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HIV Associated Nephropathy

HIV Associated Nephropathy

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HIV Associated Nephropathy

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  1. HIV Associated Nephropathy Disease Review Cheri X. Ye, MD 12/10/08

  2. Introduction: HIVAN • Initially described in 1984 • Renal disease found in HIV-1 patients • HIVAN is not the only cause of kidney disease in HIV infection • Usually a late manifestation of HIV-1 infection • Especially prevalent among those of African descent (majority of cases occur in blacks)

  3. Rates of ESRD due to AIDS While the rate of new cases of ESRD due to AIDS has fallen slightly since the beginning of the decade—reaching 2.7 per million population in the 2004–2005 period—prevalence has grown steadily, reaching 8.9 in 2004–2005, and indicating that people are living longer with the disease USRDS 2008

  4. Clinical Presentation • Renal insufficiency with proteinuria, usually nephrotic range • Peripheral edema, HTN are uncommon • Urinalysis typically bland, except for proteinuria • Renal US generally shows echogenic kidneys that are normal-to-large, unlike most cases of chronic renal failure

  5. Clinical Presentation • Lack of signs such as edema or HTN may lead to delay in diagnosis of renal failure • Uremic symptoms (anorexia, fatigue etc) may be attributed to underlying HIV infection, thus further delaying diagnosis • Thus, timely diagnosis of HIVAN requires close monitoring of chemistries/UA with a high degree of suspicion in at risk populations

  6. Differential Diagnosis • Etiologies of renal failure in HIV positive patients are similar to seronegative patients • Prerenal 2/2 poor PO, diarrhea, vomiting • Medications causing ATN, AIN • Hypotension, sepsis in hospitalized pts • Rule out acute/reversible causes first

  7. Ross MJ. Aids Patient Care and STDs 2000; 14 (12): 637-645

  8. Differential Diagnosis • Suspected cases of HIVAN are often not HIVAN on biopsy • MPGN, IgA nephropathy, amyloidosis, minimal change, diabetic nephropathy, AIN, cryoglobulinemia etc • Thus, a kidney biopsy is necessary to make the diagnosis of HIVAN as the diagnosis cannot be made on clinical grounds alone

  9. Pathology • HIVAN is defined by the presence of characteristic morphologic abnormalities on renal biopsy • Light microscopy: • collapsing focal glomerulosclerosis • marked hypertrophy and hyperplasia of overlying visceral epithelial cells • microcystic dilatation of tubules • lymphocytic infiltration of interstitium

  10. Normal glomerulus Collapsing FGS Light micrograph of a normal glomerulus. There are only 1 or 2 cells per capillary tuft, the capillary lumens are open, the thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes (short arrow), and the mesangial cells and mesangial matrix are located in the central or stalk regions of the tuft (arrows). Light micrograph showing collapsing glomerulosclerosis with few open loops in the sclerotic areas (long arrows); these findings are characteristic of HIV nephropathy but can also be seen in idiopathic disease. The degree of collapse can be appreciated by the openness of Bowman's space. Vacuolization and crowding of the glomerular epithelial cells (short arrows) is also frequently seen and reflects the primary epithelial cell injury in this disorder.

  11. Light microscopy from human biopsy with HIVAN. • Characteristic collapsing focal segmental glomerulosclerosis with podocyte proliferation. • B.Microcystic tubular dilatation and inflammatory interstitial infiltrates. Lu T. The Mount Sinai Journal of Medicine 2005; 72 (3): 193-199

  12. Renal biopsy characteristic of HIV-associated nephropathy: glomeruli show collapsing sclerosis (arrows) characterized by a global glomerular basement membrane wrinkling and collapse with narrowing and early obliteration of the capillary lumens. Adjacent tubules demonstrate marked microcystic dilation with flatting of the tubular epithelial cells (arrow heads) and are filled with proteinaceous casts. The interstitium shows an inflammatory cell infiltrate composed primarily of lymphocytes (periodic acid-Schiff, 200X) Yalavarthy R et al. International Journal of STD & AIDS 2008; 19; 789-790

  13. Pathology • Electron microscopy: may show numerous tubuloreticular structures in glomerular endothelial cells • Immunofluorescence: may be staining for IgM, C3 and less frequently, C1.

  14. EM of a normal glomerular capillary loop showing the fenestrated endothelial cell (Endo), the glomerular basement membrane (GBM), and the epithelial cells with its interdigitating foot processes (arrow). The GBM is thin and no electron dense deposits are present. Two normal platelets are seen in the capillary lumen. EM in HIV-induced focal collapsing glomerulosclerosis shows numerous intraendothelial (End) tubuloreticular structures (arrow). These structures are not seen in the idiopathic form of the disease. The epithelial cell (Ep) has no discrete foot processes, a reflection of primary epithelial cell injury.

  15. Pathogenesis • Pathogenesis not well understood • Animal models suggest pathogenesis is due to viral infection of the renal cells • HIV-1 RNA/DNA has been detected in human renal epithelial cells, suggesting that renal cells may act as a reservoir for HIV-1 • Mechanism of cellular entry is unclear

  16. In situ hybridization for HIV-1 mRNA in kidney biopsies. (A and B) Kidney biopsy from an HIV-negative patient demonstrating no HIV-1 mRNA in the sense control (A) or the antisense (B) hybridization of a serial section. (C and D) Kidney biopsy from an HIV-positive patient with kidney disease. No hybridization was observed in the sense control (C). Antisense hybridization (D) demonstrates HIV-1 mRNA in the cytoplasm of tubular epithelial cells and in cellular casts (CC) in the tubular lumen (TL) but not in protein casts (PC). Wyatt, C. M. et al. Clin J Am Soc Nephrol 2007;2:S20-S24

  17. Clinical Course • Without treatment with HAART or ACEi, most cases progress to ESRD rapidly (weeks to months), necessitating dialysis • Mortality usually a complication of AIDS itself rather than the renal disease

  18. Host Factors • Predisposition of pts of African descent suggests that host genetic factors are important in development of disease • Patients with HIVAN are more likely to have a family history of ESRD

  19. Yalavarthy R et al. International Journal of STD & AIDS 2008; 19; 789-790

  20. Treatment • Antiretroviral therapy • ACEi • Steroids • No well controlled clinical trials regarding treatment of HIVAN • No proven effective therapy

  21. HAART • Decline nationally of incidence of HIVAN since inception of HAART ~ 1996 • HAART effective in slowing down progression to ESRD in HIVAN patients • HAART also associated with reduction in risk for developing HIVAN • Reduces HIV-1 viral replication

  22. HAART • Atta et al. (2006), retrospective study, 36 patients with biopsy proven HIVAN, not on dialysis yet. 26 treated with HAART; 10 were not. • Median renal survival was substantially longer in the 26 pts who received treatment (18 months vs 4 months)

  23. Impact of highly active antiretroviral therapy on AIDS-related mortality (A), incidence of HIV-related ESRD (B), and mortality in patients with HIV and ESRD (C) Wyatt, C. M. et al. Clin J Am Soc Nephrol 2007;2:S20-S24

  24. ACE inhibitors • Wei et al. (2003) studied 44 pts with bx-proven HIVAN. Cr <2. All offered fosinopril 10mg QD. 28 pts agreed (study group); 16 refused (control group). • After 5.1 years, all except 1 on fosinopril had maintained stable renal fxn (median Cr 1.55) • All pts in the control group reached dialysis • Study limited by self selection, other meds not controlled for

  25. Steroids • Smith et al. (1996), observational study, the effects of prednisone in 20 pts (17 had biopsy proven HIVAN.) Majority with advanced renal insufficiency (Cr>2) and proteinuria (>2 g/day.) Followed for median 44 wks. • 17 pts had a reduction in serum creatinine and/or protein excretion • Relapse common after stopping therapy • 6 had infections (MAC, CMV, Candidemia)

  26. Conclusions • HIVAN is most common cause of CRF in HIV-1 patients, especially blacks • Can occur at any stage of HIV, but majority of published cases are in AIDS • Prognosis is poor • Definitive diagnosis requires renal biopsy, since HIV patients can develop a wide variety of renal diseases

  27. Conclusions • HIV infection of the renal epithelium is a critical component of HIVAN pathogenesis • HAART, ACEi, prednisone used in small observational studies. Long term benefits of steroids remains to be demonstrated. • Need for controlled prospective studies

  28. References • Atta MG, Gallant JE, Rahman MH, et al. Antiretroviral therapy in the treatment of HIV-associated nephropathy. Nephrol Dial Transplant 2006; 21; 2809-2813 • Lu T, Ross M. HIV-associated nephropathy: a brief review. The Mount Sinai Journal of Medicine 2005; 72 (3): 193-199 • Rose BD, Appel GB. Collapsing FGS and other renal diseases associated with HIV infection. • Ross MJ, Klotman PE, Winston JA. HIV-associated nephropathy: case study and review of the literature. Aids Patient Care and STDs 2000; 14 (12): 637-645 • Smith MC, Austen JL, Carey JT, et al. Prednisone improves renal function and proteinuria in human immunodeficiency virus-associated nephropathy. Am J Med 1996; 101 (1):41-48 • US Renal Data System Annual Data Report 2008 • Wei A, Burns GC, Williams BA, et al. Long-term renal survival in HIV-associated nephropathy with angiotensin-converting enzyme inhibition. Kidney Int 2003; 64(4):1462-1471 • Wyatt CM, Klotman PE. HIV-1 and HIV-associated nephropathy 25 years later. Clin J Am Soc Nephrol 2007; 2: S20-S24 • Yalavarthy R, Smith ML, Edelstein CL. HIV-associated nephropathy in Caucasians: case report and review of literature. International Journal of STD & AIDS 2008; 19; 789-790