Review

10.1586/14787210.6.3.365 © 2008 Expert Reviews Ltd ISSN 1478-7210 365www.expert-reviews.com

HIV-associated nephropathy: epidemiology, pathogenesis, diagnosis and managementExpert Rev. Anti Infect. Ther. 6(3), 365–371 (2008)

Mohamed G Atta†, Gregory M Lucas and Derek M Fine†Author for correspondence1830 E. Monument Street, Suite 416, Baltimore, MD 21287, USATel.: +1 410 955 5268Fax: +1 410 955 0485matta1@jhmi.edu

HIV-associated nephropathy (HIVAN) is the most well-known and aggressive kidney disease inHIV-1-infected patients. A variant of focal segmental glomerulosclerosis, it is characterized bythe collapse of the glomerular tuft with podocyte hypertrophy/hyperplasia and foot processeffacement, often with concurrent tubular microcystic dilation and tubulointerstitial nephritis.The disease has been intimately linked to the direct effect of HIV-1 on the kidney. It affectspatients of African descent exclusively and is manifested by an acute decline in kidney function,most often in conjunction with high-grade proteinuria and uncontrolled HIV-1 infection. Withthe widespread use of highly active antiretroviral therapy (HAART), its prevalence is declining inWestern countries. However, the epidemiology of the disease is not well defined in the poorestareas of the world, which bear a disproportionate share of the HIV-1 epidemic burden. Scientificevidence suggests that HAART can prevent the development of HIVAN. Furthermore, HAART,corticosteroids and inhibition of the renin–angiotensin axis are potentially helpful in delayingdisease progression, as well as the need for renal replacement therapy.

KEYWORDS: end-stage renal disease • highly active antiretroviral therapy • HIV-1 • HIV-associated nephropathy • kidney

EpidemiologyOriginally named ‘AIDS nephropathy’, HIV-asso-ciated nephropathy (HIVAN) was first describedin 1984 [1–3]. Although HIVAN has beendescribed in early HIV infection [4], late-stage dis-ease and advanced immunosuppression arestrongly associated with HIVAN incidence [5,6].In the USA and Western Europe, the prevalenceof HIVAN is driven by host factors and boththe availability and use of highly active antiret-roviral therapy (HAART). As an exclusive disor-der of individuals of African descent [7–13], prev-alence of HIVAN leading to end-stage renaldisease (ESRD) in this segment of the popula-tion has ranged from 3 to 12%. For example,the prevalence of HIVAN was 12% amongAfrican–Americans in a large autopsy series ofHIV-infected individuals who died in the TexasDepartment of Criminal Justice System [14].HIVAN is a rare entity in HIV-1-infected pop-ulations that are predominantly white [15–17]

and its predilection to black race has also beenreported in Europe [18,19]. Other than racial dif-ferences, there is no compelling evidence foranother associated risk factors, such as gender,

mode of HIV acquisition or presence of othercomorbidities. In the USA, the incidence ofHIVAN peaked in the mid-1990s andremained stable after an initial decline [20].This decline can be attributed to the introduc-tion of HAART in 1996. However, as survivalimproves, prevalence of HIV-1 individuals islikely to increase, as is the prevalence of indi-viduals with kidney disease, usually of non-HIVAN variety [21]. In the poorest areas in theworld, such as sub-Saharan Africa and parts ofAsia, which bear a disproportionate share ofthe HIV-1 epidemic burden, there is a paucityof data regarding the epidemiology of HIVANin individuals with HIV-1 infection. Onecross-sectional study from South Africa sug-gested that HIVAN is the most common dis-ease in patients with proteinuria and HIV-1infection [22].

PathogenesisRole of HIV-1Although HIVAN has been described as partof an acute HIV-1 seroconversion, as well as ina patient with well-controlled HIV-1 infection

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on HAART [4,23,24], it is typically a late manifestation of HIVinfection, associated with low CD4 cell counts and high viralloads. This suggests a direct role of the virus in the pathogen-esis of the syndrome. Several HIV-1 gene products have beenshown to trigger histological renal changes in different HIV-1transgenic models, similar to those observed in humanHIVAN [25–28]. In addition, HIV-1 replication within renalcells has been demonstrated in biopsy tissue from HIV-1-infected individuals with HIVAN [4,29,30]. Furthermore,HIV-1 has been detected in renal epithelial cells and podo-cytes in patients with HIVAN [4,29]. This may, in part, explainthe dysregulated podocyte’s cell cycle that has been describedin association with HIVAN [31]. Immunohistochemisterystudies have revealed the upregulation of markers of prolifera-tion and downregulation of markers of differentiation in thepodocytes [32].

The direct role of the virus in the disease is also supported bythe beneficial impact of HAART in the prevention and treatmentof the disease [6,33,34]. Further support is provided by the observa-tion that relapse of HIVAN can occur with the discontinuationof HAART [35].

Host factorsDespite the evidence implicating a direct role of HIV-1pathogenesis of HIVAN, the mechanism by which HIV-1enters renal cells has not yet been elucidated. Normal renalepithelial cells lack the chemokine receptors CCR5 andCXCR4, which serve as cellular receptors in conjunctionwith CD4 for HIV-1 entry and infection of target cells. Inaddition, the mechanisms underlying disease susceptibilityand progression remain unknown. Since only a subset ofpatients with HIV-1 infection develop HIVAN, despite thepresence of HIV-1 DNA in those with and without kidneydisease [29], additional host factors, such as responses to dif-ferent HIV-1 proteins, are likely to play an important role ininitiating the disease process. In a historic cohort in the USA,HIVAN had the strongest association with black race of allcauses of renal failure among patients who were on mainte-nance dialysis [11]. The exclusiveness of the disorder to indi-viduals of African descent suggests the existence of geneticfactors. This is further supported by the familial clustering ofkidney disease among family members of African–Americanindividuals diagnosed with HIVAN [36]. Although a geneticsusceptibility locus has been identified in a Tg26 mousemodel [37], to date, no genetic association has been identifiedin humans with HIVAN.

Clinical presentation

HIVAN typically presents with rapid decline in renal function,often with high-grade proteinuria. The proteinuria is typicallyin the nephrotic range (>3 g/24 h), with serum creatinine levelsabove 2 mg/dl and progressive kidney failure [38,39]. TABLE 1 liststhe clinical presentation of 53 patients with biopsy-proven

HIVAN [39]. In the one study from South Africa, seven out of90 (8%) HIV-infected patients without known renal diseasewere found to have persistent microalbuminuria, and six out ofthe seven who had kidney biopsies were found to haveHIVAN [22]. This study raises the question of whether HIVANmay have an indolent preclinical phase where only mild abnor-malities are present that would not generally lead to biopsy.However, as this indolent presentation has not yet beendescribed, additional corroborating evidence is needed. Lowerextremity edema and hypertension are uncommon in patientswith HIVAN and their absence may contribute to delayed diag-nosis [38]. Urinalysis shows bland sediment with varying num-bers of proteinaceous casts and renal tubular epithelial cells [38].

As described previously, the histopathological findings are of acollapsing form of focal segmental glomerulosclerosis (FSGS),with significant tubulointerstitial injury and microcystic tubulardilation [40]. Recognizing this histopathology is extremely

Table 1. Baseline characteristics of 53 patients with HIV-associated nephropathy.

Characteristic Value

Mean age (years) 40.8 (range: 26–63)

Men (n) 32 (60.4%)

African–American origin (n) 52 (98.1%)

Hypertension (n) 30 (56.6%)

Diabetes mellitus (n) 4 (7.6%)

Hepatitis B (n) 3 (6%)

Hepatitis C (n) 30 (58.8%)

Injection drug user (n) 31 (59.6%)

Mean proteinuria (g/day) 8.0 (range: 0.18–42)

Range of proteinuria (g/day)<1.0 1.0–3.5>3.5

4 (7.8%)12 (23.5%)35 (68.6%)

Mean serum creatinine (mg/dl) 6.57

Mean estimated glomerular filtration rate (ml/min/1.73 m2)

15.0

Estimated glomerular filtration rate (ml/min/1.73 m2)≥9060–8930–5915–290–14

0 (0%)1 (1.9%)6 (11.3%)9 (17.0%)37 (69.8%)

CD4 count (cells/mm3)<200 200–500 >500

39 (73.6%) 13 (24.5%) 1 (1.9%)

Mean HIV-1 viral load (copies/ml) 166.73

Adapted from [39].

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important as the clinical presentation of HIVAN may be mim-icked by other glomerular diseases, with potentially significantlydifferent treatment options and prognoses.

The natural history of HIVAN without antiretroviral ther-apy is an ominous one. When first reported in 1984 [3],HIV-1-infected individuals presented with nephrotic-rangeproteinuria and progression to ESRD occurred within8–16 weeks. Mortality in these patients approached 100%within 6 months of diagnosis. In the HAART era, prognosisremains poor in these patients compared with other kidneydiseases in HIV-1-infected patients. In a recent, observationalstudy by Berliner et al. of HIV-1-infected patients who under-went kidney biopsy, HIVAN patients were more likely to ulti-mately require hemodialysis (p < 0.0001) and had significantlyworse survival compared with patients without HIVAN(p = 0.02) [39]. However, patients with HIVAN that weretreated with HAART had significantly better renal survivalcompared with untreated individuals [41].

Diagnosis

Diagnosis of HIVAN requires a kidney biopsy, which should beperformed promptly whenever possible and when the proce-dure is not contraindicated. It is often difficult to distinguishHIVAN from other kidney lesions on clinical grounds alone.Identifying valid, surrogate, noninvasive measures in the diag-nosis of HIVAN has been disappointing [42,43]. For example,nephrotic-range proteinuria, even in the presence of a low CD4cell count, does not reliably predict HIVAN [43]. HIVAN wasdiagnosed in only 53% of 55 patients with nephrotic-rangeproteinuria, with a sensitivity of only 73% and a positive pre-dictive value of 53% [43]. In individuals with nephrotic-rangeproteinuria without HIVAN, common diagnoses included clas-sic FSGS, membranoproliferative glomerulonephritis, amyloidA amyloidosis, diabetic nephropathy and other diagnoses [43].Measurable viremia is a typical feature of HIVAN presentationand the diagnosis of HIVAN has been shown to be unlikely ifthe HIV-1 RNA level is less than 400 copies/ml [44]. By con-trast, those with HIV viral load of at least 400 copies/ml, werediagnosed with HIVAN in only 37% (23 out of 63) of cases.Similarly, kidney size on ultrasound has not been found to pre-dict HIVAN [42]. However, patients with HIVAN have a signif-icantly increased renal echogenicity in comparison with HIV-1infected individuals with other renal diseases at the time ofrenal biopsy [42]. A normal or low level of renal echogenicityargues against the diagnosis of HIVAN. In the study by Ber-liner et al. [39], the risk of HIVAN was significantly decreased asCD4 counts rose to between 200 and 500 cells/mm3 (oddsratio [OR]: 0.09; 95% confidence interval [CI]: 0.02–0.32;p = 0.001) and then to more than 500 cells/mm3 (OR: 0.06;95% CI: 0.01–0.60). Higher estimated glomerular filtrationrate (eGFR) was also a negative predictor of HIVAN(OR: 0.93; 95% CI: 0.90–0.97; p = 0.001). In summary, clini-cal criteria may be useful in excluding, rather than establishing,

the diagnosis of HIVAN. The disorder is unlikely in the settingof low-grade proteinuria, suppressed viral load and low-level ornormal echogencity on ultrasound.

Differential diagnosisThere are myriad of glomerular diseases with clinical presenta-tions that resemble HIVAN but that differ from HIVAN interms of management approach and prognosis. Other glomeru-lar diseases that have been described in HIV-1-infected individ-uals are shown in BOX 1. Therefore, although kidney biopsy car-ries a small risk, the benefit of definitive diagnosis of HIVANoutweighs such a risk.

Management

If left untreated, HIVAN almost uniformly progresses to ESRDwithin weeks to months. However, there have not been anyrandomized, controlled trials evaluating any type of therapy forthe management of HIVAN. Several retrospective analyses haveexamined the clinical benefit of various therapies, including theuse of steroids, inhibition of the renin–angiotensin–aldosteronesystem, and HAART.

CorticosteroidsThe scientific rationale for considering the use of corticoster-oids in individuals with HIVAN is the significant tubulo-interstitial inflammation present on histological examination ofthe renal tissue in these individuals. In vitro microarray datahave demonstrated upregulation of many of the proinflamma-tory genes in renal tubular cells of individuals with HIVANproviding a potential role for proinflammatory mediators in thedevelopment of tubulointerstitial disease [45]. The markedreductions in interstitial inflammatory cells after treatmentwith corticosteroids provide more support for the use of corti-costeroids in this population [46]. However, there are no long-term studies examining the efficacy of corticosteroids onHIVAN, and the benefit of corticosteroids has only been dem-onstrated in retrospective, nonrandomized and short-termstudies [47,48]. Interestingly, there appears to be a glomerulareffect, evidenced by a reduction in proteinuria with this treat-ment [48]. Due to the aggressiveness of HIVAN and, therefore,the need for rapid intervention in order to attenuate disease, werecommend a limited course of corticosteroid therapy inselected patients who have biopsy-proven HIVAN. This courseof corticosteroid should only be considered as long as there issimultaneous use of HAART (see later) as the effects of steroidsare not likely to be sustained in the absence of a more definitivetherapy. Based on doses used in published studies [46,47], a start-ing dose of prednisone 1 mg/kg/day (up to a maximum of60 mg) with a taper over 2 months is our standard practice.The use of steroids in the treatment of Pneumocystis cariniipneumonia, although at lower doses and for a shorter durationthan was used for HIVAN, does not appear to be associatedwith significant risk, even in advanced HIV disease [49,50].

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Inhibition of the renin–angiotensin–aldosterone system The support for the use of angiotensin-converting enzymeinhibitors and angiotensin receptor blockers in this popula-tion is primarily driven by the benefit of these agents in otherkidney diseases. There are very limited data on the efficacy ofthese agents in HIV-1-infected patients with HIVAN andmost of the evidence is derived from small, nonrandomizedstudies [51–54].

HAARTThe rationale for using HAART is based on the potential directrole of HIV-1 in the development of HIVAN. This is also sup-ported by response to HAART in cases with HIVAN andrelapse of disease with cessation of therapy [33,35]. Furthermore,the benefit of HAART was recently examined in a retrospectivecohort [34]. In this study, the use of antiretroviral therapyshowed renal survival benefit in 26 patients treated withantiretroviral therapy in comparison to ten patients who did

not receive antiretroviral therapy. Median renal survival was sig-nificantly improved for the treated group compared with theuntreated group (18.4 vs 3.9 months, respectively).

Renal replacement therapyIn general, initial reports suggested a dismal prognosis forHIV-1-infected individuals undergoing maintenancedialysis [55,56]. Using the United States Renal Data System,Abbott et al. reported poor survival in individuals withHIVAN who were dependent on hemodialysis between Janu-ary 1992 and June 1997 [11]. The 2-year all-cause unadjustedsurvival was 36% compared with 64% for all other patientswith ESRD [11]. During the HAART era, there have beenreports of improved survival among HIV-1-infected individualsundergoing maintenance dialysis [57,58]. However, inresource-limited areas, where HAART is not universally utilized,improvement of survival has not yet been demonstrated [41]. Fur-thermore, survival among those HIV-1 individuals undergoingmaintenance dialysis remains significantly lower than forpatients not infected with HIV-1 undergoing maintenance dialy-sis [57]. In resource-limited urban areas, the 1- and 2-year survivalfigures during the HAART era were 63 and 43%, respectively [41],which is significantly lower than the reported 80 and 68%,respectively, in non-HIV-1-infected African–Americans thatwere undergoing dialysis [59].

Kidney transplantationIn the pre-HAART era, HIV-1 infection was an absolutecontraindication for organ transplantation in the majority ofmedical centers in the USA. Currently however, improvementin the overall survival rate of HIV-infected individuals hasresulted in organ transplantation emerging as a potential thera-peutic option for those with end-organ failure. HIV-1-infectedindividuals with ESRD are considered renal transplant candi-dates if their CD4 count is at least 200 cells/mm3 and HIV-1is undetectable. Given the absence of long-term data regardingthe complexity of HAART regimens, and frequent drug inter-actions with immunosuppressive medications, a multisitestudy sponsored by the University of California, San Francisco

Box 1. Differential diagnosis of HIV-associated nephropathy.

• Classic focal segmental glomerulosclerosis

• Diabetic nephropathy

• Membranous nephropathy (e.g., primary; associated with hepatitis B infection and syphilis)

• Membranoproliferative glomerulonephritis (associated with hepatitis C infection and mixed cryoglobulinuria)

• Postinfectious glomerulonephritis

• Rapidly progressive glomerulonephritis form antineutrophil cytoplasmic antibody-related glomerulonephritis, lupus nephritis or antiglomerular basement membrane disease

• IgA nephropathy

• HIV-1-associated immune complex disease (e.g., ‘lupus-like’, IgA, membranoproliferative glomerulonephritis or nonspecific)

• Minimal change nephropathy (primary or secondary; most often NSAIDs)

• Thrombotic microangiopathy (HIV associated or other)

• Renal amyloidosis (primary or secondary)

Key issues

• HIV-associated nephropathy (HIVAN) is the most aggressive kidney disease in HIV-1-infected patients.

• HIVAN almost exclusively affects uncontrolled HIV-1-infected individuals of African descent.

• HIVAN presents with rapid decline in renal function, often with high-grade proteinuria.

• HIVAN is a collapsing form of focal segmental glomerulosclerosis with significant tubulointerstitial injury and microcystic tubular dilation.

• Only renal biopsy is diagnostic and should be performed whenever feasible since no one clinical criterion, including nephrotic range proteinuria or kidney size by ultrasound, has a good predictive value in the diagnosis of HIVAN.

• Treatment with highly active antiretroviral therapy has been shown to reduce development of HIVAN by 60% and slow progression to end-stage renal disease by 38% in those with HIVAN. Short-term corticosteroids may also be of benefit.

• Adjunctive therapy with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers should also be considered.

• Response to therapy requires prompt diagnosis since, in light of the aggressiveness of the disorder, immediate therapy is likely to result in a better outcome.

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(CA, USA) and supported by the NIH, has been launched inthe USA to explore safety and efficacy of solid organ transplan-tation in HIV-1-infected individuals with end-organ damage.This nationally coordinated effort will ultimately providemuch needed data on graft survival, drug interactions, optimalimmunosuppressive therapy and potential complications inthis population. It will also provide the basis for future devel-opment of clinical practice guidelines in managing transplantrecipients with HIV-1 infection.

Expert commentary

The lack of epidemiological data on the scope of earlier stagesof HIVAN deters the development of an early identificationmethod for the syndrome and also the design of a risk stratifica-tion model that may guide the assessment of different interven-tion modalities. Furthermore, clinical evaluation is also neededto determine whether response to HAART regimens is classspecific. If HIVAN is driven by viral replication, one may arguethat antiretroviral regimens with maximal and rapid suppres-sion of viral replication, as well as a maximal dose-responsecurve slope, would be the most effective in treating HIVAN.Since podocyte injury and proliferation are features of HIVAN,these pathogenic mechanisms may provide another therapeutictarget. Cyclin-dependent kinase inhibitors, which inhibit cellcycle processes [60], and all-transretinoic acid, which inhibitsproliferation via cell cycle arrest at G1 and also restores the

expression of podocyte differentiation markers in HIV-1-infected podocytes [61], may prove to have a potential role as anadjunctive therapy for HIVAN.

Five-year view

In Western countries, the introduction of HAART (whichbecame the standard of care in 1996) resulted in the substan-tial declines of both morbidity and mortality directly linkedto complications of HIV-1 infection. As a result, the spectrumof kidney diseases encountered in HIV-1-infected individualshas changed where both incidence and prevalence of HIVANhave declined in the HAART era [6,39,62]. Currently, this pop-ulation is faced with accelerated rates of chronic diseases thatafflict the general population, including diabetes mellitus,hypertension, dyslipidemia and cardiovascular, liver andchronic kidney disease.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvementwith any organization or entity with a financial interest in orfinancial conflict with the subject matter or materials discussed in themanuscript. This includes employment, consultancies, honoraria, stockownership or options, expert testimony, grants or patents received orpending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Affiliations

• Mohamed G Atta, MD, MPH1830 E. Monument Street, Suite 416, Baltimore, MD 21287, USATel.: +1 410 955 5268Fax: +1 410 955 0485matta1@jhmi.edu

• Gregory M LucasDepartment of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA

• Derek M FineDepartment of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD, USA