Abstract

HIV-associated nephropathy (HIVAN), when first recognized, was viewed as a rapidly progressive inexorable disorder that ended within weeks to months in end-stage renal disease (ESRD) with short term high mortality. With a longer retrospective perspective now possible, HIVAN has been found responsive to highly active antiretroviral therapy (HAART), when coupled with appropriately administered antibiotics and angiotensin converting enzyme inhibitors or blockers. Indeed, survival beyond ten years after onset of ESRD is an attainable goal for ESRD patients without extensive comorbidity. A key unexplained aspect of HIVAN is its disproportionately greater attack rate in African-Americans compared with white HIV positive individuals. Placed in perspective of African-American-white differences in responsiveness to glomerular disorders, HIVAN is but one of several diseases that cause African-Americans to sustain an ESRD attack rate that is more than three times that of whites. With the exception of their superior survival on hemodialysis or peritoneal dialysis, compared with whites, mortality for African Americans with kidney disease is uniformly greater. No single explanation for the discordant African-American-white response in renal disorder has been discerned and the phenomenon is, at present, unsatisfactorily attributed to an admixture of genetic, cultural, environmental and socioeconomic "factors".

Introduction

Race is a major factor in determining the clinical course of diverse kidney disorders. Glomerular diseases associated with a greater attack rate in African-Americans compared with whites include: idiopathic focal sclerosis, lupus nephritis, diabetic nephropathy and hypertensive nephropathy.(1)

HIV-associated nephropathy (HIVAN) affords a unique opportunity to unravel the mystery of why some renal disorders preferentially afflict African-Americans at a rate almost four times higher than in whites.(2) Factors suggested to explain this disproportionate risk include genetic, environmental, cultural and socioeconomic differences. As reported by the United States Renal Data System (USRDS), of 375,152 patients started on ESRD therapy between January 1992 and June 1997, 3653 (0.97%) had HIVAN of whom 87.8% were African American.(3) Among all tabulated causes of ESRD, only sickle cell anemia had a closer correlation with African-American race than did HIVAN.

Clinical Features

HIVAN is a syndrome characterized by rapidly progressive renal failure with a severe nephrotic syndrome. The sentinel findings are enlarged kidneys, normotension and collapsing focal and segmental glomerular sclerosis with variable tubulo-interstitial nephritis [figures 1-3].(4)

Figure 1.

HIVAN: A 32-year-old male heroin addict who complained of worsening leg swelling for 6 months had a blood pressure of 110/70 mm Hg, a serum creatinine concentration of 1.5 mg/dl and urinary protein excretion of 14 g/day. Renal size was increased to 16 cm bilaterally. He was HIV positive with a CD4 count of 60 mm.(3) A percutaneous right renal biopsy disclosed focal and segmental glomerulosclerosis with severe interstitial fibrosis, inflammation, tubuloar atrophy and focal tubular microcysts containing proteinaceous casts (trichrome stain).

Figure 2.

HIVAN with typical segmental sclerosis (in blue) and adhesion formation (trichrome stain).

Figure 3.

HIVAN with extensive microcystic dilatation of renal tubules (thyroidization) characteristic of the disorder but also described in chronic pyelonephritis.

Epidemiology

That HIVAN is a disease of African-Americans is inferred by its presence in only 1.7% of white patients in a prospective study of 230 individuals autopsied after dying with AIDS between 1981 and 1989 in Switzerland.(5) Similarly, another fact that points to a link between HIVAN and some aspect of being African-American is HIVAN's absence among Asians -- a study of 26 HIV-infected Thai patients with proteinuria greater than 1.5 g/day who had a renal biopsy between 1995 and 1996 demonstrated complete absence of focal and segmental glomerulosclerosis.(6) In a limited chart review of 858 HIV positive patients in Bronx, New York, the risk of HIVAN in Hispanics was similar to that for whites.(7) Researchers, looking for a genetic basis in African-Americans that might predispose to HIVAN, suspected but soon discarded the Duffy antigen/receptor for chemokines.(8)

Pathogenesis and Clinical Course

When first recognized by Rao et al., HIVAN carried a dismal prognosis with survival on hemodialysis limited to weeks to several months at most.(9) Because both HIVAN and heroin-associated nephropathy (HAN) induced massive proteinuria and focal and segmental glomerulosclerosis,(10) we must remember that confirmation of a diagnosis of HIVAN in an intravenous narcotics abuser infected with HIV was often not possible until the disappearance of HAN eliminated confusion.(11)

Concurrent with distinction of HAN from HIVAN has been a remarkable improvement in the prognosis of patients who begin hemodialysis for HIVAN. An initial report of the efficacy of hemodialysis applied to HIVAN patients with ESRD noted that only two of 55 patients in Brooklyn survived for more than six months and concluded that maintenance hemodialysis is not effective in prolonging life.(12) Ortiz et al. reached a similar conclusion, confirming the lack of effectiveness of maintenance hemodialysis in extending life in patients with AIDS. The researchers noted that every one of the 17 AIDS patients in Miami died after a short course of hemodialysis (mean of 93 days).(13)

So dismal was the outcome of dialytic therapy in uremic AIDS patients that scientific debate as to the ethics of initiating dialysis in HIVAN was conducted in national medical societies.(14)

Improving Prognosis

By the end of the 1980s, sporadic reports of survival of AIDS patients beyond a year of hemodialysis(15) or peritoneal dialysis(16) signaled a transformation in prognosis induced by more effective antiviral therapy. Thereafter, as HIV infected patients rose to 2% of all US ESRD patients, enhanced AIDS management translated into a mean survival of HIV positive ESRD patients on peritoneal dialysis of 15.5 months compared with a mean of 44 months non-HIV patients.(17)

Recognition of the brighter outcome of dialyzed AIDS patients was slow -- as late as 1994 investigators continued to infer that dialysis therapy did not substantially prolong life in most patients with AIDS and irreversible renal failure.(18) Outside of the US, ESRD in AIDS was uniformly fatal by mid-decade with a London report noting that all hemodialysis patients died within one month, while peritoneal dialysis afforded a median survival of five months.(19)

However, by the latter part of the 1990s, it became evident to Ifudu et al. and other inner city nephrologists that a positive change in prognosis was occurring among dialyzed AIDS patients in Brooklyn who now evinced a mean survival of 57 months.(20) With the advent of highly active antiretroviral treatment (HAART) in the mid-1990s, ESRD in AIDS had become a chronic disease.(21),(22) Kirchner et al. reported 3 patients with marked improvement in renal function after treatment with a regimen comprising 2 nucleoside reverse transcriptase inhibitors and a protease inhibitor.(23) European experience with HIVAN also improved; a French national survey in 1999 found that HIVAN accounted for 0.36% of all dialysis patients who had been on dialysis for a mean of 58 months (range 1-235 months).(24)

Now a Chronic Disease

Researchers attributed the improved life expectancy to the effect of angiotensin-converting enzyme inhibitors and improved aggressive antiretroviral therapy. Ross, Klotman, and Winston, at the turn of the century, concluded that the long-term renal prognosis may be changing.(25) An impressive comprehensive data analysis by Ahuha, Grady and Khan suggested that survival of HIV-infected dialysis patients has "remarkably improved" in the United States. Of 6166 HIV-infected ESRD patients who received dialysis in the United States from 1990 to 1999, 1-yr survival improved from 56 to 74%, while the death rate declined from 458 deaths to 240 deaths per 1000 patient-years.(26)

Still Unknown Causative Factors

Still to be elucidated are which specific "factors" are responsible for the sharp divergence in survival outcome between African-Americans and whites afflicted with glomerular disease (Table 1).

If you look at Table 2, which is constructed from the 2001 annual data report of the USRDS, there are truly startling differences between the proportion of African-American and white survivors of ESRD therapy.

Table 2. Survival (%) During ESRD Therapy by Race and Modality: USRDS^*.

Click to see full sized image

By the second year of dialysis support, whether hemodialysis or peritoneal dialysis, African-Americans exhibit superior survival (71.1%) over whites (57.2%). Conversely, after equivalent surgical stress and risk, as indicated by equal patient survival of African Americans (94.7%) and whites (94.7%), one year following a cadaver donor kidney transplant, after five years, though patient survival continues equivalent (African-Americans 79.5%, whites 80.5%), graft survival falls off inexplicably (African-Americans 48.6%, whites 61.3%). A similar rate of graft loss afflicts recipients of living donor kidneys after five years (African-Americans 57.7%, whites 74.4%).

Posssible Genetic Basis

Klotman et al. underscore the potential involvement of genetic predisposition to the pathogenesis of HIVAN and other glomerular diseases that target African Americans.(27),(28) What has been discovered thus far is that deletion of the CCR5 coreceptor protects against HIV infection, while individuals who are heterozygous for a deletion mutation in CR5, or harbor mutations in the CXCR4 coreceptor, experience a slower progression to AIDS. Klotman's team, using transgenic mice, detected expression of HIV in both glomerular and tubular epithelial cells. This suggests an etiologic link between intracellular expression of HIV and HIVAN.(29),(30)

What's Ahead

Given the rapid pace of progress, it appears safe to predict that during the next decade the pandemic of HIVAN will continue to subside and the genetic basis for severity of glomerular disease in African Americans will be elucidated. Erlich's dream of a "magic bullet" for syphilis(31) is supplanted by the quest to eradicate HIVAN with inderdictive molecular biological missiles.