Authors: Christina M Wyatt, MD, Paul E Klotman, MD

Section Editor: Richard J Glassock, MD, MACP

Deputy Editor: Albert Q Lam, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2019. | This topic last updated: May 24, 2019.

INTRODUCTION

Human immunodeficiency virus (HIV) infection has been associated with both acute kidney
injury (AKI) and chronic kidney disease (CKD). (See "Overview of kidney disease in HIV-
positive patients".)

HIVAN, the classic kidney disease associated with HIV infection, was first described in
1984 as a complication of acquired immune deficiency syndrome (AIDS) [1-3], although
HIVAN may also occur in patients with less advanced HIV infection or following acute
seroconversion [4,5]. Histologically, HIVAN is a collapsing form of focal segmental
glomerulosclerosis (FSGS) (picture 1), accompanied by microcystic tubular dilatation and
interstitial inflammation [6].

Issues related to HIVAN will be discussed in this topic. An overview of kidney disease in
patients with HIV infection and discussions of electrolyte abnormalities, dialysis, and
transplantation in HIV-positive patients are provided elsewhere:

● (See "Overview of kidney disease in HIV-positive patients".)

● (See "Electrolyte disturbances with HIV infection".)

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 ● (See "Human immunodeficiency virus and dialysis".)

● (See "Kidney transplantation in HIV-infected individuals".)

PATHOGENESIS

The pathogenesis of HIV-associated nephropathy (HIVAN) is hypothesized to involve

several factors:

● Infection of kidney epithelial cells by HIV and expression of HIV genes within infected
kidney cells
● Host factors, including genetic susceptibility

Much of our current understanding of the pathogenesis of HIVAN has been derived from
animal models, in particular the Tg26 HIV-1 transgenic mouse model [7]. This transgenic
mouse model expresses a gag/pol-deleted HIV-1 provirus in kidney and develops
proteinuria, renal failure, and histologic findings resembling human HIVAN [7,8]. Following
the reciprocal transplantation of kidneys between transgenic and wild-type mice, kidney
disease develops only in kidneys donated by transgenic animals, suggesting that HIV
gene expression in kidney cells is required for the development of HIVAN [9]. Transgenic
mouse models suggest that certain HIV genes, in particular, Nef and Vpr, are specifically
involved in the pathogenesis of HIVAN [10-13].

HIV directly infects glomerular and renal tubular epithelial cells in humans with HIVAN
[14,15]. In addition, in vitro experiments have shown that HIV transgene expression
induces dedifferentiation and proliferation of glomerular epithelial cells and impairs
cytokinesis in tubular epithelial cells.

The strong association between HIVAN and black race indicates that host genetic factors
are also important. Human genetic studies have identified single-nucleotide
polymorphisms in the APOL1 gene (on chromosome 22) that are strongly linked to
increased risk of HIVAN as well as idiopathic focal segmental glomerulosclerosis (FSGS)
[16-20]. However, these variants, which are present almost exclusively in individuals of

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 West African descent, do not appear to be associated with the severity of disease among
those with biopsy-proven HIVAN [21]. The mechanism through which variants in APOL1
promote HIVAN pathogenesis is not known. (See "Epidemiology of chronic kidney
disease", section on 'APOL1 in African Americans' and "Focal segmental
glomerulosclerosis: Genetic causes", section on 'FSGS in African Americans'.)

Several other genes have been identified based upon differential expression in HIVAN,
although their role in pathogenesis has not been elucidated [22,23]. Breeding the Tg26
transgenic mouse onto different genetic backgrounds resulted in varying severity of kidney
disease. Genetic studies in this model resulted in the identification of a susceptibility locus
on chromosome 3, a genetic region that has been linked to other kidney diseases [24].

EPIDEMIOLOGY

HIVAN displays a striking racial predilection for individuals of African descent and is more
closely associated with black race than any other cause of end-stage renal disease
(ESRD) except sickle cell nephropathy [25]. In studies of adult and pediatric patients with
HIVAN, 96 to 100 percent were of African descent [26-29]. According to data from the
United States Renal Data System (USRDS), more than 85 percent of new ESRD cases
attributed to HIVAN occur in African Americans [30].

The introduction of combination antiretroviral therapy (ART) has reduced the incidence of
ESRD attributed to HIVAN [30]. In a large urban cohort study, for example, the incidence of
clinical or biopsy-proven HIVAN declined following the introduction of ART [31]. A large
series of kidney biopsies from the same urban HIV population demonstrated that, between
1995 and 2004, the proportion of biopsies revealing HIVAN declined from approximately
80 percent in 1997 to less than 30 percent in 2004 [32]. Data from the United States Renal
Data System (USRDS) demonstrate a plateau in the annual incidence of ESRD attributed
to HIVAN after 1995, with evidence of further decline in subsequent years [30]. Survival of
patients with ESRD attributed to HIVAN has also improved, although it remains lower than
that of patients with ESRD from other causes [30].

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 CLINICAL MANIFESTATIONS

In patients with HIVAN, the following features are usually present:

● Advanced HIV disease – In a study of 57 patients with proven HIVAN, approximately

half of whom were taking antiretroviral therapy (ART), the mean HIV viral load was
greater than 30,000 copies/mL, and the mean CD4 cell count was 127 cells/mm3 (64
percent had a CD4 count less than 200 cells/mm3) [28]. In two other studies, 81 and
90 percent of patients who presented with HIVAN had CD4 positive T-cell counts less
than 200 cells/mm3 [26,27]. It is apparent from these studies that HIVAN can present
in patients with less advanced HIV infection. In addition, HIVAN has been reported in
patients with acute HIV infection [4,5].

● Heavy proteinuria – In a study of 71 children with HIVAN, 72 percent had nephrotic-

range proteinuria at the time of presentation [29]. Studies in adults had similar findings
[26-28]. Among 57 patients with HIVAN, for example, mean proteinuria was 4.1 g/day,
and only 14 percent of patients had proteinuria less than 1.5 g/day [28]. However,
patients with HIVAN may have substantially less proteinuria early during the course of
their disease. As an example, a study from South Africa found early HIVAN in six of
seven ART-naïve patients who had persistent moderately increased albuminuria
(formerly called "microalbuminuria"); such patients would rarely undergo kidney biopsy
in routine clinical practice [33]. These findings suggest that HIVAN should also be
considered in patients with lesser degrees of proteinuria.

● Rapid decline in kidney function – At the time of HIVAN diagnosis, adult patients
often have severely reduced kidney function, which is attributed to the rapidly
progressive course. In two studies of adults with HIVAN, the mean estimated
glomerular filtration rates (eGFR) at the time of HIVAN diagnosis were, respectively,
10 and 20 mL/min per 1.73 m2 [27,28]. Children may not have similarly severe kidney
dysfunction at the time of presentation, although this may be a result of ascertainment
bias rather than a true difference in the disease course. Among 71 South African
children diagnosed with HIVAN, for example, only one-third had an eGFR less than 60

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 mL/min per 1.73 m2 [29].

Other manifestations, such as hematuria, hypertension, and edema, may also be present,
although the frequency of hypertension and edema are lower than may be expected in
patients with severe proteinuria and decreased eGFR. In three studies of adult and
pediatric patients with HIVAN, the following characteristics were observed [27-29]:

● Hematuria (45 to 75 percent)

● Hypertension (12 to 26 percent)
● Edema (22 to 59 percent)

DIAGNOSIS

In a patient suspected of having HIVAN based upon clinical manifestations, the diagnosis
must be established by a kidney biopsy as patients suspected of having HIVAN on clinical
grounds often have an alternative histologic diagnosis [34].

Histology — HIVAN is characterized by the collapsing form of focal segmental

glomerulosclerosis (FSGS) (picture 1). (See "Focal segmental glomerulosclerosis:
Epidemiology, classification, clinical features, and diagnosis", section on 'Collapsing
variant'.)

In addition to collapsing FSGS, HIVAN is typically characterized by dilated tubules and

significant interstitial inflammation. Tubuloreticular inclusions may also be identified on
electron microscopy (picture 2) [6,25]. While this unique histologic pattern was initially
considered pathognomonic for HIVAN, virtually indistinguishable findings have been
reported in patients treated with bisphosphonates and interferon. (See "Collapsing focal
segmental glomerulosclerosis not associated with HIV infection", section on
'Bisphosphonates and other drugs'.)

The glomerular lesion of HIVAN is also characterized by dedifferentiation and proliferation

of glomerular epithelial cells, which are typically considered terminally differentiated cells,
resulting in pseudocrescent formation. Dedifferentiation can be demonstrated by loss of

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 maturity markers such as synaptopodin and expression of the cell-cycle protein Ki-67 in
glomerular epithelial cells from animal models and patients with HIVAN [35].

Differential diagnosis — As noted above, patients suspected of having HIVAN based

upon the clinical presentation may actually have a different histologic diagnosis. As an
example, in a study of 107 HIV-positive African-American patients with proteinuria greater
than 3 g/day, kidney biopsy revealed the following [36]:

● HIVAN (56 percent)

● Classic FSGS (21 percent)
● Membranoproliferative glomerulonephritis (6 percent)
● Amyloidosis (4 percent)
● Diabetic nephropathy (4 percent)
● Lupus-like immune complex glomerulonephritis (4 percent)
● Other (5 percent)

In a series of 152 kidney biopsies performed in HIV-positive adults at the same urban
center between 1995 and 2004, the proportion of kidney biopsies demonstrating HIVAN
declined over time [32]. Overall, HIVAN accounted for only 35 percent of biopsies; other
common diagnoses included non-collapsing FSGS (22 percent of biopsies) and a variety
of immune complex glomerular diseases. In an updated biopsy series from the same
center, both HIVAN and HIV immune complex kidney disease (HIVICK) occurred
predominantly in African Americans with advanced HIV disease [37], and the addition of
APOL1 genotype to clinical data did not significantly improve the prediction of HIVAN [38].

These and other studies illustrate the importance of obtaining a kidney biopsy to confirm a
suspected diagnosis of HIVAN and exclude alternative diagnoses. The differential
diagnosis in HIV-positive patients who present with proteinuria and decreased glomerular
filtration rate (GFR) includes HIVAN and also the following:

● Non-collapsing FSGS. The roles of HIV infection and antiretroviral therapy (ART) in
the pathogenesis and treatment, respectively, of non-collapsing FSGS are not known.

● Immune complex-mediated glomerulonephritis, including IgA nephropathy,

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 membranous nephropathy, membranoproliferative glomerulonephritis, and a "lupus-
like" proliferative glomerulonephritis. (See "Overview of kidney disease in HIV-positive
patients", section on 'Immune complex mediated glomerulonephritis'.)

● Glomerulonephritis due to co-infection with hepatitis C virus. (See "Overview of kidney

disease in HIV-positive patients", section on 'Glomerulonephritis due to hepatitis C
virus coinfection'.)

● Amyloidosis, diabetic nephropathy, or other noninfectious glomerulopathies. With

aging of the HIV-positive patient population, comorbid kidney disease due to
traditional chronic kidney disease (CKD) risk factors is increasingly important. (See
"Overview of kidney disease in HIV-positive patients".)

TREATMENT AND FOLLOW-UP

Overview of medical therapy — Treatments that have been examined for patients with
HIVAN include antiretroviral therapy (ART); inhibitors of the renin-angiotensin system, such
as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers
(ARBs); and glucocorticoids. Our recommendations and suggestions pertaining to these
potential therapies are as follows:

● In patients diagnosed with HIVAN who are not already receiving ART, we recommend
initiation of ART, in accordance with the United States Department of Health and
Human Services (HHS) Guidelines for Antiviral Agents in HIV-Infected Adults and
Adolescents.

● In proteinuric and/or hypertensive patients with HIVAN, we suggest therapy with either
an ACE inhibitor or ARB.

● In patients with HIVAN, we suggest not routinely treating with glucocorticoids.

However, some experts use a trial of glucocorticoids in patients with progressive
disease despite optimal therapy with ART and renin-angiotensin system inhibition.

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 The rationale for these recommendations and suggestions is presented in the following
sections.

ART and HIVAN — Clinical practice guidelines recommend antiretroviral therapy (ART)
initiation in all HIV-positive individuals, regardless of CD4 cell count. (See "When to initiate
antiretroviral therapy in HIV-infected patients", section on 'Benefits of antiretroviral
therapy'.)

No randomized trials have specifically examined the effect of ART in patients with HIVAN
[39]. Thus, the literature suggesting benefit from ART in HIVAN consists of observational
studies [37,40-42] and case reports of kidney function recovery after initiation of ART
[43,44]. In addition, data from the US Renal Data System (USRDS) suggest a benefit of
ART on the epidemiology of end-stage renal disease (ESRD) attributed to HIVAN.

As an example, the association of ART initiation with kidney disease outcomes was
analyzed in a retrospective cohort of 36 patients with biopsy-proven HIVAN who did not
require dialysis at the time of kidney biopsy; 26 were treated with ART, and 10 received no
ART [41]. Kidney disease outcomes were significantly better among patients treated with
ART:

● Median renal survival was significantly longer among those receiving ART (18.4
versus 3.9 months). However, the mean serum creatinine at baseline was significantly
lower in patients who received ART (4.7 versus 7.8 mg/dL), and the results were not
adjusted for baseline kidney function.

● Among patients treated with ART within three months of biopsy, the risk of needing
dialysis was lower if a complete virological response was achieved, although this was
not significant (62.5 versus 81.1 percent among those with a partial virological
response).

Other retrospective biopsy series have also demonstrated improved kidney disease
outcomes with ART among patients with HIVAN [37,40].

Renin-angiotensin system inhibition — The efficacy and safety of ACE inhibitors and

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 ARBs have been extrapolated from rigorous studies in other glomerular diseases and from
observational studies in patients with HIVAN [40,45-47]. There are no randomized trials of
renin-angiotensin system inhibitors for the treatment of HIVAN.

The following examples illustrate the range of findings in support of treating patients who
have HIVAN with ACE inhibitors or ARBs:

● A short-term study of 11 non-nephrotic and 9 nephrotic patients with biopsy-proven

HIVAN reported more favorable changes in serum creatinine and 24-hour urine
protein excretion among patients treated with fosinopril (10 mg/day) as compared with
untreated patients [47]:

• During approximately six months of follow-up, the creatinine rose from 1.3 to 1.5
mg/dL among treated patients, compared with a creatinine rise from 1 to 4.9
mg/dL among untreated patients.

• During the same interval, the 24-hour protein excretion in patients given fosinopril
changed from 1.6 to 1.2 g/day, compared with an increase from 0.8 to 8.5 g/day
among untreated patients.

● A subsequent study demonstrated significantly longer renal survival for patients

treated with fosinopril as compared with untreated patients, despite similar
characteristics and kidney function at baseline (median renal survival of 480 days for
treated patients versus 146 days for untreated patients) [46].

The appropriate intensity of therapy with ACE inhibitors or ARBs is unknown. Both of the
aforementioned studies employed a fixed, low-dose regimen of fosinopril (10 mg/day). In
the absence of additional data, it is reasonable to adopt the goals for blood pressure and
proteinuria control used in other nondiabetic chronic kidney diseases (CKD). (See
"Antihypertensive therapy and progression of nondiabetic chronic kidney disease in
adults".)

Glucocorticoids — Small, uncontrolled studies have suggested that glucocorticoid

therapy may improve kidney function and reduce proteinuria in patients with HIVAN

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 [48,49], although the biologic mechanism is not clear. These studies were conducted
before or early after the introduction of effective ART, and adverse events were common.
Thus, in the absence of additional data, we suggest not routinely using glucocorticoid
therapy for the treatment of HIVAN. It is reasonable to consider the addition of
glucocorticoids in patients with rapid progression despite optimal therapy with ART and
renin-angiotensin system inhibition.

Routine chronic kidney disease care — Care of patients with HIVAN should be shared
with a nephrologist or someone with expertise in managing patients with kidney disease.

Supportive therapy of HIVAN and other CKD in patients with HIV includes appropriate
medication dose adjustment, enhanced monitoring for medication toxicity, and avoidance
of potentially nephrotoxic medications. (See "Overview of kidney disease in HIV-positive
patients".)

Patients with HIVAN should have routine monitoring and care, including management of
bone mineral metabolism and timely preparation for dialysis or transplantation, similar to
patients with CKD who do not have HIV. The general care of such patients is discussed
elsewhere. (See "Overview of the management of chronic kidney disease in adults".)

Prognosis — The prognosis in patients with HIVAN is poor, even among those treated
with ART. Many such patients will develop ESRD. The following examples illustrate the
range of findings:

● A French study examined the outcomes of 57 patients diagnosed with HIVAN, half of
whom were already taking ART at the time of diagnosis [28]. The other half initiated
ART within one month of the diagnosis of HIVAN. Most patients were also treated with
inhibitors of the renin-angiotensin system. A total of 51 patients were followed for a
median of approximately two years. During that time, 6 patients died, and 30
developed ESRD (71 percent of those followed had one of these two outcomes).
Patients who were already taking ART at the time of HIVAN diagnosis were more
likely to develop ESRD, as were those who developed HIVAN despite complete
virologic suppression.

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 ● A British study followed 31 patients with biopsy-proven HIVAN for a median of four
and a half years; ART was initiated in 29 of the 31 patients within one month of HIVAN
diagnosis [50]. ESRD developed in 15 of these 31 patients (48 percent). Virological
suppression was achieved in approximately 70 percent of patients, with no difference
among patients who did and did not subsequently develop ESRD.

Dialysis and transplantation — Survival rates of HIV-positive patients on dialysis have

improved substantially with the introduction of effective ART, but mortality remains higher
than among HIV-negative dialysis patients [51]. There is no evidence favoring one dialysis
modality over another. Specific issues related to HIV infection in dialysis patients are
discussed separately. (See "Human immunodeficiency virus and dialysis".)

Transplantation is a viable option for patients with HIVAN and ESRD; however, there is a
risk of HIVAN recurrence in the allograft. Patient and graft survival in HIV-positive
transplant recipients appears to be similar to non-HIV-infected, high-risk transplant
recipients. Kidney transplantation in patients with HIV is presented elsewhere. (See
"Kidney transplantation in HIV-infected individuals".)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and

regions around the world are provided separately. (See "Society guideline links:
Glomerular disease in adults".)

SUMMARY AND RECOMMENDATIONS

● The pathogenesis of human immunodeficiency virus (HIV)-associated nephropathy

(HIVAN) is hypothesized to involve direct infection of kidney epithelial cells by HIV with
subsequent expression of HIV genes in a genetically susceptible host. The strong
associations of HIVAN with black race and APOL1 gene polymorphisms illustrate the
importance of host genetic factors. (See 'Pathogenesis' above.)

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 ● HIVAN is more closely associated with black race than any other cause of end-stage
renal disease (ESRD) except sickle cell nephropathy. The introduction of antiretroviral
therapy (ART) has reduced the incidence of ESRD attributed to HIVAN. (See
'Epidemiology' above.)

● In patients with HIVAN, the following features are common (see 'Clinical
manifestations' above):

• Black race
• Advanced HIV disease
• Heavy proteinuria
• Rapid decline in kidney function

● In a patient suspected of having HIVAN based upon clinical manifestations, the

diagnosis should be established by a kidney biopsy as many patients suspected of
having HIVAN on clinical grounds will have an alternative histologic diagnosis that
may alter management. (See 'Diagnosis' above and 'Differential diagnosis' above.)

● HIVAN is characterized by the collapsing form of focal segmental glomerulosclerosis

(FSGS) (picture 1). In addition to collapsing FSGS, HIVAN is typically characterized by
dilated tubules and significant interstitial inflammation. Tubuloreticular inclusions may
also be identified on electron microscopy (picture 2). (See 'Histology' above.)

● In patients diagnosed with HIVAN who are not already receiving ART, we recommend
initiation of ART (Grade 1B). Our stance is in agreement with the United States
Department of Health and Human Services (HHS) Guidelines for Antiviral Agents in
HIV-Infected Adults and Adolescents, which recommend the initiation of ART in all
HIV-positive individuals. (See 'Overview of medical therapy' above and 'ART and
HIVAN' above.)

● In proteinuric and/or hypertensive patients with HIVAN, we suggest therapy with either
an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker
(ARB) (Grade 2C). (See 'Overview of medical therapy' above and 'Renin-angiotensin
system inhibition' above.)

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 ● In patients with HIVAN, we suggest not routinely treating with glucocorticoids (Grade
2C). However, some experts use a trial of glucocorticoids in patients with progressive
disease despite optimal therapy with ART and angiotensin inhibition. (See 'Overview
of medical therapy' above and 'Glucocorticoids' above.)

● The prognosis in patients with HIVAN is poor, even among those treated with ART.
Many such patients will develop ESRD. (See 'Prognosis' above.)

● Survival rates of patients with HIV on dialysis are now similar to rates among dialysis
patients without HIV. Transplantation is a viable option for patients with HIVAN and
ESRD, although there is a risk of HIVAN recurrence in the allograft. Patient and graft
survival may be similar to non-HIV-infected, high-risk transplant recipients. (See
'Dialysis and transplantation' above.)

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