HIV-associated nephropathy (2004)

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 [1,2]. 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 [3,4]. 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 [5,6]. 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 [7]. Although the majority have been HIV-1 seropositive for several years and have CD4 counts below 200 × 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 [8–10]. 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 [11–13] 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 [14]. Despite the presence of proteinuria that is often in the nephrotic range, most patients with HIVAN do not have significant peripheral edema [15]. 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 [16]. These observations, coupled with the finding that HIV-seropositive patients often have a decreased ability to conserve sodium [17] 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) [18]. Because membranoproliferative glomerulonephritis (most often related to HCV infection) is frequently diagnosed in HIV-seropositive patients with renal disease [19], 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 [12,15]. 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 (Fig. 1, arrow). Tubular disease is characterized by the development of tubular dilatation (Fig. 1, asterisks), 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 [20]. Tubuloreticular inclusions, however, are found with decreasing frequency [21], perhaps due to the efficacy of antiretroviral therapy in reducing plasma interferon levels [22].Fig. 1. Typical histopathologic findings in HIVAN.: Periodic acid–Schiff staining demonstrates focal segmental glomerulosclerosis (arrowhead) with collapse of the glomerular tuft (arrow), tubular microcystic disease (asterisks), interstitial lymphocytic infiltration, and interstitial fibrosis. Magnification, × 200.Epidemiology of HIVAN After the first clinical description of HIVAN in 1984 [2], 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 (Fig. 2). 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 (Fig. 2).Fig. 2. ESRD due to AIDS nephropathy and deaths in African Americans with AIDS.: Data adapted from 2003 USRDS annual report [33] and the 2001 CDC HIV/AIDS Surveillance Report [27]. Notice: The data here have been supplied by the USRDS. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the US Government.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 (Fig. 3) [23]. 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 [24].Fig. 3. Prevalence of AIDS in the USA and among African Americans.: Data adapted from the 2001 CDC HIV/AIDS surveillance report [27].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 [25]. Another recent study reported that the prevalence of HIVAN in black patients dying with AIDS who underwent autopsy was 12% [26]. 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 [27]. 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. [28]. 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 [29]. 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 [30]. 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 [13]. Since most Africans with HIV/AIDS receive little or no treatment for their illness [30], 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 [31,32]. 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 [27,33,34] (Fig. 4), and European cities such as Paris and London [11,35,36].Fig. 4. Geographic variation of incidence of ESRD due to HIVAN in the USA.: Each color of the map represents quintiles of the mean incidence of ESRD due to AIDS nephropathy (per million population) [33]. Notice: The data here have been supplied by the USRDS. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the US Government.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 [37]. 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 [11] and London [36] 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 [38]. 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 [39]. 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 [40]. 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 [41]. 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 [42,43] and some unable to detect virus [44,45]. 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 of the HIV-1 promoter These proteinuria, progressive renal and disease that is to HIVAN studies by and coworkers that the HIVAN in these is upon HIV-1 gene in the renal epithelium Recently, a transgenic model this HIV-1 has also been to cause the HIVAN Data from models also a role for direct infection of renal parenchymal cells in the pathogenesis of HIVAN renal disease that closely HIVAN infection with a virus The frequency with which these renal disease is upon the of suggesting that there are determinants of renal disease The investigators were to from the of but it was whether renal parenchymal cells were infected or whether virus was from cells. Though animal models that HIV-1 infection and in renal parenchymal cells in HIVAN, of such infection in remained when et al. reported a series of 20 HIV-seropositive patients with renal disease who had renal biopsy Renal was at time biopsy and to of the patients were diagnosed with HIVAN and in these patients, HIV-1 was by in (Fig. In several was by the use of for and and by in (Fig. HIV-1 infection has been in epithelial cells from several of the the and epithelial and the of and the Furthermore, the of disease this of epithelial infection In infection of other renal parenchymal cells such as cells or cells by HIV-1 has not been in HIVAN. The types of renal parenchymal cells are in to be infected by HIV-1 in HIVAN are in HIV-1 infects renal epithelium in patients with HIVAN.: from et al. with HIV-1 are by in and in Magnification, × of a and epithelial cells also as epithelial cells and tubular epithelial cells are of HIV-1 infection in HIVAN. HIV-1 infection of cells and cells has not been in HIVAN. Magnification, × adapted from by which HIV-1 renal epithelial cells is and the by the of HIV-1 from kidney are unknown. While et al. have and in of renal epithelial cells the presence of these has not been in that in patients with HIVAN, HIV-1 can be in renal epithelial cells. however, whether HIV-1 seropositive patients without HIVAN also virus in the renal HIV-1 infection disease in the renal epithelium The kidney many distinct epithelial cell types the of In the the epithelial or is a epithelial cell that forms a of the glomerular Most renal that are characterized by increases in proteinuria are accompanied by in the As are infected by HIV-1 in HIVAN This infection several increased and decreased of of and Similar in are found in the of HIV-1 transgenic In studies using from HIV-1 transgenic and infected with HIV-1 have increased levels of and in HIV-1 abnormalities of the tubular epithelium are also prominent with increased and microcystic flattening and atrophy of epithelial cells and of of with of the There is that HIV-1 cell in HIVAN. et al. reported that the and were in in HIVAN biopsies was is upregulated in HIVAN and has been to increase of renal epithelial cells in the of factors and cell may the increased epithelial in HIVAN. HIVAN is also associated with the of which may in increased renal and have recently difference to expressed in from HIV-1 transgenic and Using this approach, a which in in HIV-1 transgenic The role of in HIVAN pathogenesis is of HIV-1 in renal epithelial cells to similar as in in of and to the of HIV-1 in using an of in decreased and of in of these to HIV-1 transgenic the HIVAN the decreased of HIV-1 in cells however, it is whether have similar in from with HIVAN. HIV-1 to HIVAN models and in studies have been to map the HIV-1 that are important for HIVAN pathogenesis. The HIV-1 transgenic mouse and models of HIVAN a HIV-1 of the Thus, in these models of HIVAN, the and are not for development of the HIVAN and coworkers transgenic mouse different HIV-1 the of the CD4 In these transgenic of HIV-1 was and to an and renal disease. was not in this study however, closely the renal HIVAN. the was primarily expressed in although in renal parenchymal cells could not be The of investigators that the of HIV-1 in transgenic expressed of the CD4 was by of the of Moreover, these with caused a in development of the The investigators that since is to with an may be an important of of which the is of the as HIV-1 suggesting that to the is not for In the of genetic were not et al. infected in with a series of HIV-1 in the of HIV-1 as as a series of HIV-1 The the in the of the HIV-1 transgenic model of HIVAN. In these in was and to increased and was to of of of in in In study, investigators reported increased in when was to or on the of the problem the of this study to HIVAN, however, is that it from an ethnic in whom the development of HIVAN is The kidney is a for HIV-1 HIV-1 infection of renal epithelial cells has the role of the virus in the development of HIVAN. Renal epithelial cells are a where HIV-1 may in patients who have no HIV-1 in In the series reported by et al. of the 21 HIV-1 seropositive patients with renal disease who underwent renal biopsy had HIV-1 in In of these patients, HIV-1 was in renal epithelial cells. and reported a patient who HIVAN in the setting of acute seroconversion After treatment with the patient had clinical and of renal disease. Despite the of HIVAN to however, HIV-1 in renal epithelial cells remained To this epithelial et al. by to HIV-1 from infected renal tubular epithelial cells from HIVAN biopsy These were with those from peripheral cells from the patients. These studies in major there was in the from the renal epithelial that these cells are to support had not been revealed that the from kidney within the of from the peripheral cells. These data suggest that the renal epithelium is a for HIV-1 that is not in with the this renal to of plasma in patients who had been is unknown. There is also very little about the ability of antiretroviral to levels in renal epithelial cells and whether the of these on the HIV-1 in renal epithelial cells is similar to that in of HIVAN Though HIVAN is an important cause of renal failure in HIV-1 seropositive patients, no treatment for HIVAN has been in a most studies the treatment or of HIVAN are and/or will the best for the use of of and In 1995, et al. reported a series of patients with HIV-1 infection and renal disease from to of whom had at 2+ proteinuria Of the patients who underwent renal biopsy, all had HIVAN. patients were with Of the patients who were with all had renal at a mean of months of follow patients who were however, progressed to ESRD after a mean of is whether the were at with to of proteinuria or renal In a of patients with HIVAN, et al. found treatment was associated with of renal failure only when before advanced renal failure was present There has been only one study the efficacy of antiretroviral therapy for the treatment of HIVAN since the introduction of et al. studied patients with a clinical diagnosis of HIVAN Patients were for a of After adjusting for multiple the investigators found a significant association between and a of the decline in creatinine There have been several case reports of patients with HIVAN and severe renal disease that have had clinical and even in their renal disease after the of HAART (Fig. In of these cases patients were before and after treatment with patients of their renal disease by clinical and histopathologic of HIVAN in a patient after treatment with to treatment biopsy revealed focal of tubular microcystic disease, and and lymphocytic in the interstitium. 3 months of biopsy revealed tubular and mild focal interstitial fibrosis. Periodic acid–Schiff × from et al. with most data suggesting a of antiretroviral therapy on the of HIVAN is the in incidence in ESRD due to HIVAN since the introduction of HAART in (Fig. 2). During the years the incidence of ESRD due to HIVAN in the USA increased Since 1995, however, the number of living with AIDS at risk of developing HIVAN has the number of cases of ESRD due to HIVAN has remained Based on these data and the clinical studies that all patients with HIVAN should be with HAART they have to further suggest that renal disease the use of HAART of the CD4 have been to or of renal failure in a variety of renal et al. reported of renal failure in a cohort of patients with HIVAN when compared to Burns and studied a cohort of 20 patients with HIVAN all of whom were treatment with Patients in this study were diagnosed with HIVAN at a very early stage of disease (mean serum 114.9 In the patients who were with renal remained at and of follow In the patients who however, serum creatinine increased from to of these studies were before HAART was study by the has been published In this study, patients with HIVAN and early renal disease (mean serum creatinine than with proteinuria > 3 were all treatment with In patients who to serum creatinine remained in most patients, with only one of to ESRD after a follow up of In patients who did not all progressed to ESRD after a mean of a higher percentage of patients in the were with antiretroviral therapy to the study versus and no data were provided regarding the use of antiretroviral the study Though of a of in HIVAN when to the of severe renal disease, these studies are by their and of patients. There a need for further studies to the role for for the treatment of HIVAN. studies have the efficacy of in the treatment of HIVAN. et al. reported a series of 20 patients with HIVAN who were with Renal failure was advanced in most patients with a mean serum creatinine of patients had CD4 counts than 200 × 106 cells/l and patients were antiretroviral therapy at baseline. In patients, serum creatinine decreased from a mean of mmol/l to mmol/l and proteinuria decreased in most patients. patients were and had not progressed to ESRD at a mean of of follow many patients when was Moreover, six patients infections on and patients follow and coworkers reported a series of 21 patients with HIVAN, of whom were with revealed that treatment with was associated an ratio of for developing ESRD. There however, more complications in the due to the longer follow up in that Another study reported by investigators in France included patients with HIVAN In the patients with treatment was associated with an ratio of for to ESRD. There has only been one study the efficacy of for the treatment of HIVAN in the HAART et al. studied patients with HIVAN or renal The patients who an increase in creatinine of per the patients who did not receive a decline in creatinine of per Despite the of an association between and renal in HIVAN in these their follow and lack of ability to regarding the efficacy or of for the treatment of HIVAN. that in should not be for the treatment of HIVAN. In patients with HIVAN who have no active there may be some of using HAART is to of that there are no to support this 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 In the of treatment with antiretroviral or most patients with HIVAN to ESRD within months of the diagnosis As in the on with a variety of has been found to be associated with renal Clinical that are associated with increased risk of progressive renal failure include serum creatinine decreased CD4 cell increased proteinuria higher HIV-1 and antiretroviral therapy Patients with HIVAN have decreased survival when compared to other patients with ESRD. In an of patients with ESRD from with HIVAN, the diagnosis of HIVAN was associated with a increased risk of mortality after for clinical other than HIV-1 The survival in this cohort was more recent data has that survival of HIV-1 seropositive patients with ESRD in the USA has to in the of HAART in this patient While data from clinical studies that the for patient and renal survival are in the HAART more data are needed to better predict patient upon clinical Patients should be to for studies early in the course of their renal disease, as treatment to be most when before renal failure has Furthermore, late of patients with renal failure to has been to be an risk for early death on and HIVAN is the most common cause of chronic renal failure in HIV-1 seropositive patients and disproportionately affects patients of African Patients with HIVAN are diagnosed late in the course of their HIV illness when they present with renal insufficiency and HIV-1 infection of renal epithelial cells has been to be in the of HIVAN pathogenesis. Furthermore, the kidney represents a where HIV-1 infection can treatment with clinical case and data suggest a of HAART in the treatment of HIVAN. Although not the that the diagnosis of HIVAN be by for HIV infected patients. when also that patients be on HAART of their CD4 cell and and for their in of for this and for and