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HIV-associated nephropathy: a disease of ethnic disparity for Blacks
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AIDS: Volume 18(8) 21 May 2004 pp 1089-1099
Ross, Michael J; Klotman, Paul E
"...we believe that all patients with HIV associated nephopathy (HIVAN) should be treated with HAART unless they have compelling contraindications to treatment. We would further suggest that renal disease compels the use of HAART independent of the CD4 count..." (note from Jules Levin: Klotman is suggesting a change to Treatment Guidelines for individuals with HIVAN and HIVAN disproportionately affects African-Americans.)
"...Patients are usually diagnosed with HIVAN late in the course of their HIV illness and most have advanced renal failure at the time of diagnosis..."
"...In the absence of treatment with antiretroviral drugs, ACE-inhibitors, or prednisone, most patients with HIVAN progress to ESRD within 1-4 months of the diagnosis being established...pharmacotherapy with a variety of agents has been found to be associated with prolonged renal survival..."
"...HIVAN is the most common cause of chronic renal failure in HIV-1 seropositive patients and disproportionately affects patients of African descent. Patients with HIVAN are typically diagnosed late in the course of their HIV illness when they present with renal insufficiency and proteinuria. HIV-1 infection of renal epithelial cells has been shown to be crucial in the initiation of HIVAN pathogenesis. Furthermore, the kidney represents a reservoir where HIV-1 infection can persist despite treatment with HAART. Small clinical trials, case reports, and epidemiologic data strongly suggest a benefit of HAART in the treatment of HIVAN. Although not currently the standard, we recommend that the diagnosis of HIVAN be sought aggressively by physicians caring for HIV infected patients. And, when found, we also recommend that patients be started on HAART independent of their CD4 cell count and viral load...
...Since early after the initial descriptions of HIVAN, it has been recognized that HIVAN occurs predominantly in patients of African descent... Thus, HIVAN is diagnosed primarily in areas with large populations of HIV-1 seropositive black patients; most notably large cities in the USA such as New York City, Miami, Baltimore, and Cleveland, and European cities such as Paris and London...The actual prevalence of HIVAN, however, is much higher than is indicated by USRDS data...Studies have been undertaken to investigate the true prevalence of HIVAN... According to the US Centers for Disease Control (CDC), in 2001 (the most recent year for which data is available), 151,717 African Americans were living with AIDS...these data predict a prevalence of HIVAN in the USA of 5300-18,200 persons (estimated, 3.5% with HIVAN & 12% dying from it). Thus, HIVAN continues to be a substantial problem for the ESRD program in the USA and a growing presence in the AIDS epidemic in general... kidney disease has become the fourth-leading condition contributing to death... the presence of renal disease was disproportionately higher in black (11.9%) compared to white patients (3.3%), suggesting that a this difference (8.6%) may reflect underlying HIVAN. Recently, published data from the HIV Epidemiology Research Study Group revealed that among HIV-1 seropositive women (without AIDS), 7.2% had renal abnormalities (defined as serum creatinine > 1.4 mg/dl or > 2+ proteinuria on urinary dipstick) at baseline. By the end of follow up (mean of 21 months), over 21% of women had renal abnormalities. Furthermore, after adjusting for multiple comorbidities, the presence of renal disease was associated with a 2.5-fold increased risk of death... While the epidemiology of HIVAN has been best studied in the USA, it is likely to be most prevalent in Africa... If the prevalence of HIVAN among Sub-Saharan Africans is similar to that among African Americans, there are between 1.1 and 3.6 million cases of HIVAN in this region... There is abundant evidence that HIV-1 induces cell cycle progression in HIVAN... The kidney is a reservoir for HIV-1...HIV-1 infection of renal epithelial cells has ramifications beyond the role of the virus in promoting the development of HIVAN... Though HIVAN is an important cause of renal failure in HIV-1 seropositive patients, no treatment for HIVAN has been evaluated in a prospective randomized-controlled trial. Unfortunately, most studies assessing the treatment or prevention of HIVAN are retrospective and/or poorly controlled. Nevertheless, we will discuss the best available evidence for the use of three classes of pharmaceutical agents: antiretrovirals, angiotensin converting enzyme (ACE) inhibitors, and steroids (see below)..."
Introduction
Early in the HIV-1 epidemic, clinicians in US urban centers began to recognize the presence of a renal syndrome characterized by proteinuria and rapidly progressive renal failure in nearly 10% of AIDS cases. The most common glomerular abnormality found at the time of renal biopsy was focal segmental glomerulosclerosis. The high prevalence of injecting drug use among affected patients prompted some authors to conclude that concurrent heroin nephropathy, not HIV-1 infection per se, was responsible for this renal syndrome. During the middle and late 1980s, the existence of a distinct 'HIV nephropathy' was debated. But, increasingly, patients were recognized where injecting drug use could be definitively excluded as an etiologic factor, particularly children. As a result, HIV-associated nephropathy (HIVAN) became recognized as a separate entity and soon was found to be the most common cause of chronic renal failure and end stage renal disease (ESRD) in HIV-1 infected patients. Although much has been learned about the pathogenesis of HIVAN over the past 20 years, it continues to be an important cause of morbidity and mortality in HIV-seropositive patients.
Clinical manifestations of HIVAN
Most patients with HIVAN are of African descent, presenting late in the course of their HIV-1 infection. Although the majority have been HIV-1 seropositive for several years and have CD4 counts below 200 x 106 cells/l at the time HIVAN is diagnosed, there have been case reports of HIVAN occurring even in the setting of acute HIV-1 seroconversion. As more patients are screened early in the course of HIV-1 infection for renal disease, it is predictable that additional cases will be identified.
Patients with HIVAN usually are diagnosed when they have severe proteinuria, often, but not always, in the nephrotic range (> 3 g/day). Most patients also have advanced renal failure at the time of diagnosis although Burns and coworkers have reported a cohort of patients with HIVAN and mild renal insufficiency with a mean serum creatinine of 114.9 mmol/l.
Despite the presence of proteinuria that is often in the nephrotic range, most patients with HIVAN do not have significant peripheral edema. Moreover, patients with HIVAN are usually not hypertensive, a remarkable finding considering that more than 90% of black patients with renal insufficiency of other causes exhibit hypertension. These observations, coupled with the finding that HIV-seropositive patients often have a decreased ability to conserve sodium suggest that HIVAN may be a salt-wasting disease.
Laboratory studies are nonspecific in HIVAN. Serologic studies are usually negative although a significant percentage of HIV-1 seropositive patients are co-infected with hepatitis C virus (HCV). Because membranoproliferative glomerulonephritis (most often related to HCV infection) is frequently diagnosed in HIV-seropositive patients with renal disease, the presence of positive HCV serologies in an HIV-infected patient with renal disease increases the need for renal biopsy. Urinalysis is commonly unremarkable with the exception of proteinuria with hyaline casts.
In most chronic renal diseases, the kidneys become progressively smaller as renal failure progresses. In HIVAN, however, renal ultrasound commonly reveals bilateral echogenic kidneys that are often enlarged. Despite the reporting of this finding by several authors, the predictive value of renal ultrasound to rule in or exclude the diagnosis of HIVAN has not been studied.
The only reliable test to establish (or rule out) the presence of HIVAN is renal biopsy. In patients who are HIV-1 seropositive and undergo renal biopsy, in whom clinical suspicion of HIVAN is high, 40-55% are diagnosed with other forms of renal disease. Since firmly establishing the diagnosis of HIVAN versus a different renal disease is important to guide treatment and provides prognostic information, clinicians should have a low threshold for obtaining renal biopsies in HIV-1-seropositive patients with significant proteinuria and/or renal insufficiency.
Pathologic findings in HIVAN
HIVAN is characterized by a constellation of pathologic findings involving glomerular, tubular, and interstitial compartments. Glomerular pathologic findings include focal glomerulosclerosis, with prominent collapse of the glomerular tuft. Tubular disease is characterized by the development of tubular dilatation, accompanied by atrophy and flattening of tubular epithelial cells. There is also prominent lymphocytic infiltration of the interstitium. Endothelial tubuloreticular inclusions had been reported to be a common pathologic finding upon examination by electron microscopy in the pre-highly active antiretroviral therapy (HAART) era. Tubuloreticular inclusions, however, are found with decreasing frequency, perhaps due to the efficacy of antiretroviral therapy in reducing plasma interferon levels.
Epidemiology of HIVAN
After the first clinical description of HIVAN in 1984, most research in this field focused on whether HIVAN was an actual entity or simply misdiagnosed heroin nephropathy. No matter what the etiology, HIVAN was clearly an uncommon cause of end stage renal disease (ESRD) and with mortality from AIDS expected within months to a year after diagnosis, the issue of a complicating renal disease was an appropriately low priority. From a rare and unusual cause of renal failure in the 1980s, HIVAN became the most rapidly increasing cause of ESRD in the USA by the early 1990s. In 1995, when HAART became widely available, the decline in AIDS mortality and opportunistic infections was dramatic. The number of new cases of ESRD due to HIVAN, reported as 'AIDS nephropathy' by the United States Renal Data Service (USRDS), did not demonstrate a similar decline, but instead, has reached a plateau.
As a result of the decline in mortality from AIDS, however, the number of black patients who are living with HIV infection or AIDS has increased dramatically. This is the very patient population at risk for developing HIVAN. Based on mathematical models of the HIVAN epidemic and recent confirming data, the incidence of ESRD due to HIVAN is expected to increase dramatically in the future because of the expansion of the population at risk.
The actual prevalence of HIVAN, however, is much higher than is indicated by USRDS data, because only cases of renal disease that have progressed to ESRD are reported to the USRDS. These data, therefore, exclude patients with chronic renal disease who have not yet progressed to ESRD. Studies have been undertaken to investigate the true prevalence of HIVAN. Ahuja and coworkers studied the prevalence of HIVAN in a cohort of 557 HIV-1 seropositive outpatients, half of whom were black. Patients were screened using urinalysis and those with > 1.5 g/day of proteinuria underwent renal biopsy. Using this screening approach, 3.5% of black patients were diagnosed with HIVAN. Another recent study reported that the prevalence of HIVAN in black patients dying with AIDS who underwent autopsy was 12%. From these data, a true prevalence of HIVAN can be estimated from the number of HIV-1 seropositive black patients living in the USA. According to the US Centers for Disease Control (CDC), in 2001 (the most recent year for which data is available), 151 717 African Americans were living with AIDS. Assuming, in these patients, a prevalence of HIVAN of 3.5-12%, these data predict a prevalence of HIVAN in the USA of 5300-18 200 persons. Thus, HIVAN continues to be a substantial problem for the ESRD program in the USA and a growing presence in the AIDS epidemic in general.
In support of the prevalence data, the appearance of HIVAN as a major complication of HIV-1 infection is one of the most distinctive changes in the AIDS pandemic. Selik et al. recently reviewed multiple-cause death certificate data for all deaths among HIV-infected patients in the USA from 1987 through 1999. The proportion of patients dying with conditions such as wasting/cachexia or dementia/encephalopathy has decreased dramatically since the introduction of HAART in 1995. While these complications of AIDS have waned, kidney disease has become the fourth-leading condition contributing to death (after septicemia, pneumonia, and liver disease). Though this study did not specify the types of renal disease, the presence of renal disease was disproportionately higher in black (11.9%) compared to white patients (3.3%), suggesting that a this difference (8.6%) may reflect underlying HIVAN. Recently, published data from the HIV Epidemiology Research Study Group revealed that among HIV-1 seropositive women (without AIDS), 7.2% had renal abnormalities (defined as serum creatinine > 1.4 mg/dl or > 2+ proteinuria on urinary dipstick) at baseline. By the end of follow up (mean of 21 months), over 21% of women had renal abnormalities. Furthermore, after adjusting for multiple comorbidities, the presence of renal disease was associated with a 2.5-fold increased risk of death.
While the epidemiology of HIVAN has been best studied in the USA, it is likely to be most prevalent in Africa. Of the more than 42 million people living with HIV/AIDS worldwide, nearly 30 million reside in Sub-Saharan Africa. If the prevalence of HIVAN among Sub-Saharan Africans is similar to that among African Americans, there are between 1.1 and 3.6 million cases of HIVAN in this region. Despite these predictions, however, there is a paucity of published data regarding the epidemiology of HIVAN in Africa for many reasons. These include a lack of general surveillance, a failure to report renal disease as a specific finding in HIV infection, and the presentation of HIVAN in the late stages of HIV infection. Since most Africans with HIV/AIDS receive little or no treatment for their illness, it is likely that most die of opportunistic infections before HIVAN becomes clinically apparent. As the health care delivery to Africans with HIV/AIDS improves, increased survival of patients can be expected. Almost certainly, as African patients live longer with HIV-1 infection, HIVAN will emerge as a major complication of HIV-1 infection and will become a major cause of morbidity and mortality in Africa.
Racial predilection of HIVAN: a disease of ethnic disparity
Since early after the initial descriptions of HIVAN, it has been recognized that HIVAN occurs predominantly in patients of African descent. Thus, HIVAN is diagnosed primarily in areas with large populations of HIV-1 seropositive black patients; most notably large cities in the USA such as New York City, Miami, Baltimore, and Cleveland, and European cities such as Paris and London.
The extent to which HIVAN disproportionately affects black patients is highlighted by a recent article in which the authors examined the association between race and etiology of ESRD in the USA. In this study, HIVAN was more closely associated with black race (odds ratio 12.2) than any cause of ESRD other than sickle cell disease. Similar findings have been reported in European case series. Series from France and London reported that 97/102 and 17/17 of patients diagnosed with HIVAN were black, respectively. In a recently reported autopsy series from Switzerland, 239 patients with AIDS were studied between 1981 and 1989. There was one case of HIVAN detected-in one of only six black patients included in the study.The strong racial predilection of HIVAN for black patients suggests that genetic factors are important determinants of HIVAN pathogenesis. This view is further supported by the finding that African Americans with ESRD due to HIVAN are 5.4 times more likely to have first- or second-degree relatives with ESRD (non-HIVAN) than are black people without renal disease.
Despite these data, the genetic determinants of HIVAN susceptibility are unknown. One candidate gene has been studied for a potential role in HIVAN. The Duffy antigen/receptor for chemokines (DARC) is a chemokine receptor that has been reported to be upregulated in the kidneys of HIV-seropositive children with renal disease. Since polymorphisms in the promoter for DARC are common in black people, Wooley et al. searched for an association between DARC polymorphisms and the development of HIVAN, however, no association was found.
Pathogenesis of HIVAN
Evidence for HIV-1 infection of renal epithelium
To better understand the pathogenesis of HIVAN, one of the first questions that needed to be answered was whether HIVAN was caused by a direct effect of HIV-1 infection of renal parenchymal cells or an indirect effect of HIV-1 mediated by immune dysregulation. During the late 1980s and 1990s, investigators attempted to detect HIV-1 in renal parenchymal cells using a variety of methods. Results were conflicting with some concluding that HIV-1 was present in renal epithelial cells and some unable to detect virus. Thus, the question of whether HIV-1 infects renal parenchymal cells remained unsettled.
While the issue of whether HIV-1 infects renal epithelial cells remained unresolved, data from animal models of HIVAN provided important insight into HIVAN pathogenesis. In 1991, Dickie et al. reported an HIV-1 transgenic mouse model that harbors a gag/pol deleted provirus expressed under control of the endogenous HIV-1 long terminal repeat (LTR) promoter. These mice develop proteinuria, progressive renal failure, and histologic disease that is identical to HIVAN. Reciprocal transplantation studies performed by Bruggeman and coworkers demonstrated that the HIVAN phenotype in these mice is dependent upon HIV-1 gene expression in the renal epithelium. Recently, a rat transgenic model expressing this same HIV-1 transgene has also been shown to cause the HIVAN phenotype.
Data from primate models also suggested a role for direct infection of renal parenchymal cells in the pathogenesis of HIVAN. Macaques develop renal disease that closely resembles HIVAN following infection with a chimeric simian-human immunodeficiency virus (SHIV). The frequency with which these animals develop renal disease is dependent upon the strain of SHIV used, suggesting that there are viral determinants of renal disease progression. The investigators were able to isolate SHIV from the glomeruli of diseased animals but it was unclear whether renal parenchymal cells were infected or whether virus was isolated from infiltrating mononuclear cells.
Though animal models suggested that HIV-1 infection and expression in renal parenchymal cells occur in HIVAN, definitive proof of such infection in humans remained elusive until 2000, when Bruggeman et al. reported a series of 20 HIV-seropositive patients with renal disease who had undergone diagnostic renal biopsy. Renal tissue was collected prospectively at time biopsy and immediately processed to optimize RNA preservation. Fifteen of the patients were diagnosed with HIVAN and in 11 these patients, HIV-1 RNA was detectable by RNA in situ hybridization. In several specimens, specificity was confirmed by the use of riboprobes for both gag and nef and by DNA in situ PCR. HIV-1 infection has now been detected in epithelial cells from several segments of the nephron, including the glomerulus (visceral and parietal epithelial cells) and tubules, including the proximal tubule, thick ascending limb of Henle, and the collecting duct. Furthermore, the pattern of histologic disease overlaps this distribution of epithelial infection. In contrast, infection of other renal parenchymal cells such as mesangial cells or endothelial cells by HIV-1 has not been conclusively demonstrated in HIVAN. The various types of renal parenchymal cells are depicted in fig. 6 (cells demonstrated to be infected by HIV-1 in HIVAN are labeled in black).
The mechanism by which HIV-1 enters renal epithelial cells is unknown and the receptors utilized by the envelopes of HIV-1 isolated from kidney are similarly unknown. While Conaldi et al. have demonstrated CD4, CXCR4, and CCR5 expression in subsets of cultured renal epithelial cells, the presence of these receptors has not been demonstrated in vivo. We know that in patients with HIVAN, HIV-1 can generally be detected in renal epithelial cells. It remains unclear, however, whether HIV-1 seropositive patients without HIVAN also harbor virus in the renal epithelium.
HIV-1 infection induces disease in the renal epithelium
The kidney contains many phenotypically distinct epithelial cell types along the length of each nephron. In the glomerulus, the visceral epithelial cell, or podocyte, is a highly specialized epithelial cell that forms a critical component of the glomerular filter. Most renal diseases that are characterized by abnormal increases in proteinuria are accompanied by phenotypic derangements in the podocyte. As mentioned above, podocytes are infected by HIV-1 in HIVAN. This infection induces several abnormalities, including increased proliferation and decreased expression of markers of differentiation, including synaptopodin, WT-1, GLEPP-1, and podocalyxin. Similar alterations in podocyte phenotype are found in the glomeruli of HIV-1 transgenic mice. In vitro studies using podocytes from HIV-1 transgenic mice and wild-type murine podocytes infected with HIV-1 have demonstrated increased levels of proliferation and anchorage-independent growth in podocytes expressing HIV-. Phenotypic abnormalities of the tubular epithelium are also prominent with increased proliferation and apoptosis, microcystic dilatation, flattening and atrophy of epithelial cells, and loss of expression of differentiation markers, with abnormal polarization of the sodium-potassium ATPase.
There is abundant evidence that HIV-1 induces cell cycle progression in HIVAN. Shankland et al. reported that the cyclin-dependent kinase (CDK) inhibitors p27 and p57 were downregulated in podocytes in HIVAN biopsies while p21 was upregulated. Basic fibroblast growth factor is upregulated in HIVAN and has been shown previously to increase proliferation of renal epithelial cells in vitro. Combined, the actions of growth factors and cell cycle regulatory proteins may mediate the increased epithelial proliferation observed in HIVAN.
HIVAN is also associated with the upregulation of transforming growth factor-b, which may in part, mediate increased renal fibrosis and apoptosis. We have recently used representational difference analysis to examine differentially expressed genes in podocytes from HIV-1 transgenic and normal mice. Using this approach, we identified a novel small leucine-rich repeat protein, Podocan, which accumulates in sclerotic glomeruli in HIV-1 transgenic mice. The role of Podocan in HIVAN pathogenesis is currently under study.
Transcriptional regulation of HIV-1 in renal epithelial cells appears to occur via similar mechanisms as in lymphocytes. Transcription in murine podocytes requires binding of inducible nuclear factor-kB and Sp1 to the viral LTR. Inhibition of HIV-1 transcription in murine podocytes using an inhibitor of CDK-9 resulted in decreased proliferation and re-expression of podocyte differentiation markers in vitro. Systemic administration of these CDK-9 inhibitors to HIV-1 transgenic mice ameliorated the HIVAN phenotype. Given the markedly decreased efficiency of HIV-1 transcription in murine cells, however, it is unclear whether CDK-9 inhibition would have similar effects in podocytes from humans with HIVAN.
Which HIV-1 genes contribute to HIVAN pathogenesis?
Animal models and in vitro studies have been used to map the HIV-1 genes that are important for HIVAN pathogenesis. The HIV-1 transgenic mouse and rat models of HIVAN express a gag/pol-deleted HIV-1 transgene under control of the endogenous viral LTR promoter. Thus, in these rodent models of HIVAN, the gag and pol genes are not required for development of the HIVAN phenotype.
Hanna and coworkers developed 18 transgenic mouse lines expressing five different HIV-1 mutant constructs under the control of the human CD4 regulatory sequences. In these transgenic lines, expression of HIV-1 nef was both necessary and sufficient to induce an AIDS-like phenotype and renal disease. It was not clear in this study however, how closely the renal phenotype resembled HIVAN. Also, the transgene was primarily expressed in leukocytes, although low-level expression in renal parenchymal cells could not be excluded. The same group of investigators later determined that the pathogenicity of HIV-1 nef in transgenic mice (with nef expressed under control of the same human CD4 promoter) was abolished by mutation of the P72XXP75 SH3-binding domain of Nef. Moreover, crossing these nef-mutant mice with hck-mutant mice caused a delay in development of the phenotype. The investigators postulated that since Hck is known to associate with Nef via an SH3 domain, Hck may be an important effector of Nef. However, expression of SIV Nef, which lacks the SH3 binding domain, is capable of causing the same phenotype as HIV-1 wild-type Nef, suggesting that binding to Hck via the SH3-binding domain is not crucial for Nef activity. In addition, the effects of murine genetic background admixture were not addressed.
Hussain et al. infected murine podocytes in vitro with a series of HIV-1 vectors containing mutations in the stop codons of each HIV-1 open reading frame as well as a series of monogenic HIV-1 retroviral vectors. The multigenic vectors contained the same parental backbone used in the generation of the HIV-1 transgenic model of HIVAN. In these studies, Nef expression in cultured podocytes was necessary and sufficient to induce increased proliferation and anchorage-independent growth. Nef expression was subsequently shown to induce loss of expression of markers of differentiation in podocytes in vitro.
In another study, investigators reported increased proliferation in cultured human podocytes when Tat protein was added to culture media or immobilized on the surface of the culture plates. A problem limiting the relevance of this study to HIVAN, however, is that it used podocytes derived from Caucasians, an ethnic group in whom the development of HIVAN is exceedingly rare.
The kidney is a reservoir for HIV-1
HIV-1 infection of renal epithelial cells has ramifications beyond the role of the virus in promoting the development of HIVAN. Renal epithelial cells are a reservoir where HIV-1 may persist in patients who have no detectable HIV-1 in plasma. In the series reported by Bruggeman et al., four of the 21 HIV-1 seropositive patients with renal disease who underwent diagnostic renal biopsy had undetectable HIV-1 in plasma. In each of these patients, HIV-1 RNA was detected in renal epithelial cells. Winston and colleagues reported a patient who developed HIVAN in the setting of acute seroconversion. After treatment with HAART, the patient had clinical and histologic resolution of his renal disease. Despite the dramatic response of HIVAN to HAART, however, HIV-1 RNA expression in renal epithelial cells remained unchanged.
To explore this epithelial compartment, Marras et al. used laser-capture microdissection followed by PCR to clone HIV-1 gp120 sequences from infected renal tubular epithelial cells taken from HIVAN biopsy samples.
These gp120 clones were sequenced along with those derived from peripheral blood mononuclear cells from the same patients. These studies resulted in two major findings. First, there was divergence in the gp120 sequences cloned from the renal epithelial cells, indicating that these cells are able to support full viral replication (which had not been shown previously). Second, phylogenetic analysis revealed that the gp120 sequences from kidney clustered separately within the radiation of gp120 sequences from the same patients' peripheral blood mononuclear cells. These data suggest that the renal epithelium is a reservoir for HIV-1 that is not in equilibrium with the blood compartment. Whether this renal reservoir contributes to rebound of plasma viral loads in patients who had previously been well controlled is unknown. There is also very little known about the ability of antiretroviral medications to achieve therapeutic levels in renal epithelial cells and whether the effects of these medications on the HIV-1 lifecycle in renal epithelial cells is similar to that in leukocytes.
Treatment of HIVAN
Though HIVAN is an important cause of renal failure in HIV-1 seropositive patients, no treatment for HIVAN has been evaluated in a prospective randomized-controlled trial. Unfortunately, most studies assessing the treatment or prevention of HIVAN are retrospective and/or poorly controlled. Nevertheless, we will discuss the best available evidence for the use of three classes of pharmaceutical agents: antiretrovirals, angiotensin converting enzyme (ACE) inhibitors, and steroids.
Antiretrovirals
In 1995, Ifudu et al. reported a series of 23 patients with HIV-1 infection and renal disease identified from 1989 to 1992, 14 of whom had at least 2+ proteinuria. Of the five patients who underwent renal biopsy, all had HIVAN. All patients were offered monotherapy with zidovidine. Of the 15 patients who were compliant with zidovidine, all had stable renal function at a mean of 20.4 months of follow up. All eight patients who were noncompliant, however, progressed to ESRD after a mean period of 8 weeks. It is unclear whether the groups were well matched at baseline with regards to severity of proteinuria or renal function. In a retrospective analysis of 11 patients with biopsy-proven HIVAN, Michel et al. found zidovidine treatment was associated with slowed progression of renal failure only when started before advanced renal failure was present.
There has been only one study evaluating the efficacy of antiretroviral therapy for the treatment of HIVAN since the introduction of HAART. Szczech et al. retrospectively studied 19 patients with a clinical diagnosis of HIVAN. Patients were followed for a median of 16.6 months. After adjusting for multiple factors, the investigators found a significant association between protease inhibitor usage and a slowing of the decline in creatinine clearance.
There have now been several case reports of patients with biopsy-proven HIVAN and severe renal disease that have had dramatic clinical and even histologic improvement in their renal disease after the onset of HAART. In two of these cases, patients were biopsied before and after commencing treatment with HAART. Both patients experienced remission of their renal disease by both clinical and histopathologic criteria.
The most compelling data suggesting a benefit of antiretroviral therapy on the natural history of HIVAN is the abrupt change in incidence in ESRD due to HIVAN since the introduction of HAART in 1995. During the years 1990-1995, the incidence of ESRD due to HIVAN in the USA increased 5.6-fold. Since 1995, however, though the number of persons living with AIDS at risk of developing HIVAN has risen steadily, the number of incident cases of ESRD due to HIVAN has remained relatively constant. Based on these epidemiologic data and the suggestive clinical studies described above, we believe that all patients with HIVAN should be treated with HAART unless they have compelling contraindications to treatment. We would further suggest that renal disease compels the use of HAART independent of the CD4 count.
ACE inhibitors
ACE inhibitors have been shown to prevent or slow progression of renal failure in a variety of proteinuric renal diseases. Kimmel et al. reported delayed progression of renal failure in a retrospective cohort of nine patients with HIVAN when compared to controls. Burns and colleagues studied a prospective cohort of 20 patients with biopsy-proven HIVAN all of whom were offered treatment with fosinopril. Patients in this study were diagnosed with HIVAN at a very early stage of disease (mean serum creatinine, 114.9 mmol/l). In the 12 patients who were compliant with treatment, renal function remained stable at 12 and 24 weeks of follow up. In the eight patients who refused fosinipril, however, serum creatinine increased from 88.4 to 433.2 mmol/L. Both of these studies were performed before HAART was available. A longer-term study by the same group has just been published. In this study, 44 patients with biopsy-proven HIVAN and early renal disease (mean serum creatinine < 176.8 mmol/l, less than 50% with proteinuria > 3 g/day) were all offered treatment with fosinopril. In patients who consented to fosinopril, serum creatinine remained stable in most patients, with only one out of 28 progressing to ESRD after a median follow up of 479.5 days. In patients who did not take fosinopril, all progressed to ESRD after a mean period of 146 days. However, a higher percentage of patients in the fosinopril group were treated with antiretroviral therapy prior to the study (57% versus 31%) and no data were provided regarding the use of antiretroviral medication during the study period.
Though suggestive of a benefit of ACE-inhibitors in HIVAN when used prior to the onset of severe renal disease, these studies are limited by their design and small numbers of patients. There remains a need for further prospective studies to define the optimal role for ACE-inhibitors for the treatment of HIVAN.
Prednisone
Several studies have evaluated the efficacy of prednisone in the treatment of HIVAN. Smith et al. reported a series of 20 patients with HIVAN who were treated with oral prednisone. Renal failure was advanced in most patients with a mean baseline serum creatinine of 742.6 mmol/l. All patients had CD4 counts less than 200 x 106 cells/l and 19 patients were receiving concomitant antiretroviral therapy at baseline. In 17 patients, serum creatinine decreased from a mean of 742.6 mmol/l to 265.2 mmol/l and proteinuria decreased significantly in most patients. Seven patients were still alive and had not progressed to ESRD at a mean of 25 weeks of follow up. However, many patients experienced relapses when prednisone was tapered. Moreover, six patients developed serious infections while on prednisone, and 11 patients died during follow up. Eustace and coworkers reported a series of 21 patients with HIVAN, 12 of whom were treated with prednisone. Multivariate analysis revealed that treatment with prednisone was associated an odds ratio of 0.2 for developing ESRD. There were, however, significantly more infectious complications in the prednisone-treated group, possibly due to the longer follow up in that group. Another retrospective study reported by investigators in France included 108 patients with HIVAN. In the 13 patients treated with prednisone, treatment was associated with an odds ratio of 0.29 for progressing to ESRD.
There has only been one study examining the efficacy of prednisone for the treatment of HIVAN in the HAART era. Szczech et al. retrospectively studied 19 patients with suspected HIVAN or 'another HIV-related renal lesion'. The five patients who received prednisone experienced an increase in creatinine clearance of 5.57 ml/min per month whereas the 14 patients who did not receive prednisone experienced a decline in creatinine clearance of 3.32 ml/min per month (P = 0.003).
Despite the suggestion of an association between prednisone usage and improved renal function in HIVAN in these studies, their small size, short follow up, and lack of randomization preclude our ability to draw conclusions regarding the efficacy or safety of prednisone for the treatment of HIVAN. We believe that in general, corticosteroids should not be used for the treatment of HIVAN. In patients with biopsy-proven HIVAN who have no active infectious complications, there may be some short-term benefit of using corticosteroids while HAART is being titrated to achieve maximal suppression of HIV-1. But we emphasize that there are no trials to support this application.
Prognosis of patients with HIVAN
Patients are usually diagnosed with HIVAN late in the course of their HIV illness and most have advanced renal failure at the time of diagnosis. In the absence of treatment with antiretroviral drugs, ACE-inhibitors, or prednisone, most patients with HIVAN progress to ESRD within 1-4 months of the diagnosis being established. As discussed in the section on treatment, pharmacotherapy with a variety of agents has been found to be associated with prolonged renal survival. Clinical variables that are associated with increased risk of progressive renal failure include elevated serum creatinine concentration, decreased CD4 cell count, increased proteinuria, higher viral HIV-1 viral load, and previous antiretroviral therapy.
Patients with HIVAN have decreased survival when compared to other patients with ESRD. In an analysis of 3374 incident patients with ESRD from 1996, including 36 with HIVAN, the diagnosis of HIVAN was associated with a 4.74-fold increased risk of mortality after adjustment for clinical variables other than HIV-1 seropositivity. The 1-year survival in this cohort was 53%, however more recent data has shown that 1-year survival of HIV-1 seropositive patients with ESRD in the USA has improved to 74% in 1999-2000, reflecting the dramatic benefit of HAART in this patient population.
While data from clinical studies indicate that the prognosis for patient and renal survival are improving in the HAART era, more prospective data are needed to better predict patient outcomes based upon clinical variables. Patients should be referred to nephrologists for diagnostic studies early in the course of their renal disease, as treatment seems to be most effective when started before renal failure has advanced. Furthermore, late referral of patients with renal failure to nephrologists has been shown to be an independent risk factor for early death on dialysis.
Summary and conclusions
HIVAN is the most common cause of chronic renal failure in HIV-1 seropositive patients and disproportionately affects patients of African descent. Patients with HIVAN are typically diagnosed late in the course of their HIV illness when they present with renal insufficiency and proteinuria. HIV-1 infection of renal epithelial cells has been shown to be crucial in the initiation of HIVAN pathogenesis. Furthermore, the kidney represents a reservoir where HIV-1 infection can persist despite treatment with HAART. Small clinical trials, case reports, and epidemiologic data strongly suggest a benefit of HAART in the treatment of HIVAN. Although not currently the standard, we recommend that the diagnosis of HIVAN be sought aggressively by physicians caring for HIV infected patients. And, when found, we also recommend that patients be started on HAART independent of their CD4 cell count and viral load.
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