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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 Saleem Bharmal 9/23/08

  2. HIV-Associated Nephropathy • Association between HIV and renal disease first reported in 1984 • HIV-1 seropositive patients • Renal syndrome characterized by progressive renal failure and proteinuria • Most common kidney biopsy finding was FSGS

  3. HIV-Associated Nephropathy • HIV-1 seropositive • Low CD4 counts (< 250) and/or other criteria for AIDS • Proteinuria, often in the nephrotic range • Most patients have moderate to severe renal insufficiency at the time of diagnosis • Peripheral edema is uncommon • Hypertension is rare • Renal ultrasound shows echogenic kidneys that are normal-to-large in size

  4. Key Histopathologic Features • Collapsing form of Focal segmental glomerulosclerosis (FSGS) • Microcystic dilatation or renal tubules • Globally sclerotic glomeruli • Lymphocytic interstitial infiltrates and Interstitial fibrosis • Podocyte proliferation and loss of podocyte differentiation markers • Endothelial tubuloreticular inclusions seen on EM

  5. Collapsing FGS and Microcystic Dilatation of the Tubules

  6. Endothelial Tubuloreticular Inclusions (TRI)

  7. Role of Biopsy • Only 40-50% are confirmed to be HIVAN by renal biopsy in suspected cases • Alternative findings include: MPGN (Hep C) MN (Hep B) IgA nephropathy Diabetic nephropathy Amyloidosis AIN Cryoglobulinemia MCD

  8. Racial Predilection and Genetic Factors • Effects mainly black and hispanic patients • In the US, black patients with HIV-1 are 12 times more likely to develop HIVAN than non-black patients. • Now the third leading cause of ESRD in African Americans between age 20 and 64 • Marked racial disparity suggests genetic factors are important determinants of HIVAN

  9. HIV-1 transgenic mouse model • Mice transgenic for replication defective HIV-1 construct lacking gag/pol genes developed proteinuria, renal failure, and histologic disease identical to HIVAN • Nephropathy developed in kidney transplanted from transgenic mice into wild type, but not in kidneys from normal wild type transplanted into transgenic mice

  10. Confirmation that HIV-1 infects Renal Epithelial Cells • Bruggemanet al. reported a series of 20 HIV-1 seropostive pts with renal disease who underwent renal biopsy • 15 of the 20 pts had HIVAN confirmed by biopsy • In 11 of the 15 pts with HIVAN, HIV-1 was detectable in renal epithelial cells by RNA in situ hybridization • HIV-1 RNA was detected in renal tubular epithelial cells, glomerular visceral and parietal epithelial cells, and interstitial leukocytes

  11. Reservoir for HIV-1 • Bruggeman et al. later detected HIV-1in renal cells by both RNA in situ hybridization and DNA in situ PCR in 3 patients with undetectable viral loads • Case repot by Winston et al. described a pt who developed HIVAN with acute HIV-1 seroconversion that imporved with HAART however the pt continued to express HIV-1 in renal epithelial cells

  12. HIV-1 Genome • Consists of 9 genes that encode fifteen protein

  13. Podocytes • Podocytes are normally terminally differentiated, quiescent cells that do not proliferate • The collapsing glomerulopathy of HIVAN is characterized by marked podocyte dedifferentiation and proliferation • Husain et al. showed that nefin vitro is necessary to cause most of the podocyte changes seen in HIVAN

  14. Treatments (HAART) HIV-1-associated nephropathy incidence stratified by AIDS status and antiretroviral use. White bars, no antiretroviral therapy; light grey bars, nucleoside reverse transcriptase inhibitor therapy; dark gray bars, highly active antiretroviral therapy. The incidence of HIV-1-associated nephropathy by calendar period and AIDS status. Lucas: AIDS, Volume 18(3).February 20, 2004.541-546

  15. Treatments • ACE Inhibitors – Small studies have shown benefit in patients who have been put on ACEI complared to those who were not on ACEI with decrease in proteinuria and decrease rate of renal dysfunction • ? Prednisone – Only a few small retrospective cohort studies have shown decrease in serum Cre and prtoeinuria after treatment with prednisone