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Review

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HIV-associated nephropathy:
epidemiology, pathogenesis,
diagnosis and management
Expert Rev. Anti Infect. Ther. 6(3), 365371 (2008)

Mohamed G Atta, HIV-associated nephropathy (HIVAN) is the most well-known and aggressive kidney disease in
Gregory M Lucas HIV-1-infected patients. A variant of focal segmental glomerulosclerosis, it is characterized by
and Derek M Fine the collapse of the glomerular tuft with podocyte hypertrophy/hyperplasia and foot process
effacement, often with concurrent tubular microcystic dilation and tubulointerstitial nephritis.
Author for correspondence
The disease has been intimately linked to the direct effect of HIV-1 on the kidney. It affects
1830 E. Monument Street,
Suite 416, Baltimore, patients of African descent exclusively and is manifested by an acute decline in kidney function,
MD 21287, USA most often in conjunction with high-grade proteinuria and uncontrolled HIV-1 infection. With
Tel.: +1 410 955 5268 the widespread use of highly active antiretroviral therapy (HAART), its prevalence is declining in
Fax: +1 410 955 0485 Western countries. However, the epidemiology of the disease is not well defined in the poorest
matta1@jhmi.edu areas of the world, which bear a disproportionate share of the HIV-1 epidemic burden. Scientific
evidence suggests that HAART can prevent the development of HIVAN. Furthermore, HAART,
corticosteroids and inhibition of the reninangiotensin axis are potentially helpful in delaying
disease 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

mode of HIV acquisition or presence of other


Epidemiology comorbidities. In the USA, the incidence of
Originally named AIDS nephropathy, HIV-asso- HIVAN peaked in the mid-1990s and
ciated nephropathy (HIVAN) was first described remained stable after an initial decline [20].
in 1984 [13]. Although HIVAN has been This decline can be attributed to the introduc-
described in early HIV infection [4], late-stage dis- tion of HAART in 1996. However, as survival
ease and advanced immunosuppression are improves, prevalence of HIV-1 individuals is
strongly associated with HIVAN incidence [5,6]. likely to increase, as is the prevalence of indi-
In the USA and Western Europe, the prevalence viduals with kidney disease, usually of non-
of HIVAN is driven by host factors and both HIVAN variety [21]. In the poorest areas in the
the availability and use of highly active antiret- world, such as sub-Saharan Africa and parts of
roviral therapy (HAART). As an exclusive disor- Asia, which bear a disproportionate share of
der of individuals of African descent [713], prev- the HIV-1 epidemic burden, there is a paucity
alence of HIVAN leading to end-stage renal of data regarding the epidemiology of HIVAN
disease (ESRD) in this segment of the popula- in individuals with HIV-1 infection. One
tion has ranged from 3 to 12%. For example, cross-sectional study from South Africa sug-
the prevalence of HIVAN was 12% among gested that HIVAN is the most common dis-
AfricanAmericans in a large autopsy series of ease in patients with proteinuria and HIV-1
HIV-infected individuals who died in the Texas infection [22].
Department of Criminal Justice System [14].
HIVAN is a rare entity in HIV-1-infected pop-
ulations that are predominantly white [1517] Pathogenesis
and its predilection to black race has also been Role of HIV-1
reported in Europe [18,19]. Other than racial dif- Although HIVAN has been described as part
ferences, there is no compelling evidence for of an acute HIV-1 seroconversion, as well as in
another associated risk factors, such as gender, a patient with well-controlled HIV-1 infection

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


Review Atta, Lucas & Fine

on HAART [4,23,24], it is typically a late manifestation of HIV


Table 1. Baseline characteristics of 53 patients with
infection, associated with low CD4 cell counts and high viral
HIV-associated nephropathy.
loads. This suggests a direct role of the virus in the pathogen-
esis of the syndrome. Several HIV-1 gene products have been Characteristic Value
shown to trigger histological renal changes in different HIV-1 Mean age (years) 40.8 (range: 2663)
transgenic models, similar to those observed in human
HIVAN [2528]. In addition, HIV-1 replication within renal Men (n) 32 (60.4%)
cells has been demonstrated in biopsy tissue from HIV-1- AfricanAmerican origin (n) 52 (98.1%)
infected individuals with HIVAN [4,29,30]. Furthermore,
Hypertension (n) 30 (56.6%)
HIV-1 has been detected in renal epithelial cells and podo-
cytes in patients with HIVAN [4,29]. This may, in part, explain Diabetes mellitus (n) 4 (7.6%)
the dysregulated podocytes cell cycle that has been described Hepatitis B (n) 3 (6%)
in association with HIVAN [31]. Immunohistochemistery
Hepatitis C (n) 30 (58.8%)
studies have revealed the upregulation of markers of prolifera-
tion and downregulation of markers of differentiation in the Injection drug user (n) 31 (59.6%)
podocytes [32]. Mean proteinuria (g/day) 8.0 (range: 0.1842)
The direct role of the virus in the disease is also supported by
the beneficial impact of HAART in the prevention and treatment Range of proteinuria (g/day)
<1.0 4 (7.8%)
of the disease [6,33,34]. Further support is provided by the observa- 1.03.5 12 (23.5%)
tion that relapse of HIVAN can occur with the discontinuation >3.5 35 (68.6%)
of HAART [35]. Mean serum creatinine (mg/dl) 6.57

Host factors Mean estimated glomerular filtration rate 15.0


(ml/min/1.73 m2)
Despite the evidence implicating a direct role of HIV-1
pathogenesis of HIVAN, the mechanism by which HIV-1 Estimated glomerular filtration rate
(ml/min/1.73 m2)
enters renal cells has not yet been elucidated. Normal renal 90 0 (0%)
epithelial cells lack the chemokine receptors CCR5 and 6089 1 (1.9%)
CXCR4, which serve as cellular receptors in conjunction 3059 6 (11.3%)
1529 9 (17.0%)
with CD4 for HIV-1 entry and infection of target cells. In 014 37 (69.8%)
addition, the mechanisms underlying disease susceptibility
and progression remain unknown. Since only a subset of CD4 count (cells/mm3)
<200 39 (73.6%)
patients with HIV-1 infection develop HIVAN, despite the 200500 13 (24.5%)
presence of HIV-1 DNA in those with and without kidney >500 1 (1.9%)
disease [29], additional host factors, such as responses to dif- Mean HIV-1 viral load (copies/ml) 166.73
ferent HIV-1 proteins, are likely to play an important role in
Adapted from [39].
initiating the disease process. In a historic cohort in the USA,
HIVAN had the strongest association with black race of all
causes of renal failure among patients who were on mainte- HIVAN [39]. In the one study from South Africa, seven out of
nance dialysis [11]. The exclusiveness of the disorder to indi- 90 (8%) HIV-infected patients without known renal disease
viduals of African descent suggests the existence of genetic were found to have persistent microalbuminuria, and six out of
factors. This is further supported by the familial clustering of the seven who had kidney biopsies were found to have
kidney disease among family members of AfricanAmerican HIVAN [22]. This study raises the question of whether HIVAN
individuals diagnosed with HIVAN [36]. Although a genetic may have an indolent preclinical phase where only mild abnor-
susceptibility locus has been identified in a Tg26 mouse malities are present that would not generally lead to biopsy.
model [37], to date, no genetic association has been identified However, as this indolent presentation has not yet been
in humans with HIVAN. described, additional corroborating evidence is needed. Lower
extremity edema and hypertension are uncommon in patients
with HIVAN and their absence may contribute to delayed diag-
Clinical presentation nosis [38]. Urinalysis shows bland sediment with varying num-
HIVAN typically presents with rapid decline in renal function, bers of proteinaceous casts and renal tubular epithelial cells [38].
often with high-grade proteinuria. The proteinuria is typically As described previously, the histopathological findings are of a
in the nephrotic range (>3 g/24 h), with serum creatinine levels collapsing form of focal segmental glomerulosclerosis (FSGS),
above 2 mg/dl and progressive kidney failure [38,39]. TABLE 1 lists with significant tubulointerstitial injury and microcystic tubular
the clinical presentation of 53 patients with biopsy-proven dilation [40]. Recognizing this histopathology is extremely

366 Expert Rev. Anti Infect. Ther. 6(3), (2008)


HIV-associated nephropathy Review

important as the clinical presentation of HIVAN may be mim- the diagnosis of HIVAN. The disorder is unlikely in the setting
icked by other glomerular diseases, with potentially significantly of low-grade proteinuria, suppressed viral load and low-level or
different treatment options and prognoses. normal echogencity on ultrasound.
The natural history of HIVAN without antiretroviral ther-
apy is an ominous one. When first reported in 1984 [3], Differential diagnosis
HIV-1-infected individuals presented with nephrotic-range There are myriad of glomerular diseases with clinical presenta-
proteinuria and progression to ESRD occurred within tions that resemble HIVAN but that differ from HIVAN in
816 weeks. Mortality in these patients approached 100% terms of management approach and prognosis. Other glomeru-
within 6 months of diagnosis. In the HAART era, prognosis lar diseases that have been described in HIV-1-infected individ-
remains poor in these patients compared with other kidney uals are shown in BOX 1. Therefore, although kidney biopsy car-
diseases in HIV-1-infected patients. In a recent, observational ries a small risk, the benefit of definitive diagnosis of HIVAN
study by Berliner et al. of HIV-1-infected patients who under- outweighs such a risk.
went kidney biopsy, HIVAN patients were more likely to ulti-
mately require hemodialysis (p < 0.0001) and had significantly
worse survival compared with patients without HIVAN Management
(p = 0.02) [39]. However, patients with HIVAN that were If left untreated, HIVAN almost uniformly progresses to ESRD
treated with HAART had significantly better renal survival within weeks to months. However, there have not been any
compared with untreated individuals [41]. randomized, controlled trials evaluating any type of therapy for
the management of HIVAN. Several retrospective analyses have
examined the clinical benefit of various therapies, including the
Diagnosis use of steroids, inhibition of the reninangiotensinaldosterone
Diagnosis of HIVAN requires a kidney biopsy, which should be system, and HAART.
performed promptly whenever possible and when the proce-
dure is not contraindicated. It is often difficult to distinguish Corticosteroids
HIVAN from other kidney lesions on clinical grounds alone. The scientific rationale for considering the use of corticoster-
Identifying valid, surrogate, noninvasive measures in the diag- oids in individuals with HIVAN is the significant tubulo-
nosis of HIVAN has been disappointing [42,43]. For example, interstitial inflammation present on histological examination of
nephrotic-range proteinuria, even in the presence of a low CD4 the renal tissue in these individuals. In vitro microarray data
cell count, does not reliably predict HIVAN [43]. HIVAN was have demonstrated upregulation of many of the proinflamma-
diagnosed in only 53% of 55 patients with nephrotic-range tory genes in renal tubular cells of individuals with HIVAN
proteinuria, with a sensitivity of only 73% and a positive pre- providing a potential role for proinflammatory mediators in the
dictive value of 53% [43]. In individuals with nephrotic-range development of tubulointerstitial disease [45]. The marked
proteinuria without HIVAN, common diagnoses included clas- reductions in interstitial inflammatory cells after treatment
sic FSGS, membranoproliferative glomerulonephritis, amyloid with corticosteroids provide more support for the use of corti-
A amyloidosis, diabetic nephropathy and other diagnoses [43]. costeroids in this population [46]. However, there are no long-
Measurable viremia is a typical feature of HIVAN presentation term studies examining the efficacy of corticosteroids on
and the diagnosis of HIVAN has been shown to be unlikely if HIVAN, and the benefit of corticosteroids has only been dem-
the HIV-1 RNA level is less than 400 copies/ml [44]. By con- onstrated in retrospective, nonrandomized and short-term
trast, those with HIV viral load of at least 400 copies/ml, were studies [47,48]. Interestingly, there appears to be a glomerular
diagnosed with HIVAN in only 37% (23 out of 63) of cases. effect, evidenced by a reduction in proteinuria with this treat-
Similarly, kidney size on ultrasound has not been found to pre- ment [48]. Due to the aggressiveness of HIVAN and, therefore,
dict HIVAN [42]. However, patients with HIVAN have a signif- the need for rapid intervention in order to attenuate disease, we
icantly increased renal echogenicity in comparison with HIV-1 recommend a limited course of corticosteroid therapy in
infected individuals with other renal diseases at the time of selected patients who have biopsy-proven HIVAN. This course
renal biopsy [42]. A normal or low level of renal echogenicity of corticosteroid should only be considered as long as there is
argues against the diagnosis of HIVAN. In the study by Ber- simultaneous use of HAART (see later) as the effects of steroids
liner et al. [39], the risk of HIVAN was significantly decreased as are not likely to be sustained in the absence of a more definitive
CD4 counts rose to between 200 and 500 cells/mm3 (odds therapy. Based on doses used in published studies [46,47], a start-
ratio [OR]: 0.09; 95% confidence interval [CI]: 0.020.32; ing dose of prednisone 1 mg/kg/day (up to a maximum of
p = 0.001) and then to more than 500 cells/mm3 (OR: 0.06; 60 mg) with a taper over 2 months is our standard practice.
95% CI: 0.010.60). Higher estimated glomerular filtration The use of steroids in the treatment of Pneumocystis carinii
rate (eGFR) was also a negative predictor of HIVAN pneumonia, although at lower doses and for a shorter duration
(OR: 0.93; 95% CI: 0.900.97; p = 0.001). In summary, clini- than was used for HIVAN, does not appear to be associated
cal criteria may be useful in excluding, rather than establishing, with significant risk, even in advanced HIV disease [49,50].

www.expert-reviews.com 367
Review Atta, Lucas & Fine

not receive antiretroviral therapy. Median renal survival was sig-


Box 1. Differential diagnosis of
nificantly improved for the treated group compared with the
HIV-associated nephropathy.
untreated group (18.4 vs 3.9 months, respectively).
Classic focal segmental glomerulosclerosis
Diabetic nephropathy Renal replacement therapy
Membranous nephropathy (e.g., primary; associated with In general, initial reports suggested a dismal prognosis for
hepatitis B infection and syphilis) HIV-1-infected individuals undergoing maintenance
Membranoproliferative glomerulonephritis (associated with dialysis [55,56]. Using the United States Renal Data System,
hepatitis C infection and mixed cryoglobulinuria) Abbott et al. reported poor survival in individuals with
Postinfectious glomerulonephritis HIVAN who were dependent on hemodialysis between Janu-
Rapidly progressive glomerulonephritis form antineutrophil ary 1992 and June 1997 [11]. The 2-year all-cause unadjusted
cytoplasmic antibody-related glomerulonephritis, lupus survival was 36% compared with 64% for all other patients
nephritis or antiglomerular basement membrane disease with ESRD [11]. During the HAART era, there have been
IgA nephropathy reports of improved survival among HIV-1-infected individuals
HIV-1-associated immune complex disease (e.g., lupus-like, undergoing maintenance dialysis [57,58]. However, in
IgA, membranoproliferative glomerulonephritis or nonspecific) resource-limited areas, where HAART is not universally utilized,
Minimal change nephropathy (primary or secondary; most often improvement of survival has not yet been demonstrated [41]. Fur-
NSAIDs) thermore, survival among those HIV-1 individuals undergoing
Thrombotic microangiopathy (HIV associated or other) maintenance dialysis remains significantly lower than for
Renal amyloidosis (primary or secondary) patients not infected with HIV-1 undergoing maintenance dialy-
sis [57]. In resource-limited urban areas, the 1- and 2-year survival
Inhibition of the reninangiotensinaldosterone system figures during the HAART era were 63 and 43%, respectively [41],
The support for the use of angiotensin-converting enzyme which is significantly lower than the reported 80 and 68%,
inhibitors and angiotensin receptor blockers in this popula- respectively, in non-HIV-1-infected AfricanAmericans that
tion is primarily driven by the benefit of these agents in other were undergoing dialysis [59].
kidney diseases. There are very limited data on the efficacy of
these agents in HIV-1-infected patients with HIVAN and Kidney transplantation
most of the evidence is derived from small, nonrandomized In the pre-HAART era, HIV-1 infection was an absolute
studies [5154]. contraindication for organ transplantation in the majority of
medical centers in the USA. Currently however, improvement
HAART in the overall survival rate of HIV-infected individuals has
The rationale for using HAART is based on the potential direct resulted in organ transplantation emerging as a potential thera-
role of HIV-1 in the development of HIVAN. This is also sup- peutic option for those with end-organ failure. HIV-1-infected
ported by response to HAART in cases with HIVAN and individuals with ESRD are considered renal transplant candi-
relapse of disease with cessation of therapy [33,35]. Furthermore, dates if their CD4 count is at least 200 cells/mm 3 and HIV-1
the benefit of HAART was recently examined in a retrospective is undetectable. Given the absence of long-term data regarding
cohort [34]. In this study, the use of antiretroviral therapy the complexity of HAART regimens, and frequent drug inter-
showed renal survival benefit in 26 patients treated with actions with immunosuppressive medications, a multisite
antiretroviral therapy in comparison to ten patients who did study sponsored by the University of California, San Francisco

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.

368 Expert Rev. Anti Infect. Ther. 6(3), (2008)


HIV-associated nephropathy Review

(CA, USA) and supported by the NIH, has been launched in expression of podocyte differentiation markers in HIV-1-
the USA to explore safety and efficacy of solid organ transplan- infected podocytes [61], may prove to have a potential role as an
tation in HIV-1-infected individuals with end-organ damage. adjunctive therapy for HIVAN.
This nationally coordinated effort will ultimately provide
much needed data on graft survival, drug interactions, optimal
immunosuppressive therapy and potential complications in Five-year view
this population. It will also provide the basis for future devel- In Western countries, the introduction of HAART (which
opment of clinical practice guidelines in managing transplant became the standard of care in 1996) resulted in the substan-
recipients with HIV-1 infection. tial declines of both morbidity and mortality directly linked
to complications of HIV-1 infection. As a result, the spectrum
of kidney diseases encountered in HIV-1-infected individuals
Expert commentary has changed where both incidence and prevalence of HIVAN
The lack of epidemiological data on the scope of earlier stages have declined in the HAART era [6,39,62]. Currently, this pop-
of HIVAN deters the development of an early identification ulation is faced with accelerated rates of chronic diseases that
method for the syndrome and also the design of a risk stratifica- afflict the general population, including diabetes mellitus,
tion model that may guide the assessment of different interven- hypertension, dyslipidemia and cardiovascular, liver and
tion modalities. Furthermore, clinical evaluation is also needed chronic kidney disease.
to determine whether response to HAART regimens is class
specific. If HIVAN is driven by viral replication, one may argue
that antiretroviral regimens with maximal and rapid suppres- Financial & competing interests disclosure
sion of viral replication, as well as a maximal dose-response The authors have no relevant affiliations or financial involvement
curve slope, would be the most effective in treating HIVAN. with any organization or entity with a financial interest in or
Since podocyte injury and proliferation are features of HIVAN, financial conflict with the subject matter or materials discussed in the
these pathogenic mechanisms may provide another therapeutic manuscript. This includes employment, consultancies, honoraria, stock
target. Cyclin-dependent kinase inhibitors, which inhibit cell ownership or options, expert testimony, grants or patents received or
cycle processes [60], and all-transretinoic acid, which inhibits pending, or royalties.
proliferation via cell cycle arrest at G1 and also restores the No writing assistance was utilized in the production of this manuscript.
7 Carbone L, DAgati V, Cheng JT, Appel GB. 12 Kopp JB, Winkler C. HIV-associated
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