavir: ARF; one report of biopsy-proven interstitial nephritis

  7. Nephrotoxicity of Antiretroviral Agents • Nonnucleoside Reverse Transcriptase Inhibitor • Efavirenz: 1 case of hypersensitivity involving pneumonitis, hepatitis, and interstitial nephritis, with symptoms recurring after a rechallenge • HIV-1 Fusion Inhibitor • Enfuvirtide: binds to gp41 of HIV-1 and inhibits fusion of the virus to the membrane of CD4 cells • 1 patient with history of diabetes, proteinuria, and hematuria developed MPGN

  8. HIV-Associated Nephropathy (HIVAN) • Collapsing focal segmental glomerulosclerosis (FSGS) • Severe cystic tubular lesions • Tubuloreticular structures on electron microscopy

  9. HIV-Associated Nephropathy (HIVAN)

  10. HIV-Associated Nephropathy (HIVAN)

  11. Clinical Features • Nephrotic syndrome • Large echogenic kidneys on renal ultrasound • Typically normotensive • Progressive course – ESRD frequently develops within 1-4 months

  12. Ethnic Differences in HIV-associated Renal Disease • IgA nephritis: 7.75% of all HIV-infected patients in an autopsy study from France1 • HIVAN: primarily in patients of African descent (prevalence of 3.5% in clinical studies and 12% in autopsy studies; 3rd leading cause of ESRD in African-Americans)

  13. Role of Renal Biopsy for Diagnosis of HIVAN • Atta et al. Nephrotic range proteinuria and CD4 count as noninvasive indicators of HIV-associated nephropathy. Amer J Med (2005) 118, 1288.321-1288.e26 • 107 HIV-positive patients with a renal biopsy and urine protein measurement between 1995 and 2002 • 53% of patients with nephrotic-range proteinuria had HIVAN. • Remaining patients had non-HIV associated FSGS, MPGN, AA amyloid, diabetic nephropathy, and other diagnoses • Conclusion: HIV patients with nephrotic-range proteinuria warrant a kidney biopsy

  14. Treatment for HIVAN • HAART therapy • ACE-I or Angiotensin Receptor Blockers • Corticosteroids

  15. Effect of HAART on HIV-Associated Renal Diseases Schwartz et al. J Am Soc Nephrol. 2005 Aug;16(8):2412-20.

  16. Effect of HAART on HIV-Associated Renal Diseases • Atta et al. Antiretroviral therapy in the treatment of HIV-associated nephropathy. Nephrol Dial Transplant. 2006; 21: 2809-2813. • Retrospective chart review of 263 HIV patients referred to a single center renal clinic from 1995 to 2004 • Patients included if they had biopsy-proven HIVAN and did not require dialysis within 1 month of their kidney biopsy • 53 patients had HIVAN, 36 met inclusion criteria; 26 treated with antiretrovirals (at least 1 agent; group I) and 10 were not (group II) • Multivariate analysis and cumulative probablility of renal survival calculated

  17. Effect of HAART on HIV-Associated Renal Diseases Atta et al. Nephrol Dial Transplant. 2006; 21: 2809-2813.

  18. Effect of HAART on HIV-Associated Renal Diseases Atta et al. Nephrol Dial Transplant. 2006; 21: 2809-2813.

  19. Effect of HAART on HIV-Associated Renal Diseases Atta et al. Nephrol Dial Transplant. 2006; 21: 2809-2813.

  20. Effect of HAART on HIV-Associated Renal Diseases Atta et al. Nephrol Dial Transplant. 2006; 21: 2809-2813.

  21. ACE-Inhibitors • Burns et al. Effect of angiotensin-converting enzyme inhibition in HIV-associated nephropathy. J Am Soc Nephrol 1997; 8:1140. • 20 patients with HIVAN • 11 patients had non-nephrotic range proteinuria; 7 patients received fosinopril 10 mg daily, 4 did not • Average baseline creatinine for treated and nontreated patients was 1.3 +/- 0.24 and 1.0 +/- 0.25, (P = 0.07) • At 24 wk, creatinine of treated and nontreated patients was 1.5 +/- 0.34 and 4.9 +/- 2.4 (P = 0.006). • Average baseline 24-h urine protein excretion for treated and nontreated patients was 1.6 +/- 0.68 and 0.78 +/- 0.39 (P = 0.02) • At 24 wk, 24-h protein excretion of treated and non-treated patients was 1.25 +/- 0.86 and 8.5 +/- 1.4 (P = 0.006).

  22. ACE-Inhibitors • Burns et al. J Am Soc Nephrol 1997; 8:1140. • Of nine patients with nephrotic-range proteinuria, five were treated with fosinopril 10 mg daily and four were not • Average baseline creatinine for treated and nontreated patients was 1.7 +/- 0.46 and 1.9 +/- 0.42 (P = 0.4) • At 12 wk, creatinine for treated and nontreated patients was 2.0 +/- 1.0 and 9.2 +/- 2.0 (P = 0.02). • The baseline 24-h protein excretion for treated and nontreated patients was 5.4 +/- 1.6 and 5.2 +/- 0.97 (P = 0.9) • At 12 wk, 24-h protein excretion for treated and nontreated was 2.8 +/- 1.0 and 10.5 +/- 3.5 (P = 0.008).

  23. Corticosteroids • Smith et al. Effect of corticosteroid therapy on human immunodeficiency virus-associated nephropathy. Am J Med 1994; 97:145. • Prospective study of 20 patients with biopsy-proven HIVAN (N=17) or clinical characteristics suggestive of HIVAN (N=3) • SCr >2.0 mg/dl or proteinuria >2.0 g/day or both • Prednisone 60 mg/day for 2-11 weeks • Followed for a median of 44 weeks (range 8 to 107)

  24. Corticosteroids • Smith et al. Am J Med 1994; 97:145. • 19 patients had SCr >2.0 mg/dl • 2 patients progressed to ESRD in 4-5 weeks • 17 patients serum creatinine levels decreased from 8.1 +/- 1.2 mg/dL to 3.0 +/- 0.4 mg/dL (P < 0.001) • 5 patients relapsed after prednisone was d/c’ed and were retreated with serum creatinine declining 8.2 +/- 1.2 mg/dL to 3.9 +/- 0.5 mg/dL (P < 0.01) with the second course of steroids • 11 of 13 tested patients showed a decrease in 24-hour urinary protein excretion with an average decrease from 9.1 +/- 1.8 g/day to 3.2 +/- 0.6 g/day (P < 0.005) • 11 died from complications of HIV disease 14 to 107 weeks after institution of prednisone, none were receiving prednisone at the time of death • 2 cases of MAC infection and 3 cases of CMV retinitis

  25. HIV and Kidney Transplantation • Concerns • Overimmunosuppression leading to opportunistic infections and progression to AIDS • Drug interactions between immunosuppressive agents and HAART • Reports in the pre-HAART era of poor outcomes in HIV-positive patients receiving transplants • Perception that transplanting HIV patients is morally and ethically inappropriate for fear of wasting a limited supply of organs

  26. Renal Transplantation in the Pre-HAART Era • Swanson et al. Impact of HIV seropositivity on graft and patient survival after cadaveric renal transplantation in the United States in the pre highly active antiretroviral therapy (HAART) era: an historical cohort analysis of the United States Renal Data System. Transpl Infect Dis. 2004 Sep;4(3): 144-7. • Historical cohort analysis of 63,210 cadaveric solitary renal transplant recipients with HIV serology entries in the USRDS from 1987 to 1997 • 32 (0.05%) were HIV+ at transplant

  27. HIV+ CAD (N = 32) USRDS CAD (HIV confirmed negative) (N = 63,178) Male 18 (56%) 37,038 (61%) African-American 8 (25%) 14,800 (23%) Recipient age (mean years, SD) 37.5A (4.14) 43.1 (13,67) Donor age (mean years, SD) 25.84A (14.32) 31.80 (16.33) Recipient weight 64.82A (19,52) 71.67 (18.34), Year recipient transplanted 1990A (3,03) 1992.32 (2,82) Cause of ESRD Diabetes 5 (15.6%)B 13,737 (21.7%) Donor CMV+/recipient CMV– 6 (18.8%) 11,608 (18.4%) Rejection (treated or presumed) 16 (50%) 30,575 (48.4%) Pre-transplant dialysis 29 (93.5%) 56,695 (91.8%) Cold ischemic time (hours)C 14.88 ± 11.8 15.97 ± 11.3 Mean number of HLA antigen matches (0–6) 4.00A (1.41) 2.74 (1.62)

  28. Renal Transplantation in the Pre-HAART Era Swanson et al. Transpl Infect Dis. 2004 Sep;4(3): 144-7.

  29. Renal Transplantation in the Pre-HAART Era

  30. Renal Transplantation in Post-HAART Era • Kumar et al. Safety and success of kidney transplantation and concomitant immunosuppression in HIV-positive patients. Kidney Int. 2005 Apr; 67(4): 1622-9. • 40 HIV patients with ESRD transplanted between 2001 and 2004 • Selection criteria: adherence to dialysis and HAART, plasma HIV-1 RNA<400 copies/ml, CD4 >200 cells/ul. • Basiliximab induction; CSA (trough 150-200 ng/ml), sirolimus (trough 5-10 ng/ml), and prednisone maintenance • Protocol biopsies at 1, 6, 12, and 24 months

  31. Renal Transplantation in Post-HAART Era Kumar et al. Kidney Int. 2005 Apr; 67(4): 1622-9.

  32. Cause of death Post-transplant day Number of patients Pulmonary embolism 2 1 Anaphylactic reaction to drug 6 1 Intractable gastrointestinal bleeding 107 1 Sepsis Chest infection 37 1 Necrotizing fasciitis 238 1 Infection of the lymphocele 285 1 Myocardial infarction 545 1 Renal Transplantation in Post-HAART Era Kumar et al. Kidney Int. 2005 Apr; 67(4): 1622-9.

  33. Renal Transplantation in Post-HAART Era • Cause of graft loss Days of graft loss Number of grafts lost • Patient deaths from Table 2 2, 6, 37, 107, 238, 285 and 545 7 • Acute vascular rejection 12 1 • Bleeding at the transplant site 15 1 • Hemolytic uremic syndrome 55 1 • Steven Johnson syndrome due to Dapsone 152 1 Kumar et al. Kidney Int. 2005 Apr; 67(4): 1622-9.

  34. Renal Transplantation in Post-HAART Era Kumar et al. Kidney Int. 2005 Apr; 67(4): 1622-9.

  35. Renal Transplantation in Post-HAART Era Kumar et al. Kidney Int. 2005 Apr; 67(4): 1622-9.

  36. Renal Transplantation in Post-HAART Era • Qiu et al. HIV-positive renal recipients can achieve survival rates similar to those of HIV-negative patients. Transplantation. 2006 Jun 27; 81(12): 1658-61. • Retrospective analysis of UNOS Renal Transplant Registry • Primary kidney transplants between 1997 and 2004 • Duplicated kidneys from the same donor (N=38) transplanted to one HIV-positive patient and one HIV-negative patient • Patient and graft survival and mean serum creatinine at 6 months, 1, 3, and 5 years

  37. Renal Transplantation in Post-HAART Era Qiu et al. Transplantation. 2006 Jun 27; 81(12): 1658-61

  38. Renal Transplantation in Post-HAART Era Qiu et al. Transplantation. 2006 Jun 27; 81(12): 1658-61

  39. Renal Transplantation in Post-HAART Era Qiu et al. Transplantation. 2006 Jun 27; 81(12): 1658-61

  40. Renal Transplantation in Post-HAART Era Qiu et al. Transplantation. 2006 Jun 27; 81(12): 1658-61

  41. Conclusions • The differential diagnosis of renal failure in the HIV patient is broad and includes medication nephrotoxicity, HIV-associated TMA, and immune complex glomerulonephritis, collapsing FSGS. • There has been a plateau in the incidence of ESRD in HIV patients and a reduction in ESRD-related mortality since the advent of HAART • ACE-inhibitors should be used in patients with HIVAN and has been associated with a reduction in proteinuria and increased renal survival • Kidney transplantation is an acceptable form of renal replacement therapy for selected HIV patients

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