Dr.

 Approximately 2.7 million people a year are infected with HIV worldwide  Kidney disease is a relatively frequent complication of patients infected with HIV Nephron Clin Pract 2011;118:c346–c354

 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 Nephron Clin Pract 2011;118:c346–c354

First described by Rao et. al. in 1984: sclerosing glomerulopathy in HIV+ patients in NYC It is the third leading cause of ESRD in african americans, ages Most common cause of ESRD in HIV+ patients Nephrotic syndrome Collapsing focal glomerulosclerosis (FGS) Tubulointerstitial injury

 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

 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) Membranoproliferative glomerulonephritis (Hep C) Immune complex glomerulonephritis (IgA) Interstitial nephritis (CMV, sulfa drugs) HIVAN

Nephron Clin Pract 2011;118:c346–c354

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 1 st or 2 nd degree relative with ESRD Most patients have low CD4 counts (<200) However, may be seen in primary HIV infection

 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) Nephron Clin Pract 2011;118:c346–c354

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

 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

 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

 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

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

 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

 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

Normal glomerulusCollapsing FGS 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. 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).

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

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;

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

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.

 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

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

 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

 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

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

 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 ; 17(1): 59–71

 Antiretroviral therapy  ACEi  Steroids  No proven effective therapy

 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

 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)

Wyatt, C. M. et al. Clin J Am Soc Nephrol 2007;2:S20-S24 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)

 Atta et al. Antiretroviral therapy in the treatment of HIV- associated nephropathy. Nephrol Dial Transplant. 2006; 21: 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

Atta et al. Nephrol Dial Transplant. 2006; 21:

 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 Nephron Clin Pract 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 Nephron Clin Pract 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 Nephron Clin Pract 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 Nephron Clin Pract 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 Nephron Clin Pract 2011;118:c346–c354

 Burns et al. Effect of angiotensin-converting enzyme inhibition in HIV-associated nephropathy. J Am Soc Nephrol 1997; 8: 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 +/ and 1.0 +/- 0.25, (P = 0.07) At 24 wk, creatinine of treated and nontreated patients was 1.5 +/ and 4.9 +/- 2.4 (P = 0.006). Average baseline 24-h urine protein excretion for treated and nontreated patients was 1.6 +/ and / (P = 0.02) At 24 wk, 24-h protein excretion of treated and non-treated patients was / and 8.5 +/- 1.4 (P = 0.006).

 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 +/ and 1.9 +/ (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 +/ (P = 0.9) At 12 wk, 24-h protein excretion for treated and nontreated was 2.8 +/- 1.0 and /- 3.5 (P = 0.008).

 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 Nephron Clin Pract 2011;118:c346–c354

 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)

 Smith et al. Am J Med 1994; 97: 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

 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 Semin Nephrol 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 Semin Nephrol 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 Semin Nephrol 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 Semin Nephrol November ; 28(6): 513–522

 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

 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 Sep;4(3): Historical cohort analysis of 63,210 cadaveric solitary renal transplant recipients with HIV serology entries in the USRDS from 1987 to (0.05%) were HIV+ at transplant

HIV+ CAD (N = 32) USRDS CAD (HIV confirmed negative) (N = 63,178) Male18 (56%)37,038 (61%) African-American8 (25%)14,800 (23%) Recipient age (mean years, SD)37.5 A (4.14)43.1 (13,67) Donor age (mean years, SD)25.84 A (14.32) (16.33) Recipient weight64.82 A (19,52) (18.34), Year recipient transplanted1990 A (3,03) (2,82) Cause of ESRD Diabetes5 (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 dialysis29 (93.5%)56,695 (91.8%) Cold ischemic time (hours) C ± ± 11.3 Mean number of HLA antigen matches (0–6) 4.00 A (1.41)2.74 (1.62)

Swanson et al. Transpl Infect Dis Sep;4(3):

 Kumar et al. Safety and success of kidney transplantation and concomitant immunosuppression in HIV-positive patients. Kidney Int Apr; 67(4): HIV patients with ESRD transplanted between 2001 and 2004 Selection criteria: adherence to dialysis and HAART, plasma HIV-1 RNA 200 cells/ul. Basiliximab induction; CSA (trough ng/ml), sirolimus (trough 5-10 ng/ml), and prednisone maintenance Protocol biopsies at 1, 6, 12, and 24 months

Kumar et al. Kidney Int Apr; 67(4):

Cause of death Post-transplant day Number of patients Pulmonary embolism21 Anaphylactic reaction to drug61 Intractable gastrointestinal bleeding 1071 Sepsis Chest infection371 Necrotizing fasciitis2381 Infection of the lymphocele2851 Myocardial infarction5451 Kumar et al. Kidney Int Apr; 67(4):

 Cause of graft loss Days of graft loss Number of grafts lost  Patient deaths from Table 2 2, 6, 37, 107, 238, 285 and  Acute vascular rejection 12 1  Bleeding at the transplant site 15 1  Hemolytic uremic syndrome 55 1  Steven Johnson syndrome due to Dapsone Kumar et al. Kidney Int Apr; 67(4):

 Qiu et al. HIV-positive renal recipients can achieve survival rates similar to those of HIV- negative patients. Transplantation Jun 27; 81(12): 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

Qiu et al. Transplantation Jun 27; 81(12):

 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

 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

 Atta MG, Gallant JE, Rahman MH, et al. Antiretroviral therapy in the treatment of HIV- associated nephropathy. Nephrol Dial Transplant 2006; 21;  Lu T, Ross M. HIV-associated nephropathy: a brief review. The Mount Sinai Journal of Medicine 2005; 72 (3):  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):  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):  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;