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Magnitude, diagnosis and treatment of HIV nephropathy

Magnitude, diagnosis and treatment of HIV nephropathy. Dr. Introduction. Nephron Clin Pract 2011;118:c346–c354. Approximately 2.7 million people a year are infected with HIV worldwide Kidney disease is a relatively frequent complication of patients infected with HIV. Introduction: HIVAN.

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Magnitude, diagnosis and treatment of HIV nephropathy

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  1. Magnitude, diagnosis and treatment of HIV nephropathy Dr.

  2. Introduction NephronClinPract 2011;118:c346–c354 Approximately 2.7 million people a year are infected with HIV worldwide Kidney disease is a relatively frequent complication of patients infected with HIV

  3. Introduction: HIVAN • HIVAN (HIV Associated Nephropathy) • Defined on renal biopsy as collapsing focal glomerulosclerosis, • Is the most common cause of chronic kidney disease (CKD) in patients with HIV and overwhelmingly affects patients of African descent NephronClinPract 2011;118:c346–c354

  4. HIVAN • First described by Rao et. al. in 1984: sclerosingglomerulopathy in HIV+ patients in NYC • It is the third leading cause of ESRD in africanamericans, ages 20-64 • Most common cause of ESRD in HIV+ patients • Nephrotic syndrome • Collapsing focal glomerulosclerosis (FGS) • Tubulointerstitial injury

  5. HIVAN • 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

  6. HIVAN • Renal Disease in HIV/AIDS often NOT HIV-associated nephropathy • Always evaluate for reversible causes of RF • Common Causes of Renal Failure in HIV/AIDS • ARF – infection, hypotension, nephrotoxic drugs (HAART, antibiotics, antifungals) • Membranous nephropathy (Hep B, syphilis) • Membranoproliferativeglomerulonephritis (Hep C) • Immune complex glomerulonephritis (IgA) • Interstitial nephritis (CMV, sulfa drugs)

  7. NephronClinPract 2011;118:c346–c354

  8. HIVAN: Epidemiology • Mostly occurs in blacks; in US, blacks are 12.2 times more likely to develop it than non-blacks • Prevalence in blacks ranges from 3.5% (proteinuria screening in clinics) to 12% (autopsy) • In patients with HIVAN, 25% also have 1st or 2nd degree relative with ESRD • Most patients have low CD4 counts (<200) • However, may be seen in primary HIV infection

  9. Epidemiology NephronClinPract 2011;118:c346–c354 • Biopsy- proven HIVAN has been reported in • >80% of 30 patients with HIV screened for proteinuria in South Africa and in • 53–79% of HIV-infected patients of African descent in studies from the USA and Europe • In African-Americans, HIVAN is associated with younger age and lower estimated glomerular filtration rate (eGFR)

  10. 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

  11. 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

  12. 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

  13. 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

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

  15. 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

  16. 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

  17. 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. www.uptodate.com

  18. 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

  19. 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

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

  21. 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. www.uptodate.com

  22. 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

  23. 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

  24. 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

  25. 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

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

  27. Treatment • In the absence of randomized clinical trials, the treatment of HIVAN is based on • Small, uncontrolled studies, epidemiologic data, and pathogenic insights Adv Chronic Kidney Dis. 2010 ; 17(1): 59–71

  28. Treatment • Antiretroviral therapy • ACEi • Steroids • No proven effective therapy

  29. 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

  30. 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)

  31. 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

  32. 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

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

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

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

  36. HAART NephronClinPract 2011;118:c346–c354 • Data from uncontrolled or retrospective studies and from a randomized controlled trial suggest that • HAART (defined as combination therapy with 3 or more drugs) is beneficial in both preservation and improvement of kidney function in patients with HIV

  37. HAART NephronClinPract 2011;118:c346–c354 • Kalayjian et al. showed in an observational, prospective, multicenter cohort study involving 1,776 HIV patients that • Suppression of plasma viremia with antiretroviral therapy was associated with improvement in GFR in subjects with both CKD stage ≥ 2 and low baseline CD4+ cell counts ( <200 cells/ l) • In this subset of patients, viral suppression was associated with an average increase in GFR of 9.2 ml/min/1.73 m 2 from baseline over a median follow-up of 160 weeks

  38. HAART NephronClinPract 2011;118:c346–c354 • There is also data suggesting that HAART may prevent the development of HIVAN • Among patients with a prior diagnosis of AIDS, HIVAN incidence was significantly reduced from 26.4 per 1,000 person-years in patients not receiving antiretroviral therapy, to 14.4 per 1,000 person-years in patients treated with nucleoside analogue therapy only, and to 6.8, per 1,000 person-years in those treated with HAART • In multivariate analysis, HIVAN risk was reduced 60% by use of HAART, and no patient developed HIVAN when HAART had been initiated prior to the development of AIDS

  39. HAART NephronClinPract 2011;118:c346–c354 On the other hand, limited information is available regarding the incidence of proteinuria in patients with HIV or its relation to antiviral therapy

  40. Angiotensin II Blockade NephronClinPract 2011;118:c346–c354 • Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are effective antihypertensive agents that can • Reduce proteinuria and slow progression of renal disease in both diabetic and non-diabetic chronic nephropathy patients, and for these reasons • they are indicated in any patient with proteinuria regardless of the cause

  41. 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).

  42. 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).

  43. Corticosteroids NephronClinPract 2011;118:c346–c354 A number of retrospective, observational or uncontrolled studies conducted before or during the initial phases of HAART reported variable success with the use of corticosteroids in patients with HIV-associated kidney diseases

  44. 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)

  45. 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

  46. Treatment summary SeminNephrol. 2008 November ; 28(6): 513–522 Recognizing that randomized controlled trials comparing ART to placebo are no longer ethically tenable, recently updated expert guidelines consider HIVAN an indication for the initiation of ART, regardless of CD4 cell count

  47. Treatment summary SeminNephrol. 2008 November ; 28(6): 513–522 • The guidelines also recommend adjunctive therapy with ACE inhibitors or angiotensin receptor blockers as tolerated • based on evidence of benefit from cohort studies in patients with HIVAN and from randomized clinical trials in other glomerular diseases

  48. Treatment summary SeminNephrol. 2008 November ; 28(6): 513–522 • The addition of corticosteroids may be considered in patients with • Aggressive disease or a prominent interstitial inflammatory component, based on uncontrolled clinical studies and in vitro evidence that HIV infection induces a local inflammatory reaction in tubular epithelial cells

  49. Treatment summary SeminNephrol. 2008 November ; 28(6): 513–522 With improvements in the survival of HIV-positive dialysis patients, patients with HIVAN who are approaching ESRD should be offered a choice between hemodialysis and peritoneal dialysis, which offer similar survival in adults with HIV infection. Selected patients with remote HIVAN and well-controlled HIV infection may also be candidates for kidney transplantation

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