Division of Nephrology, The Mount Sinai School of Medicine, New York, New York.
Correspondence to Dr. Michael J. Ross, One Gustave L. Levy Place, Box 1243, New York, NY 10029. Phone: 212-241-0131; Fax: 212-987-0389;E-mail: Michael.Ross{at}mssm.edu
The association between HIV and renal disease was first reportedin 1984 by investigators in New York City and Miami, who reporteda series of HIV-1—seropositive patients who developeda renal syndrome characterized by progressive renal failureand proteinuria (1–3). The most common kidney biopsy findingwas focal segmental glomerulosclerosis (FSGS). During the nextseveral years, the existence of a specific HIV-associated nephropathy(HIVAN) was debated, in part, because of its similarity to heroinnephropathy and the frequent occurrence of intravenous druguse in this population 4). Finding HIVAN in patients in whoma history of IVDU could be ruled out definitively helped toestablish HIVAN as a distinct clinical entity (5,6).
In the 18 years since HIVAN was first described, much has beenpublished regarding the epidemiology, pathogenesis, and treatmentof this disease. Despite these advances, however, HIVAN continuesto be an important cause of renal failure in the United Statesand other countries with large populations of African descent.Several excellent reviews on clinical aspects of HIVAN haverecently been published (7–10). This article will focuson recent advances in our understanding of HIVAN epidemiology,pathogenesis, and treatment.
HIVAN is usually diagnosed in patients who have been HIV-1—seropositivefor several years, and most patients have low CD4 counts and/orother criteria for the diagnosis of AIDS (11). In the post—highlyactive antiretroviral therapy (HAART) era, however, more patientsare being identified who present earlier in the course of HIVinfection with CD4 counts above 200 (12,13). HIVAN is characterizedclinically by the presence of proteinuria, often but not necessarilyin the nephrotic range (13,14). Most patients have moderateto severe renal insufficiency at the time of diagnosis (11,14,15),although a cohort of patients with HIVAN and mild renal insufficiencyhas been recently described (13).
The most common histopathologic abnormalities found in HIVANinclude collapsing FSGS, microcystic dilation of renal tubules,lymphocytic interstitial infiltrates, and interstitial fibrosis(Figure 1) (16,17). The finding of collapsing FSGS, especiallywith coexistent tubular microcystic disease in an HIV-1—seropositivepatient is diagnostic of HIVAN. Moreover, these pathologic findingsin a patient who is not known to be HIV-1—seropositiveshould alert the physician to the possibility of the presenceof HIV-1 infection in that patient.
Figure 1. Typical histopathologic findings in HIV-associated nephropathy (HIVAN). (A) Periodic acid-Schiff (PAS) staining reveals focal segmental glomerulosclerosis (FSGS) with segmental collapse. Podocyte hypertrophy and hyperplasia are evident overlying the area of collapse (arrow). Tubular microcystic disease is a prominent finding in HIVAN as well as interstitial lymphocytic infiltration and interstitial fibrosis. (B) Hematoxylin and eosin. Magnifications: x400 in A; x200 in B.
In studies published in the pre-HAART era, endothelial tubuloreticularinclusions (TRI) were present in a large percentage of HIVANbiopsy specimens (16). In the post-HAART era, however, TRI areless commonly found (17). TRI are inducible by -interferon exposure;therefore, the disappearance of TRI likely reflects the effectivenessof HAART in reducing systemic -interferon levels (18).
A variety of renal diseases have been reported in HIV-1—seropositivepatients. Even among seropositive black patients, although HIVANis the most common finding at the time of renal biopsy, approximately40% will have diagnoses other than HIVAN (17,19). Renal biopsy,therefore, is required to establish a definitive diagnosis ofHIVAN.
Epidemiology of HIVAN in the Pre- and Post-HAART Era
During the 1980s and early 1990s, the incidence of end-stagerenal disease (ESRD) due to HIVAN increased more rapidly thanany other etiology of renal disease (20). In 1999, HIVAN becamethe third leading cause of ESRD in African Americans aged 20to 64, and HIVAN is the leading cause of chronic renal failurein HIV-1—seropositive patients (19,21,22). Since the introductionof HAART, the incidence of death due to AIDS has decreased markedlyin the United States for all ethnic groups, including AfricanAmericans (Figure 2) (23). The incidence of ESRD due to HIVANhas decreased much less rapidly, however (Figure 2). New casesof ESRD due to HIVAN (reported as AIDS nephropathy by the USRDS)increased rapidly until 1995 and then suddenly began to decreaseslightly in 1996 (21) (presumably reflecting the effect of HAART).However, the rate of decline in the incidence of ESRD due toAIDS nephropathy has slowed; in 1999 (the most recent year forwhich data are available), the number of new cases actuallyincreased (Figure 2).
Figure 2. End-stage renal disease (ESRD) due to AIDS nephropathy and deaths in African Americans with AIDS. Data adapted from 2001 USRDS annual report (21) and the 2001 CDC HIV/AIDS Surveillance Report (23). Notice: The data here have been supplied by the United States Renal Data System (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 reported incidence of ESRD caused by HIVAN does not reflectthe many patients with chronic renal failure and/or proteinuriadue to HIVAN who have not yet reached ESRD and are thus notlisted in the national databases. The prevalence of HIVAN amongHIV-1–seropositive black patients has been estimated tobe between as low as 3.5% in a cohort of HIV-1—seropositivepatients screened for proteinuria in a primary care setting(24) and as high as 12% in a recent autopsy series (25). Accordingto the Centers for Disease Control, there are approximately140,000 African Americans currently living with AIDS (23). Thesedata suggest that there are between 4900 to 17,000 black patientsin the United States with HIVAN. The prevalence of HIV-1 infectionand AIDS are increasing in the United States, particularly amongblack patients (Figure 3), thereby continually increasing thepool of patients at greatest risk of developing HIVAN (23).
Figure 3. Prevalence of AIDS in the US and among African Americans. Data adapted from the 2001 CDC HIV/AIDS surveillance report (23).
Of the 40 million people living with HIV/AIDS worldwide, 28.5million reside in Sub-Saharan Africa (26). The incidence ofHIVAN in Africa, however, is unknown. Assuming the prevalenceof HIVAN among black patients in this region is similar to thatfor HIV-1—infected black patients in the United States,one would predict that there are between 1 and 3.4 million prevalentcases of HIVAN in Sub-Saharan Africa. It is likely that thelack of published literature on HIVAN in Africa is related tomultiple factors, including a lack of surveillance and reportingfor renal disease. HIVAN is usually a late manifestation ofHIV infection (11); therefore, it is likely that many Africanswith AIDS die of opportunistic infections early in the courseof AIDS, before HIVAN becomes clinically evident. It is predictablethat when medical care for HIV-infected Africans improves andpatients live longer with AIDS, HIVAN will become an increasinglyimportant cause of morbidity and mortality in Africa.
Recent data suggest that as mortality due to opportunistic infectionsis decreasing among patients with AIDS in the United States,other disease processes are becoming increasingly importantin this patient population. A recent review of causes of deathreported on death certificates of HIV-infected patients in theUnited States from 1987–1999 revealed that, although somediseases such as wasting/cachexia and dementia/encephalopathywere decreasing in incidence, renal disease was increasinglyreported (27). In this series, renal disease ranked fourth amongconditions contributing to death in this patient population.
The marked racial predilection of HIVAN for black and Hispanicpatients has been reported previously (19,28–30). Recentstudies have confirmed this association. A recent analysis ofdata from the United States Renal Data System (USRDS) revealedthat HIVAN is more strongly associated with black race thanany other cause of renal failure with the exception of sicklecell disease (31). Hailemariam et al. (32) reported a seriesof 239 autopsies performed on patients with AIDS in Switzerlandfrom 1981 to 1989 (before the introduction of HAART). Variousrenal abnormalities were reported among the 228 white patients.However, the only case of HIVAN in this series was detectedin one of six African patients included in the study.
The marked racial disparity in HIVAN suggests genetic factorsare important determinants of HIVAN pathogenesis. Nearly 25%of patients with HIVAN have first-degree or second-degree familymembers with ESRD, and black patients with HIVAN are 5.4 timesmore likely to have a first-degree or second-degree relativewith ESRD than are black patients without renal disease (33).
The Duffy antigen/receptor for Chemokines (DARC) has been proposedas a candidate gene involved in HIVAN pathogenesis. The DARCpromoter has a high prevalence of polymorphisms in black patients,and Liu et al. (34) have demonstrated increased DARC expressionin renal specimens from children with HIVAN and hemolytic uremicsyndrome. A subsequent study, however, failed to detect an associationbetween DARC promoter polymorphisms and HIVAN (35).
Role of HIV-1 Infection of Renal Epithelial Cells.
Until recently, it was unknown whether HIV-1 infection of renalparenchymal cells caused HIVAN directly or whether HIVAN wasan indirect renal response to HIV-induced immune dysregulation.The primary reason for this uncertainty was the presence ofconflicting data regarding the presence of HIV-1 in renal parenchymalcells in clinical HIVAN specimens. In 1989, Cohen et al. (36)reported detection of HIV-1 in renal epithelial cells by DNAin situ hybridization. Other investigators reported detectingHIV-1 by PCR in tubules microdissected from HIVAN biopsies specimens(37). However, other groups disputed the presence of HIV-1 inrenal parenchymal cells in HIVAN biopsy specimens (38,39).
Studies using an HIV-1 transgenic mouse model of HIVAN haveprovided important insight into HIVAN pathogenesis. Mice transgenicfor a replication-defective HIV-1 construct lacking the gagand pol genes, expressed under control of the viral promoter(long terminal repeat or LTR), develop proteinuria, renal failure,and histologic renal disease identical to HIVAN (40,41). Bruggemanet al. (42) later demonstrated that the HIV-1 transgene is expressedin renal glomerular and tubular epithelial cells and that transgeneexpression in renal epithelial cells was required for the developmentof the HIVAN phenotype.
Further support for a role of direct infection of renal parenchymalcells in HIVAN pathogenesis was provided by a macaque modelof HIV-induced renal disease (43–46). Stephens et al.(46) reported that passage of a chimeric simian-human immunodeficiencyvirus (SHIV) containing sequence from HIV-1 and the simian immunodeficiencyvirus (SIV) was capable of causing severe glomerulosclerosisand tubular disease. Infection with different strains of SHIVresulted in varying severity of renal disease, suggesting differencesin viral strains mediated renal pathogenesis. Viral RNA wasdetected in the glomerular fractions of diseased animals; however,the RNA was not localized to a particular cell type within theglomerulus.
Accumulating data from animal models of HIVAN led to renewedattempts to determine definitively whether HIV-1 infects renalepithelial cells in HIVAN. In 2000, Bruggeman et al. (47) reporteda series of 20 HIV-1–seropositive patients with renaldisease who underwent renal biopsies. All but one of the patientswere black or Hispanic, and 15 had HIVAN. In 11 of 15 patientswith HIVAN, HIV-1 was detectable in renal epithelial cells byRNA in situ hybridization. In several samples, the presenceof HIV-1 was confirmed using riboprobes specific for both thenef and gag genes and by DNA in situ hybridization. HIV-1 RNAwas detected in renal tubular epithelial cells (Figure 4A),glomerular visceral and parietal epithelial cells (Figure 4B),and interstitial leukocytes. The pattern of HIV-1 infectionof renal tubules is focal (Figure 4A) and may involve epithelialcells from multiple nephron segments, including proximal tubule,thick ascending loop of Henle, and collecting duct. The distributionof HIV-infection of renal tubules is similar to the patternof microcystic tubular disease in HIVAN (48).
Figure 4. In situ hybridization for HIV-1 mRNA in HIVAN. Adapted from Bruggeman et al. (47) with permission. (A) HIV-1 mRNA is detected in the cytoplasm of tubular epithelial cells. Tubular lumens (TL) are frequently filled with cellular casts (CC) or protein casts (PC). The CC result from apoptosis of infected epithelial cells that slough into the lumen, although some cells may have detached but remain viable. (B) HIV-1 mRNA is detected in podocytes (arrowheads), and parietal epithelial cells (arrows). G, glomerulus; US, urinary space. Magnifications: x60 in A; x200 in B.
The mechanism by which HIV-1 gains entry into renal epithelialcells is unknown. CD4, the receptor for HIV-1, and CCR5 andCXCR4, the major co-receptors for HIV-1 are not expressed inmost normal renal epithelial cells. Some authors have detectedCD4 and the major co-receptors in cultured renal epithelialcells (49); however, no published studies have definitivelydemonstrated their expression in vivo (39,50). Several otherco-receptors for HIV-1 have been recently identified (51), butwhether they are expressed in renal epithelial cells remainsto be determined.
The constellation of collapsing focal glomerulosclerosis combinedwith extensive tubular microcystic disease was previously thoughtto be relatively specific to HIVAN. Markowitz et al. (52), however,recently reported a series of seven white HIV-negative patientswho developed renal failure, proteinuria, and histopathologicdisease identical to HIVAN after treatment with high-dose pamidronate.These findings suggest that high-dose pamidronate, like HIV-1,is capable of injuring glomerular and tubular epithelial cells,resulting in a phenotype that is similar to HIVAN. Moreover,it is now clear that kidneys of white patients are capable ofproducing the HIVAN phenotype when exposed to a particular epithelialtoxin. It is not clear whether HIV-1 fails to cause HIVAN inwhite patients because it is unable to infect their renal epitheliumor because HIV-1 infection of their renal epithelium is notas injurious as it is in black patients.
The Kidney as a Reservoir for HIV-1.
Infection of renal epithelial cells by HIV-1 has important implicationsfor HIV-1—seropositive patients not only because it contributesto renal disease but also because the kidney may be an importantreservoir for HIV-1. Bruggeman et al. (47) detected HIV-1 byboth RNA in situ hybridization and DNA in situ PCR in threepatients who had undetectable viral loads in peripheral bloodsamples. Moreover, Winston et al. (12) reported a patient whodeveloped HIVAN in the setting of acute HIV-1 seroconversion.Proteinuria, renal failure, and histologic abnormalities improveddramatically after treatment with HAART. Despite an undetectableviral load in the peripheral blood while on HAART, the patientcontinued to express HIV-1 in renal epithelial cells as determinedby RNA in situ hybridization. Thus, even in the face of an optimalvirologic response to antiretroviral therapy and clinical remissionof HIVAN, HIV-1 infection persisted in the renal epitheliumand the virus remained transcriptionally active at a low level.
Marras et al. (53) isolated HIV-infected renal tubules fromtwo patients with HIVAN using laser capture microdissectionto characterize the HIV-1 quasi-species present in the renaltubular epithelium. HIV-1 envelope sequences were amplifiedfrom isolated tubules by PCR and sequenced. Phylogenetic analyseswere performed on envelope sequences from renal tubular epithelialcells and peripheral blood mononuclear cells (PBMC) from thesame patient. In each patient, there was variation in the HIV-1envelope sequences present in the renal epithelium. As viralreplication is required for viral evolution and sequence variation,this study provided direct evidence that the HIV-infected tubularepithelium in HIVAN is capable of supporting viral replication.Moreover, the quasi-species of HIV-1 present in renal epithelialcells clustered separately from sequences derived from the samepatients’ PBMC, indicating that HIV-1 infection of tubularepithelial cells represents a viral compartment that is separatefrom the blood. Thus, the renal tubular epithelium is a reservoirfor actively replicating HIV-1 and may support evolution ofviral strains that differ significantly from virus present ina patient’s blood. It is not known whether the renal epithelialcompartment is more likely to harbor drug-resistant HIV-1 strainsor whether the renal epithelium is susceptible to currentlyavailable antiretroviral drugs.
Mapping the Genes Responsible for HIVAN Pathogenesis.
The HIV-1 genome consists of nine genes encoding fifteen proteins(Figure 5). Transgenic animal models and in vitro assays modelingthe HIVAN phenotype have been used to map the HIV-1 genes responsiblefor HIVAN pathogenesis. The HIV-1 transgenic mouse model ofHIVAN studied in our laboratory (40,41) and a recently publishedtransgenic rat HIVAN model (54) expressing the same transgenelack the structural gag and pol genes. Thus both the rat andmouse models express just seven of the fifteen HIV-1 gene products.It is unlikely, therefore, that the gag or pol genes are requiredfor HIVAN pathogenesis, although they may have an impact ondisease phenotype or progression in man.
One of the pathologic hallmarks of HIVAN is focal glomerulosclerosis,often of the collapsing type (16). These collapsing lesionsare associated with vigorous podocyte proliferation and lossof podocyte differentiation markers, including synaptopodin,podocalyxin, and WT-1 (55). These podocyte abnormalities havealso been demonstrated in the HIV-1 transgenic mouse model ofHIVAN (56). In vitro studies have demonstrated that podocytesderived from HIV-1 transgenic mice demonstrate a lack of contactinhibition and increased anchorage-independent growth in culture(57,58). Employing a series of scanning mutations in the originalparental backbone that placed stop codons in each of the openreading frames as well as a series of monogenic HIV-1 gene constructs,Husain et al. (58) determined that nef is necessary and sufficientto cause most of the HIV-induced changes in podocyte cell biologyin vitro. Conversely, inhibition of HIV-1 viral transcriptionusing synthetic cyclin-dependent kinase-9 (CDK9) inhibitorsto inhibit tat transactivation of the LTR inhibits podocyteproliferation and cause re-expression of podocyte differentiationmarkers in vitro (59).
Other animal models support an important role for nef in HIVANpathogenesis. Hanna et al. (60) reported that mice transgenicfor HIV-1 expressed under the control of the human CD4 regulatorysequences develop an AIDS-like illness as well as renal disease,although how closely the renal disease resembles HIVAN is unclear.They also generated several transgenic lines with mutationsin one or more HIV genes and found that expression of nef wasnecessary and sufficient to produce their renal phenotype (61).It is not clear whether the transgene was expressed in renalepithelial cells, as is the case in HIVAN. The same group laterextended this work by demonstrating that the renal phenotypein their model was ameliorated by mutating one of the nef SH3binding domains. The authors postulated that nef exerts itspathogenic effect in the kidney, in part, via activation ofsrc-family tyrosine kinases. Nef has previously been shown tobe capable of binding Hck as well as several other src-familytyrosine kinases in vitro. To determine whether Hck was importantin modulating the renal disease in the nef transgenic mice,they crossbred their transgenic mice with Hck knockout miceand found that the development of renal disease was delayed,suggesting Hck may play a role in the pathogenesis of HIV-inducedrenal disease. Other studies using mice that express nef derivedfrom simian immunodeficiency virus (SIV) under the same CD4promoter construct develop a similar renal phenotype (62). SIVnef has much lower affinity for Hck than HIV-1 nef (63,64);therefore, Hck is unlikely to be the only pathway responsiblefor the development of renal disease in their animal model.
Podocytes and tubular epithelial cells proliferate in vivo inHIVAN (42,55,65,66). Cyclin-dependent kinase (CDK) inhibitorsregulate cell cycle through inhibiting cyclin-CDK complexes(66). Shankland et al. (66) found that expression of two CDKinhibitors, p27 and p57, were decreased in podocytes from HIVANbiopsies while expression of another CDK inhibitor, p21, wasincreased. These host genes may play an important role in mediatingthe increased epithelial proliferation present in HIVAN.
Despite HIVAN becoming an important cause of renal failure inthe United States, no prospective randomized controlled studiesevaluating treatment modalities for HIVAN have been published.Unfortunately, most existing studies are retrospective and/orlack proper controls. The following discussion will focus onthe best available evidence concerning the efficacy of antiretroviralmedications, angiotensin-converting enzyme (ACE) inhibitors,and steroids in the treatment of HIVAN.
Antiretrovirals.
During the years of 1990 to 1995 (before the introduction ofHAART), the number of new cases of ESRD caused by HIVAN roseby over 75% annually (21). After the introduction HAART in theUnited States, however, the rise in new cases of ESRD due toHIVAN ceased abruptly (Figure 2). It is likely that this changereflects the efficacy of HAART in either preventing HIVAN orslowing progression to end-stage renal failure in patients withHIVAN.
Several studies have evaluated the use of antiretroviral medicationsfor the treatment of HIVAN. Ifudu et al. (67) studied 23 HIV-1—seropositivepatients, 14 of whom had at least 2+ proteinuria. HIVAN wasdiagnosed in the five patients who underwent renal biopsy. Allpatients were offered treatment with zidovidine. None of the15 patients who were compliant had deterioration of renal functionafter a mean follow-up of 20.4 mo. The eight patients who werenot compliant with zidovidine treatment all progressed to ESRDafter a mean of 8 wk. It is not clear whether the baseline renalfunction or proteinuria was different in those who developedprogressive renal failure. A retrospective case series reportedby Michel et al. (68) suggested that the efficacy of zidovidinein preventing renal failure in HIVAN is greatest when startedwhen before the onset of renal failure.
Szezech et al. (69) recently evaluated the association of HIV-1protease inhibitor usage with change in creatinine clearancein patients with HIV and renal disease. Nineteen patients wereretrospectively identified, 16 of whom were black. Multivariateanalysis revealed a significant association between proteaseinhibitor usage and decrease loss of creatinine clearance.
As discussed above, there is compelling evidence that treatmentwith HAART has had a beneficial effect on the incidence of HIVANin the United States. Although no prospective studies evaluatingthe efficacy of HAART in the prevention or treatment of renaldisease exist, there have been case reports of patients withbiopsy-proven HIVAN and advanced renal failure whose renal failureand proteinuria resolved dramatically after the patients weretreated with HAART (12,70,71). In case reports from Winstonet al. (12) and Wali et al. (70), the patients had renal failurerequiring hemodialysis and had renal biopsies before and aftertreatment with HAART. Both patients responded with a dramaticimprovement in renal function and discontinuation of hemodialysis.Remarkably, in both patients, repeat renal biopsy after HAARTrevealed resolution of the histologic renal abnormalities, includingthe collapsing FSGS and tubular microcystic disease.
ACE Inhibitors.
The effect of ACE inhibitors on HIVAN progression has also beenstudied. Kimmel et al. (72) reported an increase in renal survivalassociated with captopril usage in a retrospective case-controlstudy of 18 patients with biopsy-proven HIVAN. Burns et al.(13) prospectively evaluated 20 patients with HIVAN and mildrenal insufficiency (average serum creatinine less than 2 mg/dl).All patients were offered 10 mg/d fosiniopril. After follow-upof 12 to 24 wk, renal function remained stable in the 12 patientswho consented to fosinopril therapy; in the eight patients whorefused fosinopril, serum creatinine increased from 1.4 to 6.4mg/dl. Seven patients in the study were receiving monotherapywith nucleoside reverse transcriptase inhibitors. It is notclear how the effect of antiretrovirals may have affected theresults of the study. Although the limitations of these studiesare clear, the data are suggestive and further prospective studiesshould be done to define the optimal role for ACE inhibitorsin the treatment of HIVAN.
Prednisone.
Prednisone has been found in several studies to be associatedwith reduced risk of progressive renal failure in patients withHIVAN. Smith et al. (73) reported an observational study of20 patients with HIVAN who were treated with prednisone. Mostpatients had advanced renal failure and heavy proteinuria atthe time of diagnosis. Seventeen of the patients experienceda decrease in serum creatinine and/or proteinuria after treatmentwith prednisone. However, several of the patients relapsed,requiring repeated courses of prednisone, 11 patients died duringthe study period, and 6 developed serious infectious complicationswhile on prednisone. Seven patients were still free of dialysisat a mean of 25 wk of follow-up. Although provocative, manyof the patients in this study had a poor outcome, and the lackof controls precludes drawing conclusions regarding safety andefficacy. Another study, case-control by design, evaluated theoutcome of 21 patients with HIVAN and advanced renal failure,13 of whom were treated with prednisone (74). The odds ratiofor progression to ESRD in prednisone-treated patients was 0.2,and only treatment with prednisone and initial serum creatininewere significantly associated with renal outcome after correctingfor several clinical variables. There were, however, more infectiouscomplications in the steroid-treated group, which the authorspoint out may be accounted for by the longer follow-up of thatgroup. These findings are consistent with a retrospective cohortstudy from France of 108 patients with HIVAN, 15 of whom weretreated with steroids, in which, treatment with steroids wasassociated with an odds ratio of 0.29 for the progression toESRD (15).
The only study in the HAART era evaluating the efficacy of prednisonein patients with HIVAN was recently published by Szczech etal. (69). This retrospective cohort study evaluated outcomesin 19 patients with HIVAN and other HIV-related renal diseases.After multivariate analysis of several clinical variables, theassociation between prednisone and reduced rate of decline increatinine clearance remained highly significant.
Despite the suggestion of a renal benefit in patients with HIVANwho received prednisone, we believe that until the efficacyof prednisone is validated in prospective controlled trials,the potential for increased risk of infectious complicationsshould preclude its routine use in the treatment of HIVAN. Prednisoneshould be considered only for short-term therapy in patientswith aggressive renal disease and no active infectious complicationswhile HAART is being titrated to maximally suppress viral replication.
The data regarding prognosis for renal and patient survivalafter the diagnosis of HIVAN are biased by the fact that themajority of these patients are referred to nephrologists latein the course of their renal disease and HIV-1 infection (11).Patients with HIVAN who are not treated with antiretrovirals,ACE inhibitors, or prednisone, generally have a poor renal prognosiswith a mean time to progression to ESRD of 1 to 3 mo (13,67,72).The renal prognosis in the HAART era is less well defined. Casereports of patients with mild renal insufficiency treated withantiretrovirals and/or ACE inhibitors have reported some patientswho survived for years with stable renal function (12,13,70).Clinical variables associated with progression of renal failureinclude elevated serum creatinine (15,74,75), low CD4 count(15,75), high HIV-1 viral load (75), higher level of proteinuria(15), and previous antiretroviral therapy (15). Better prospectivedata examining the outcome of patients with HIVAN are neededbefore clinical variables can be accurately used to predictthe prognosis of this patient population.
Since HIVAN was first described 18 years ago, it has becomean important cause of renal failure among black patients. Afterdecreasing slightly since the introduction of HAART, the incidenceESRD due of HIVAN in the United States is again increasing.Although data are lacking, the prevalence of HIVAN is probablyhighest in Africa, where it will likely emerge as a major causeof morbidity and mortality as the prognosis for AIDS survivalimproves.
HIV-1 infection of renal epithelial cells is an essential componentof HIVAN pathogenesis. Renal epithelial cells are a newly identifiedviral reservoir and a separate replicating compartment distinctfrom blood. Significant progress has been made in understandingthe pathogenesis of HIVAN, particularly in defining the viralgenes necessary for causing renal disease. Far less is knownconcerning host factors contributing to HIVAN pathogenesis.
Prospective-controlled trials are needed to evaluate the efficacyand optimal use of currently available agents, including antiretrovirals,ACE inhibitors, and steroids. Continued research into the mechanismsby which HIV-1 causes renal disease should eventually yieldnovel therapies for the treatment of HIVAN and other forms ofFSGS.
Acknowledgments
We thank Leslie Bruggeman for her help in the preparation offigures for this manuscript and Mary Klotman for comments andreading.
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Top
Introduction
Definition of HIVAN
-interferon exposure; therefore, the disappearance of TRI likely reflects the effectiveness of HAART in reducing systemic 
