REVIEWS

HIV-associated nephropathies: epidemiology,

pathology, mechanisms and treatment
Avi Z. Rosenberg, Saraladevi Naicker, Cheryl A. Winkler and Jeffrey B. Kopp
Abstract | HIV is a highly adaptive, rapidly evolving virus, which is associated with renal diseases including
collapsing glomerulopathy—the classic histomorphological form of HIV-associated nephropathy. Other
nephropathies related to viral factors include HIV-immune-complex kidney disease and thrombotic
microangiopathy. The distribution of HIV-associated kidney diseases has changed over time and continues
to vary across geographic regions worldwide. The reasons for this diversity are complex and include a critical
role of APOL1 variants and possibly other genetic factors, disparities in access to effective antiviral therapies,
and likely other factors that we do not yet fully understand. The mechanisms responsible for HIVAN, including
HIV infection of podocytes and tubular epithelial cells, the molecules responsible for HIV entry, and diverse
mechanisms of cell injury, have been the focus of much study. Although combined antiretroviral therapy is
effective at preventing and reversing HIVAN, focal segmental glomerulosclerosis, arterionephrosclerosis and
diabetic nephropathy are increasingly common in individuals who have received such therapy for many years.
These diseases are associated with metabolic syndrome, obesity and premature ageing. Future directions for
HIV-related kidney disease will involve regular screening for drug nephrotoxicity and incipient renal disease, as
well as further research into the mechanisms by which chronic inflammation can lead to glomerular disease.
Rosenberg, A. Z. et al. Nat. Rev. Nephrol. 11, 150–160 (2015); published online 17 February 2015; doi:10.1038/nrneph.2015.9

Introduction
HIV-associated nephropathy (HIVAN)—the first kidney about 10% are in children.2 Almost 70% of new infections
disease to be associated with HIV infection and the first occur in sub-Saharan Africa. The prevalence of HIV varies
form of collapsing glomerulopathy (also known as col- widely between geographic regions (Figure 1). The USA
lapsing focal segmental glomerulosclerosis [FSGS]) has an estimated 1.1 million HIV-infected individuals
to be recognized 1—is mechanistically attributed to and an incidence of ~50,000 new cases per year, which
HIV‑1 infection. Other renal diseases associated with has been stable for a decade.4 Among patients with HIV
Department of
Pathology, Johns
HIV include HIV-immune-complex kidney disease in the USA, it is estimated that 82% have been diagnosed,
Hopkins Medical (HIVICK), thrombotic microangiopathy and disorders 66% are linked to care, 37% rece­ive regular care and 25%
Institutions, 720 associated with nephrotoxic HIV therapies. are virally suppressed.4 Worldwide 12.9 million people are
Rutland Avenue,
Baltimore, MD 21287, In this article we review the epidemiology, histo­ receiving combined antiretroviral therapy (cART), repre-
USA (A.Z.R.). School pathology, mechanisms and genetic susceptibility to senting approximately 37% of those with HIV infection.
of Clinical Medicine,
Faculty of Health HIV-associated nephropathy. We also discuss approaches Three-quarters of those on therapy live in sub-Saharan
Sciences, University to diagnosis and treatment as well as future research Africa; treatment rates in this region are similar to those
of the Witwatersrand,
7 York Road, Parktown,
directions. in the rest of the world.
Johannesburg 2193,
South Africa (S.N.). Epidemiology HIV-associated chronic kidney disease
Basic Research
Laboratory, Center HIV infection AIDS-associated nephropathy—now known as HIVAN—
for Cancer Research, In 2013, an estimated 35 million people worldwide, was first reported in the USA in 1984.1 The disease pre-
National Cancer
Institute, Leidos
including 24.7 million people in sub-Saharan Africa, sents clinically with proteinuria and renal dysfunction and
Biomedical Research, were living with HIV infection.2 Since the start of the patho­logically with collapsing FSGS, microcystic tubular
Frederick National HIV epidemic, 78 million people have been infected and dilatation and interstitial inflammation. Prior to 1995,
Laboratory, Frederick,
MD 21702, USA 39 million have died of AIDS-related illness. By com- HIVAN was reported in 3.5–10% of the HIV-infected pop-
(C.A.W.). Kidney parison, only the 1918 influenza pandemic has caused ulation in the USA, predominantly in individuals of Afri­
Disease Section,
NIDDK, NIH, 10 Center
more deaths—an estimated 50–100 million—during the can ancestry, but is declining in prevalence as a result of
Drive, 3N116 modern era (since ~1500).3 Globally, the rate of new HIV the widespread use of cART.5 Although typically described
Bethesda, MD 20892‑ infections has decreased by 38% since 2001, but approxi- in young adults of African ancestry with advanced HIV
1268, USA (J.B.K.).
mately 2.5 million new infections occur annually, of which disease, HIVAN is occasionally diagnosed before acute
Correspondence to: HIV seroconversion has been identified, and presents
J.B.K.
jeffreyk@ Competing interests with nephrotic-range proteinuria. Without cART, HIVAN
intra.niddk.nih.gov The authors declare no competing interests. ­progresses rapidly to end-stage renal disease (ESRD).

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 FOCUS ON NEPHROLOGY IN THE DEVELOPING WORLD

Key points
■■ Widespread use of antiretroviral therapy has led to a change in the spectrum
of renal pathologies associated with HIV infection
■■ The incidence of HIV-associated nephropathy (HIVAN) has decreased since the
introduction of combined antiretroviral therapy (cART)
■■ Viral factors that likely contribute to renal injury in HIV-positive patients include
direct infection of podocytes and renal tubular epithelial cells as well as the HIV
proteins Nef and Vpr
■■ APOL1 genetic variants predispose to HIVAN but not to HIV-immune-complex
kidney disease
■■ All HIV-positive individuals should undergo periodic (at least annual) screening
of renal function
■■ All patients with HIV-associated kidney diseases should receive cART; standard
therapies for chronic kidney disease are also recommended
Unsurprisingly, rates of HIV-associated chronic kidney
disease (CKD) vary widely between calendar periods,
populations and settings. Renal disease has been reported
in approximately 6.0–48.5% of HIV-infected individu-
als in Africa;6 24–83% of these cases were classic HIVAN
in South Africa.7–9 A cross-sectional study of 31 European
countries, Israel and Argentina reported HIV-associated-
CKD in 3.5–4.7% of HIV-infected individuals.10 Other
epidemiological studies have reported rates of 18% in
Hong Kong,11 1.1–5.6% in Brazil,12 18% in Switzerland,13
27% in India and 20% in Iran.14 Renal histological ­findings
also vary between countries (Table 1).
Effects of combined antiretroviral therapy
In the USA the incidence of HIVAN has declined since the
introduction of cART; the best evidence for this decline is a
60% reduction in the risk of ESRD associated with HIVAN
following the introduction of cART.15 A French study
described the change in pattern of renal disease in patients
with HIV infection over 15 years since the introduction
of ART; the incidence of HIVAN decreased over time
and non-collapsing forms of FSGS emerged as the most
common cause of glomerular disease among patients with
HIV, occurring in 47% of patients during 2004–2007.16
HIVAN occurred more frequently in black patients with
severe immunodeficiency and severe renal failure, whereas
patients with non-collapsing FSGS were older, more likely
to have received ART, more frequently had cardiovascular
risk factors, and histologically, had more severe interstitial
fibrosis and less severe tubular lesions. Renin and the HIV
protease share certain functions; both cleave angiotensin­
ogen to angiotensin I and also cleave the HIV Gag poly-
protein, an essential step in HIV replication.17 Thus cART
might be predicted to suppress HIV-induced activation of
the renin–angiotensin system (RAS).
cART-induced nephrotoxicity is an increasing clini-
cal problem that can occur even in patients with normal
baseline renal function.18 The most common forms are
crystalluria and obstruction due to protease inhibi-
tor therapy and proximal tubular damage due to tenofo-
vir therapy (Table 2). Tenofovir-induced nephrotoxicity
causes proximal tubulopathy, acute kidney injury (AKI)
and CKD.19 Dose adjustment according to estimated glo-
merular filtration rate (eGFR) is mandatory to minimize
the nephrotoxic effects of tenofovir. Renal monitoring
in patients receiving this agent is important and drug
­cessation is advised in those with nephrotoxicity.

Adult HIV prevalence (%)

>20
15–20
10–15
5–10
2–5
1–2
0.5–1.0
0.1–0.5
<0.1
Aids free
No data
Figure 1 | Prevalence of HIV infection in adults in 2009. The highest prevalence is seen in sub-Saharan
NatureAfrica.
ReviewsImage based
| Nephrology
on data from UNAIDS and adapted from Wikimedia Commons (http://en.wikipedia.org/wiki/File:AIDS_and_HIV_prevalence_
2009.svg), which is in the public domain.

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REVIEWS

Table 1 | Spectrum of renal histology in patients with HIV infection in different countries
Biopsy series South Africa USA France
Cape Town 9
Durban 8
Johannesburg 7
Johannesburg 133
Baltimore 113
Chicago 134
Paris16
Study details
Year of publication 2012 2006 2006 2014 2008 2013 2012
Number of biopsies 192 7 99 364 152 47 88
Renal histologic findings (%)*
Classic HIVAN 79‡ 86§ 27 33 35 34 30
Focal segmental glomerulosclerosis 1 — 8 11 22 23 26
HIV-immune-complex disease
Not further specified 2 — 21 15 — 4 9
Mesangial proliferative 2 — 6 — — — 7
Membranoproliferative — — — 3 5 2 2
glomerulonephritis
Lupus-like glomerulonephritis — — — — 2 — 3
IgA nephropathy 1 — 5 4 2 — 3
Membranous nephropathy 3 — 13 8 3 — 4
Exudative proliferative or crescentic — — — — 5 — 2
Immunotactoid or fibrillary — — — — 1 — —
glomerulonephritis
HIV thrombotic thrombocytopenic — — — — — — 3
purpura or haemolytic uraemic
syndrome
Minimal change nephropathy — — 2 3 1 — 4
Other glomerular and tubular diseases 12 14 18 23 24 37 7
*Data indicate the percentage of each biopsy series that manifested particular diagnostic entities (all columns total 100%). Histomorphologic diagnosis is given as specified in the original
reference and may not reflect current diagnostic standards. ‡22% of individuals in the Cape Town series had both HIVAN and immune complex glomerulonephritis and are assigned to the
HIVAN category. §One individual in the Durban series had both HIVAN and membranous nephropathy and is assigned to the HIVAN category. Abbreviation: HIVAN, HIV-associated nephropathy.

Prolonged use of cART and the consequent increased
longevity of HIV-infected patients have led to the emer-
gence of new patterns of HIV-associated CKD. Despite
successful suppression of HIV replication using cART,
a state of chronic inflammation and dysmetabolism
persists and is associated with renal diseases includ-
ing diabetic nephropathy, arterionephrosclerosis and
possibly FSGS. Similarities between the ageing process
and HIV infection suggest that the virus compresses the
ageing process, accelerating comorbidity and frailty.20,21
The risks of drug toxicity and cardiovascular disease are
increased in individuals with low eGFR, including the
elderly and those with HIV-infection. The spectrum of
CKD in elderly patients with HIV infection is poorly
defined. Survival of elderly HIV-infected patients on
dialysis is low and delays in initiating dialysis are associ-
ated with increased morbidity and mortality. Whether
controlling blood pressure or diabetes mellitus will
improve outcomes in this population is not known.
Histopathology
HIV-associated renal diseases include a broad histo-
pathological spectrum that encompasses glomerular
and tubulointerstitial pathologies secondary to HIVAN,
AKI, cART-related toxicities and HIV-associated comor-
bidities (such as hepatitis C virus infection, hypertension
and diabetes).21,22 Glomerular entities include collapsing
glomerulopathy (classic HIVAN),1,23,24 HIV-associated
lupus-like glomerulonephritis,25–28 IgA nephropathy,29,30
thrombotic microangiopathy,31 membranoproliferative
glomerulo­nephritis,8 membranous glomerulonephritis,8,32
infection-related or hepatitis C virus-associated immune
complex glomerulo­nephritis33 and fibrillary or immuno-
tactoid glomerulo­nephritis.34,35 Tubulointerstitial changes
related to drug-induced mitochondriopathies, drug toxi­
city, acute interstitial nephritis or superimposed viral,
fungal or mycobacterial infections may also be present.
Of the above entities, classic HIVAN is the best defined in
terms of histologic features and pathomechanisms.
Early reports identified the pathognomonic constella-
tion of features that comprise HIVAN: collapse of glomer-
ular capillaries, visceral glomerular epitheliosis, podocyte
hypertrophy and proliferation, mesangial prominence
and hypercellularity, endothelial tubuloreticular inclu-
sions (TRIs) on ultrastructural examination and micro-
cystic tubules.1,23,24 Microcystic dilatation in particular
has been suggested as a histologic modifier that together
with proteinuria predicts poor outcomes.9 Differential
diagnoses to consider in patients with collapsing glo-
merulopathy include other infectious aetiologies (such
as cytomegalovirus, parvovirus B19 and Epstein Barr
virus [although the role of the latter two viruses remains
uncertain36]), drug toxicities, vascular pathologies (such
as thrombotic microangiopathy), autoimmune diseases,

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 FOCUS ON NEPHROLOGY IN THE DEVELOPING WORLD

Table 2 | Renal effects of highly active anti-retroviral therapies common in the presence of advanced disease, includ-
ing AIDS.39,40 Susceptibility to classic HIVAN is most
Class Drug Renal abnormality
striking in patients of West African descent,41 including
Nucleoside reverse Abacavir AIN (case report) African-American and Afro-Caribbean populations.42
transcriptase inhibitors Fanconi syndrome (case report)
HIVAN has been reported to a lesser degree in Hispanic
Didanosine Fanconi syndrome populations8 and variably in Asian Indian cohorts26,41 but
AKI
Lactic acidosis was notably absent in Swiss–European13 and Thai popu-
Nephrogenic diabetes insipidus lations.43 Over the past two decades, a decreasing fre-
(case reports) quency of classic HIVAN has been observed in African
Lamivudine Renal tubular acidosis patients living in Europe.44
Hypophosphataemia (case report) HIVICK and non-collapsing forms of FSGS are
Stavudine Renal tubular acidosis increasingly reported in the post-cART era.45 HIVICK
Hypophosphataemia (case report) is less likely than HIVAN to progress to ESRD and is
Zidovudine None reported thought to be associated with greater exposure to cART
Non-nucleoside reverse Nevirapine None reported and hepatitis C virus co-infection.46 In HIV-positive
transcriptase inhibitors European-derived populations HIVICK is the dominant
Delavirdine None reported
glomerular disease and HIVAN is rare in comparison to
Efavirenz Nephrolithiasis its incidence in African-derived populations.
Nucleotide reverse Tenofovir Proximal tubular dysfunction Classic HIVAN does not seem to recur in allografts
transcriptase inhibitors with Fanconi syndrome and is associated with excellent transplant outcomes
Nephrogenic diabetes insipidus
AKI similar to those of HIV-negative cohorts.47 Recurrence of
CKD lupus-like HIV-associated kidney disease has, however,
Protease inhibitors Amprenavir None reported been reported in a renal allograft.48 This finding may
present future challenges to renal transplantation in
Atazanavir AIN (case report)
HIV-positive cohorts. The potential risk of recurrence
Darunavir None reported of HIVICK but not HIVAN in transplanted kidneys may
Fosamprenavir None reported reflect differing aetiologies; HIVAN results from direct
Indinavir AKI (AIN) viral infection of renal cells or the action of viral proteins,
CKD (AIN) whereas the aetiology of HIVICK is unknown.
Nephrolithiasis
Intratubular drug precipitation
Papillary necrosis Mechanisms
Hypertension Characteristic HIVAN pathologic changes are observed
Renal atrophy along the full length of the nephron and include glo-
Lopinavir None reported merular and tubulointerstitial features. Various patho-
Nelfinavir Nephrolithiasis (case report) mechanistic processes have been implicated in HIVAN,
including effects on glomerular filtration, proliferation,
Ritonavir AKI
apoptosis, de-differentiation and immunomodulation,
Saquinavir AKI in association with Ritonavir
most of which can now be related to the presence of HIV
Tipranavir None reported transcripts in affected renal parenchymal cells. In early
Fusion or entry inhibitors Enfuvirtide Membranoproliferative mechanistic studies of HIVAN the kidney was identi-
glomerulonephritis (case report) fied as a non-productive reservoir for HIV.49 Subsequent
Maraviroc None reported cDNA localization studies of renal parenchyma showed a
Integrase inhibitor Raltegravir None reported greater role for HIV infection in some HIV-related kidney
Abbreviations: AIN, acute interstitial nephritis; AKI, acute kidney injury; CKD, chronic kidney disease.
diseases, in particular in HIVAN, than in others such as
Permission obtained from Nature Publishing Group © Izzedine, H., Harris, M. & Perazalla, M. A. The HIVICK.50,51 Nonetheless, HIV viral proteins have a role
nephrotoxic effects of HAART. Nat. Rev. Nephrol. 5, 563–573 (2009).
in HIVAN and can induce collapsing glomerulopathy and
tubular injury in t­ ransgenic mice.52–54
malignancy, genetic factors and, if none of the above,
idiopathic collapsing glomerulopathy. The presence of HIV infection of renal cells
TRIs—interferon-related features most commonly seen The process by which HIV enters renal parenchymal
with viral aetiologies and in lupus nephritis—is helpful cells is not well understood (Figure 2). The receptors
in distinguishing viral forms of collapsing FSGS, includ- that mediate entry of the virus into T cells (CD4) and
ing HIVAN. The increased numbers of epithelial cells macrophages (C‑X-C chemokine receptor type 5) seem
attached to the glomerular basement membrane and to be absent from renal cells. Receptors that may have
within the Bowman space in collapsing glomerulopathy a role in HIV infection of these cells include CD209
are now thought to be the result of aberrant proliferation antigen (also known as DC‑SIGN), which contributes to
of stem cells that originate within the parietal epithelium37 HIV infection of dendritic cells and possibly podocytes,
and/or from renin-expressing cell populations.38 and lymphocyte antigen 75 (also known as DEC‑205),
Classic HIVAN histopathology can be seen in adults which may contribute to infection of tubular epithelial
and children at any stage of HIV infection, but is most cells.55 Phagocytosis of apoptotic CD4+ T cells has also

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REVIEWS

a b
Distal
tubule

HIV

PEC
Mesangial
cell

Tat protein entry

via heparan sulphate
proteoglycan Sclerosis
and lipid rafts and collapse

Capillary

Hypertrophy and Loss of podocyte

Podocyte differentiation
hyperplasia of PECs
forming a markers and mitotic
Tubular epithelial cell pseudocrescent catastrophe

G2/M arrest and

HIV entry via DEC205 Loss of apoptosis
or phagocytosis of brush
infected cells border
Tubular dilation
Proximal tubule

Figure 2 | Mechanisms of collapsing glomerulopathy in HIVAN. a | Understanding of the mechanismsNature of

Reviews | Nephrology
HIV entry into
renal cells remains provisional, as studies have necessarily relied on cell culture models using transformed human kidney
cells and transgenic mice. In vitro, HIV enters podocytes via DC‑SIGN and tubule cells via DEC205, whereas the Tat
protein enters podocytes via lipid rafts and induced apoptosis of cultured podocytes. b | Expression of the HIV regulatory
and accessory proteins Vpr and Nef in transgenic mice produces the glomerular and tubular features of collapsing
glomerulopathy. Vpr and Tat, but not Nef, are present in human plasma. The mechanism that drives aberrant expansion
of podocyte stem cells, which are located in the parietal epithelium, remains unknown. The pathology of HIVAN is
characterized by podocyte loss, aberrant stem cell replenishment, tubular cell injury, and microcystic tubular dilatation.
Abbreviation: HIVAN, HIV-associated nephropathy.

been proposed as a mechanism by which HIV may enter
tubular cells.56 The HIV proteins Tat and Vpr circulate in
plasma and Tat can access podocytes via heparan sulfate
proteoglycans and cholesterol-enriched lipid rafts. 57
HIV has been shown to enter cultured podocytes by
dynamin-mediated endocytosis but did not establish a
productive infection.58 The study authors proposed that
this mechanism might account for the detection of some
HIV genomes in human renal tissues.
Pathomechanism of HIVAN
Studies in model systems with confirmation of findings
in human biopsy samples have been integral in study-
ing the pathomechanism of HIVAN. In murine models,
renal HIV transgene expression results in a HIVAN-like
pathology,59,60 supporting direct effects of HIV transcript
expression in glomerular (mesangial and epithelial)
and tubular cells61 as well as in microcyst formation.62,63
HIV-associated cell death has been proposed to occur in
podocytes via mitotic catastrophe,64 in which defective
chromosome replication or other DNA damage leads
to cell death, and in tubular cells via apoptosis, possibly
driven by Vpr, mediated by ubiquitin-like protein FAT1065
or caspase‑2 and Fas,66 and involving G2/M arrest.67
Studies using an early primate model of AIDS sug-
gested that mesangial cell injury was central to the devel-
opment of collapsing glomerulonephritis. Intriguingly,
the strain-limited ability of HIV to cause mesangial
collapse highlights HIV-tropism; not all strains are
capable of entrance and expression in mesangial cells
in a G‑protein coupled receptor 1 (GPR1)-dependent
manner.68,69 Expression of the HIV transgene envelope
glycoprotein gp160 results in tumour necrosis factor
and Bcl‑2-dependent proliferation and apoptosis of
mesangial cells,70 whereas Tat expression was associated
with mesangial cell production of transforming growth
factor β.71 Reduced expression of matrix proteins such as
perlecan (in an apolipoprotein E-dependent manner)72
and overexpression of matrix remodelling enzymes, such
as matrix metalloproteinase 9, have been observed in
HIVAN glomeruli.73 Together these molecular processes
regulate the sclerosing and collapsing features of HIVAN.
Alterations in nephron morphogenesis and dedif-
ferentiation are central to the development of HIVAN.

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Sidekick‑1, a cell adhesion member of the immunoglob-
ulin family involved in renal branching morphogenesis,
is overexpressed in glomeruli from patients and model
organisms with HIVAN.74 This overexpression results
in podocyte aggregation, a feature of the extraglomer-
ular prominence and/or proliferation observed in this
disease.75 Expression of HIV transgenes (particularly
Tat and Nef) in podocytes and renal tubular epithelial
cells results in dedifferentiation and/or epithelial mes-
enchymal transdifferentiation (that is, loss of expression
of nephrin, cadherin‑1 [also known as E‑cadherin])
synapto­p odin, Wilms tumour protein and protein
atonal homologue 8, and expression of zinc finger E-box-
binding homeoBox 1, α‑smooth muscle actin and fibro-
blast-specific protein‑1) and correlates with proliferation
and tubular microcyst formation.63,76–81
The effects of Nef expression on podocyte prolif-
eration and dedifferentiation are Src-dependent and
involve activation of signal transducer and activator of
transcription 3 (Stat3) and the Ras–mitogen-activated
protein kinase (MAPK) 1/2 pathway.82,83 Abrogation
of Stat3 activation in podocytes alleviates many of the
glomerular and tubulointerstitial features of HIVAN.84
Dedifferentiation seems to occur in a mammalian target
of rapamycin (mTOR)-dependent manner; the mTOR
inhibitor sirolimus reduced HIV transcript levels and
progression to HIVAN in murine models.85,86 Roles of
activation of Notch 1 and Notch 4 in HIV-associated dys-
regulation of proliferation and self-renewal mechanisms
have also been reported.87,88
HIV transgenes also affect glomerular and tubular
epithelial cells via dysregulation of proliferation and
apoptosis. The mechanism that underlies loss of growth
inhibition (that is, quiescence) of podocytes has been
associated with proliferation via reduced expression of
the cyclin dependent kinase (CDK) inhibitors p27 and
p57, resulting in activation of cyclin A.89,90 Intriguingly,
loss of expression of CDK inhibitors correlates with
increased expression of HIV transgenes,62 suggesting a
feedback loop between HIV transgene expression and
podocyte proliferation. More specifically, Vpr has been
implicated in epithelial cell hypertrophy, hyperploidy and
apoptosis via activation of the DNA damage response
pathway and subsequent ERK and Bax-mediated mito-
chondrial injury.91,92 In tubular cells interaction and
co-localization of Vpr with ubiquitin D (also known as
ubiquitin-like protein FAT10) in mitochondria has been
implicated in HIVAN-related cell death.65,93 Nuclear
factor κB-dependent processes, including Fas ligand
expression, associated apoptosis and inflammation have
been identified in the kidneys of HIV transgenic mice.94,95
Other HIVAN disease mechanisms that require further
study include HIV–associated dysregulation of micro-
RNA, effects of HIV on the cellular response to oxidative
stress, and direct effects of HIV transgenes on glomerular
permeability. The role of oxidative stress in HIV-infected
kidneys is now being investigated and redox-stress
responses, including mTOR-dependent p53 activation,
have been observed in a HIVAN model.96 HIV Tat protein
has been shown to dysregulate glomerular permeability
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© 2015 Macmillan Publishers Limited. All rights reserved
by reducing expression of nephrin97 and HIV-dependent
downregulation of miR‑33 and miR‑200 has been shown
in podocytes.98 In addition, levels of miR‑99a, miR‑100a,
miR‑199a and miR‑200 were decreased in HIV-infected
podocytes; their expression could be increased in a
rapamycin-­dependent manner.99 Among many path-
ways involved in this process, Wnt signalling and oxi-
dative stress were modulated by rapamycin. Finally,
HIV-transduced human podocytes manifest reduced
vitamin D receptor expression, enhanced expression
of cathepsin L, and increased production of angioten-
sin II.100 In summary, HIVAN histopathologic complexity
is likely the result of the convergence of many deregulated
pathways, which are altered by a small set of HIV gene
products in the structurally diverse kidney.
Viral factors
The primate lentiviruses HIV and simian immuno­
deficiency virus cause nearly identical glomerulopathies,
suggesting that retroviral gene products alter glomerular
cell function in specific ways.101 Evidence from trans-
genic mouse models suggests that expression of single
HIV genes can replicate the clinical features (proteinuria
and progressive kidney disease) and pathologic features
(collapsing glomerulopathy and tubular cell injury) of
HIVAN seen in humans. These models include the long-
studied HIV transgenic mouse Tg26 which bears a gag–
pol deleted HIV transgene and has intact open reading
frames for the accessory gene products Tat, Rev, Nef, Vpr,
Vpu and Vif, under the control of the viral long termi-
nal repeat.102 This mouse model and a rat model with the
same transgene develop glomerular and tubular disease.103
Expression of Nef under the human CD453 or nephrin
­promoter,54 or of Vpr under the nephrin54 or podocyte pro-
moter (that is, podocin)52 replicate HIVAN in mice.
Both Nef and Vpr expression models induce HIVAN in
transgenic mice; it is somewhat surprising that these two
regulatory/accessory proteins can each reproduce the key
features of HIVAN. With regard to Nef, proposed molecu-
lar pathways of podocyte injury include vascular endo­
thelial growth factor expression, downregulation of Notch
signalling 88 and activation of Stat3 signalling.83
Genetic factors
Since the initial description of HIVAN it has been recog-
nized that individuals of African descent are particularly
disposed to this complication of HIV infection. This pre-
dilection is due to high frequencies of the APOL1 genetic
variants G1 and G2 in this population.104,105 These vari-
ants arose separately on chromosome 22 and recombina-
tion to produce a chromosome that has both G1 and G2
has not been observed. Both variants must, therefore, be
genotyped when evaluating risk of renal disease; geno-
typing for only one variant makes the tacit and incorrect
assumption that the other variant is absent.106 The G2
variant seems to be the oldest; it is widely distributed
throughout sub-Saharan Africa at rates of ~8–10%.106
Frequencies of the G1 variant, which seems to have been
under recent selection pressure, range from 0% to 60%
and are particularly high among the Yoruba, Igbo and
REVIEWS
Asante people of West Africa. Rarity of these risk vari-
ants in Ethiopia likely accounts for the rarity of HIVAN
in this population.107 The G1 and G2 variants confer risk
for HIVAN and HIV-associated FSGS, as well as other
glomerular diseases and arterionephrosclerosis (also
known as hypertensive nephrosclerosis). The effect is
largely recessive; homo­zygous (G1/G1 or G2/G2) or
compound heterozygous (G1/G2) individuals have the
highest risk of HIVAN. The risk allele frequency (G1
or G2) is approximately 35% in the African American
population; ~12–14% of African Americans carry two
APOL1 risk alleles, which confer the highest risk of
APOL1-associated nephropathy.
The published odd ratios (ORs) for a recessive model
of disease (requiring two copies of the risk allele) is
29 for HIVAN and 17 for primary FSGS, with a non-­
significant trend for a single APOL1 variant to confer
risk.108 However, we have found that the OR for HIVAN
is numerically higher in South African HIV-positive
populations with two APOL1 risk alleles (OR 89, 95% CI
18–911) than in the previous US study108 and that a mar-
ginally significant effect of one risk allele exists (OR 5,
P = 0.05).109 The mechanisms by which the APOL1 variant
proteins alter kidney cell function are a matter of con-
siderable interest. A promising line of work suggests that
altered function of vesicular trafficking, including endo-
somal and autophagosomal function, may be critical.110
On other hand, the fact that individuals without risk
alleles or with one risk allele may develop HIVAN sug-
gests that other genetic and/or environmental risk factors
are sufficient to cause this disease.
Approximately 6 million African Americans have two
APOL1 risk alleles, but it seems that most will never
develop kidney disease. In the setting of untreated HIV
infection, an estimated 50% of these genetically at-risk
individuals with two APOL1 risk alleles will develop
HIVAN,108 making HIV by far the strongest environ-
mental factor to interact with this genetic risk factor.
Certainly one plausible hypothesis is that HIV induces
interferon expression, which drives APOL1 gene expres-
sion,111 and that the increased expression of the variant
APOL1 proteins is toxic to cells.110
Screening and early detection
Patients with HIV infection are at increased risk of CKD
and should receive regular screening for incipient renal
disease, including HIVAN, as well as other glomerular
and tubular diseases at diagnosis of HIV infection, on
initiation of ART or change in therapy, and annually
in stable patients. Guidelines from the HIV Medicine
Association of the Infectious Diseases Society of America
(updated in 2014) state that annual screening should
include assessment of blood pressure, serum creatinine
and eGFR as well as quantitative measurement of urine
albumin levels and markers of proximal tubular func-
tion in patients on tenofovir.112 Referral to a nephrologist
is recommended when eGFR decreases by >25% from
baseline or is <60 ml/min/1.73 m2.
We believe that annual screening should include
random spot urine measurement of protein:creatinine
156  |  MARCH 2015  |  VOLUME 11  www.nature.com/nrneph
© 2015 Macmillan Publishers Limited. All rights reserved
ratio and urine albumin:creatinine ratio. This approach
aids in the identification of glomerular disease
(albumin:protein ratio generally >40%, reflecting the value
typical of plasma) and tubular disease (albumin:protein
ratio generally <30%, reflecting the predominance of low
molecular weight proteins such as β2 microglobulins,
which are present in normal glomerular filtrate and are
resorbed by the proximal tubule, a process that is impaired
by tubular injury such as that seen with tenofovir and
other toxins). Proximal tubular disease suggested by a low
albumin:protein ratio can be confirmed by measuring the
β2 microglobulin:creatinine ratio and by demonstrating
increased excretion of phosphate and urate.
Utility of kidney biopsy
The utility of kidney biopsy in HIV-infected individuals
has been debated. As noted above, not all CKD accom-
panied by proteinuria and renal dysfunction in these
patients is due to HIVAN; a range of pathological con-
ditions may be responsible. Moreover, no single clinical
parameter is diagnostic of HIVAN: kidney size or echo-
genicity on ultrasound, nephrotic-range proteinuria and
low CD4+ T cell counts do not reliably predict the disease.
Therapeutic decision making for renal diseases is guided
by biopsy findings; cART is an essential component in
treatment of HIVAN, whereas its role in the therapy of
non-HIVAN lesions is unknown.113 In some respects, the
decision whether to perform a renal biopsy is similar in
HIV-positive patients and diabetic patients. Both decisions
involve consideration of how typical or atypical is the clini-
cal presentation, what alternative diagnoses (other than
HIVAN or diabetic nephropathy) seem likely, whether
an alternative diagnosis would lead to new therapy with a
reasonable likelihood of changing the clinical course, the
risks involved in renal biopsy in the individual patient and
the patient’s own preference with regard to biopsy.
Therapy
Antiretroviral therapy
Prior to the availability of cART, HIVAN almost uni-
formly progressed rapidly to ESRD. Current guidelines,
therefore, recommend HIVAN as an indication for initi­
ation of cART irrespective of CD4+ lymphocyte count.112
Epidemiologic data showing a decline in the incidence of
HIVAN114 and HIV-associated ESRD115 in the USA after
the introduction of cART, suggest that effective control of
viral replication can prevent the development of HIVAN.
cART has been associated with a lower incidence
of HIVAN, improved kidney function and lower risk of
ESRD in observational studies of patients with biopsy-
confirmed or clinically suspected HIVAN. Although the
evidence for initiating cART in HIVICK is inconclusive,
the approach seems to be appropriate. A study of 221
HIV-positive patients in South Africa reported that both
HIVAN and HIVICK showed response to cART.9 HIV-
associated thrombotic microangiopathy also appears to
benefit from ART and a decline in incidence has been
reported with widespread ART use.116
Several studies have demonstrated improvements in
kidney function in patients with HIV-associated CKD
 FOCUS ON NEPHROLOGY IN THE DEVELOPING WORLD
after initiation of cART. The DART study conducted in
Uganda and Zimbabwe, showed improvement in GFR by
1.9–6.0 ml/min/1.73 m2 after 4–5 years of cART, with 2.8%
of the 3,316 patients at an eGFR <30 ml/min/1.73 m2.117
A 21% improvement in median eGFR after 2 years on cART
was reported in Ugandan patients with HIV-associated
CKD.118 A study from Tanzania showed improvement in
renal function with ART over a median period of 2 years;
the number of patients with eGFR <90 ml/min/1.73 m2
decreased from 76% to 29.2% and those with eGFR <60 ml/
min/1.73 m2 decreased from 21.1% to 1.1%.119
Many antiretroviral medications are partially or
completely eliminated by the kidney and require dose
adjustment in patients with CKD. Certain drug classes,
such as protease inhibitors and non-nucleoside reverse-
transcriptase inhibitors, are metabolized by the liver and
do not require dose adjustment,120 whereas most nucleo-
side reverse transcriptase inhibitors (NRTIs) are excreted
unchanged in the urine and do require dose adjustment.
NRTI doses may also have to be supplemented following
dialysis.121 In general, drug combinations should not be
used in patients with eGFR <60 ml/min/1.73 m2.112
Management of HIV-associated kidney diseases
In the first years of the HIV epidemic, several therapies
were attempted for HIVAN. Studies in the pre-cART
era suggested a benefit of corticosteroid therapy.122 The
efficacy, however, seemed to be modest and often short-
lived, so corticosteroids are not considered standard
therapy. Similarly limited data exist on the efficacy of
ciclosporin for inducing remission of proteinuria in chil-
dren with HIVAN.123 The HIV Medicine Association of
the Infectious Diseases Society of America recommend
that all patients with HIV-associated kidney disease
should receive cART; if renal function does not improve,
angiotensin-converting enzyme (ACE) inhibitors
or ­angiotensin-receptor blockers (ARBs) and/or pred-
nisone (dose of 1 mg/kg per day; maximum dose 80 mg
per day for 2 months, with tapering over 2–4 months)
may be added.124 Progression to ESRD has been reported
to be more likely when the following parameters are
present: high grade proteinuria, severely reduced eGFR,
extensive glomerulosclerosis and chronic interstitial
fibrosis.125,126 Among patients with HIV-associated kidney
diseases other than HIVAN, those with two APOL1 renal
risk variants progress more rapidly to ESRD despite
­effective viral suppression.127
Standard therapies for CKD are recommended for HIV-
positive individuals, including control of blood pressure
to <140/90 mmHg and the use of ACE inhibitors or ARBs.
In Tg26 mice, the renin inhibitor aliskiren decreased pro-
teinuria and progression of glomerular and tubular lesions
by decreasing plasma angiotensin I and tissue angioten-
sin II levels, suggesting that inhibition of renin activity
has the potential to slow the progression  of HIVAN.128
Underdosing of cART in patients with CKD is reported
to be associated with increased mortality.129 Other general
management approaches include control of serum urate
and bicarbonate, avoidance of nephrotoxins, smoking
­cessation and weight loss in obese patients.
NATURE REVIEWS | NEPHROLOGY VOLUME 11  |  MARCH 2015  |  157
© 2015 Macmillan Publishers Limited. All rights reserved
Renal replacement therapy
Data from the US Renal Data System and from France
show that survival rates of HIV-infected patients receiv-
ing haemodialysis or peritoneal dialysis who are stable
on cART are comparable to those of patients on dialysis
without HIV infection; the choice of dialysis modality
does not impact survival.130–132 Strict use of universal
precautions with regard to blood components is the best
form of prevention of HIV transmission in dialysis units.
Kidney transplantation
Kidney transplantation has been performed successfully
in HIV-positive patients. A case series of 150 kidney trans-
plantations in the USA reported patient and graft sur-
vival at 3 years of 88.2% and 73.7% respectively.47 Despite
high rates of acute graft rejection (31% in the first year),
patient survival was similar and allograft survival was only
­somewhat lower than that in recipients without HIV.
Remaining questions and future directions
Several questions remain regarding the pathogenesis and
treatment of HIVAN. For example, the role of host factors
is not well understood. The mechanisms by which APOL1
risk variant proteins predispose podocytes, vascular cells,
tubular cells and possibly other cells to injury, and whether
they act synergistically with viral factors on host pathways
to damage renal cells are unclear. Moreover, the factors
that protect some individuals with two APOL1 risk alleles
from developing glomerular disease remain to be iden-
tified. In particular, whether protective genetic variants
contribute to resistance to kidney disease in these patients
is unknown. The AOPL1 gene product does not seem to be
essential for normal kidney function. The mechanism that
underlies the recessive phenotype (whereby two risk alleles
confer the greatest risk of HIVAN), therefore, remains to
be explained, as does the observation that 10% of patients
of African descent who have HIVAN carry no APOL1 risk
alleles, whereas 20% carry only one risk allele.108 These
estimates may not be precise, given the difficulties of dis-
tinguishing HIVAN from other forms of FSGS in certain
cases. Whether other genetic variants of African origin
predispose to HIVAN is not known.
The critical pathways by which HIV accessory proteins
drive glomerular and tubular cell injury, and whether
other viruses also activate these pathways, is also a topic
for future research, as is the potential contribution
of environmental factors, such as toxins, to the risk of
HIVAN. Improved understanding of the injury pathways
that are activated by HIV proteins and APOL1 protein
variants in HIVAN could potentially lead to new thera-
peutic strategies as well as new insights into the patho-
genesis of other collapsing glomerulopathies, such as
idiopathic collapsing glomerulopathy.
Conclusions
HIV infection and related therapies are associated with
diverse renal pathology, distinct glomerular diseases
(particularly HIVAN and HIVICK), tubular injury (par-
ticularly owing to tenofovir therapy) and increas-
ingly, diseases associated with chronic inflammation,
REVIEWS

metabolic syndrome, obesity, diabetes and premature
ageing (such as arterionephrosclerosis, diabetic nephro­
pathy and FSGS). Importantly APOL1 risk alleles are
major risk factors for HIVAN, arterionephrosclerosis
and FSGS. Clinicians must be alert to the possibility of
HIV-associated glomerular or tubular disease and screen
infected patients for these conditions on a regular basis.
From a research perspective, a major opportunity
exists to develop an understanding of how intact HIV
and its regulatory and accessory proteins interact with the
APOL1 risk allele variants to induce HIVAN. An under-
standing of the HIV–APOL1 interaction might also serve
to illuminate the mechanisms that underlie other forms
of APOL1-associated nephropathies.

1. Rao, T. K. et al. Associated focal and segmental
glomerulosclerosis in the acquired
immunodeficiency syndrome. N. Engl. J. Med.
310, 669–673 (1984).
2. UNAIDS. UNAIDS Factsheet 2014. unaids.org
[online], http://www.unaids.org/sites/default/
files/en/media/unaids/contentassets/
documents/factsheet/2014/20140716_
FactSheet_en.pdf (2014).
3. Knobler, S., Mack, A., Mahmoud, A. & Lemon, S.
(Eds) The Threat of Pandemic Influenza: Are We
Ready? Workshop Summary. (National Academies
Press, 2005).
4. The Henry J. Kaiser Family Foundation. The HIV/
AIDS Epidemic in the United States. kff.org
[online], http://kff.org/hivaids/fact-sheet/the-
hivaids-epidemic-in-the-united-states/ (2014).
5. Mallipattu, S. K., Wyatt, C. M. & He, J. C. The
new epidemiology of HIV-related kidney disease.
J. AIDS Clin. Res. S4, 001 (2012).
6. Fabian, J. & Naicker, S. HIV and kidney disease
in sub-Saharan Africa. Nat. Rev. Nephrol. 5,
591–598 (2009).
7. Gerntholtz, T. E., Goetsch, S. J. & Katz, I.
HIV-related nephropathy: a South African
perspective. Kidney Int. 69, 1885–1891 (2006).
8. Han, T. M., Naicker, S., Ramdial, P. K. &
Assounga, A. G. A cross-sectional study of HIV-
seropositive patients with varying degrees of
proteinuria in South Africa. Kidney Int. 69,
2243–2250 (2006).
9. Wearne, N., Swanepoel, C. R., Boulle, A.,
Duffield, M. S. & Rayner, B. L. The spectrum
of renal histologies seen in HIV with outcomes,
prognostic indicators and clinical correlations.
Nephrol. Dial. Transplant. 27, 4109–4118 (2012).
10. Mocroft, A. et al. Chronic renal failure among
HIV‑1‑infected patients. AIDS 21, 1119–1127
(2007).
11. Cheung, C. Y. et al. Prevalence of chronic kidney
disease in Chinese HIV-infected patients.
Nephrol. Dial. Transplant. 22, 3186–3190
(2007).
12. Cavalcante, M. A., Coelho, S. N. & Lacerda, H. R.
Prevalence of persistent proteinuria in stable
HIV/AIDS patients and its association with HIV
nephropathy. Braz. J. Infect. Dis. 11, 456–461
(2007).
13. Hailemariam, S. et al. Renal pathology and
premortem clinical presentation of Caucasian
patients with AIDS: an autopsy study from the
era prior to antiretroviral therapy. Swiss Med.
Wkly 131, 412–417 (2001).
14. Janakiraman, H. et al. Correlation of CD4 counts
with renal disease in HIV positive patients. Saudi
J. Kidney Dis. Transpl. 19, 603–607 (2008).
15. US Renal Data System. USRDS Annual Data
Report: atlas of end-stage renal disease in
the United States. ursds.org [online], http://
www.usrds.org/2012/view/ (2012).
16. Lescure, F. X. et al. HIV-associated kidney
glomerular diseases: changes with time and
HAART. Nephrol. Dial. Transplant. 27, 2349–2355
(2012).
17. Chandel, N. et al. Renin modulates HIV
replication in T cells. J. Leukoc. Biol. 96,
601–609 (2014).
18. Ryom, L. et al. Association between antiretroviral
exposure and renal impairment among HIV-
positive persons with normal baseline renal
function: the D:A:D study. J. Infect. Dis. 207,
1359–1369 (2013).
19. Cooper, R. D. et al. Systematic review and meta-
analysis: renal safety of tenofovir disoproxil
fumarate in HIV-infected patients. Clin. Infect.
Dis. 51, 496–505 (2010).
20. Mallipattu, S. K., Salem, F. & Wyatt, C. M. The
changing epidemiology of HIV-related chronic
kidney disease in the era of antiretroviral
therapy. Kidney Int. 86, 259–265 (2014).
21. Phair, J. & Palella, F. Renal disease in HIV-
infected individuals. Curr. Opin. HIV AIDS 6,
285–289 (2011).
22. Bani-Hani, S. et al. Renal disease in AIDS:
it is not always HIVAN. Clin. Exp. Nephrol. 14,
263–267 (2010).
23. Gardenswartz, M. H. et al. Renal disease in
patients with AIDS: a clinicopathologic study.
Clin. Nephrol. 21, 197–204 (1984).
24. Pardo, V. et al. Glomerular lesions in the
acquired immunodeficiency syndrome.
Ann. Intern. Med. 101, 429–434 (1984).
25. Chang, B. G., Markowitz, G. S., Seshan, S. V.,
Seigle, R. L. & D’Agati, V. D. Renal
manifestations of concurrent systemic lupus
erythematosus and HIV infection. Am. J. Kidney
Dis. 33, 441–449 (1999).
26. Madiwale, C. & Venkataseshan, V. S. Renal
lesions in AIDS: a biopsy and autopsy study.
Indian J. Pathol. Microbiol. 42, 45–54 (1999).
27. Kofman, T. et al. Collapsing glomerulopathy
associated lupus in a black female with
homozygous APOL1 mutation. Lupus 21,
1459–1462 (2012).
28. Okpechi I. G., Ayodele, O. E., Rayner, B. L. &
Swanepoel, C. R. Kidney disease in elderly
South Africans. Clin. Nephrol. 79, 269–276
(2013).
29. Ferreira, A. C., Carvalho, D., Carvalho, F.,
Galvao, M. J. & Nolasco, F. Collapsing
glomerulopathy in Portugal: a review of the
histological and clinical findings in HIV and non-
HIV patients. Nephrol. Dial. Transplant. 26,
2209–2215 (2011).
30. Mesquita, M. et al. Renal biopsy findings in
Belgium: a retrospective single center analysis.
Acta Clin. Belg. 66, 104–109 (2011).
31. Fine, D. M., Fogo, A. B. & Alpers, C. E.
Thrombotic microangiopathy and other
glomerular disorders in the HIV-infected patient.
Semin. Nephrol. 28, 545–555 (2008).
32. Haas, M., Kaul, S., & Eustace, J. A. HIV-
associated immune complex glomerulonephritis
with “lupus-like” features: a clinicopathologic
study of 14 cases. Kidney Int. 67, 1381–1390
(2005).
33. Stokes, M. B. et al. Immune complex
glomerulonephritis in patients coinfected with
human immunodeficiency virus and hepatitis C
virus. Am. J. Kidney Dis. 29, 514–525 (1997).
34. Nebuloni, M. et al. Glomerular lesions in HIV-
positive patients: a 20-year biopsy experience
from Northern Italy. Clin. Nephrol. 72, 38–45
(2009).
35. Haas, M., Rajaraman, S., Ahuja, T., Kittaka, M.
& Cavallo, T. Fibrillary/immunotactoid
glomerulonephritis in HIV-positive patients:
a report of three cases. Nephrol. Dial. Transplant.
15, 1679–1683 (2000).
36. Chandra, P. & Kopp, J. B. Viruses and collapsing
glomerulopathy: a brief critical review. Clin.
Kidney J. 6, 1–5 (2013).
37. Romagnani, P., & Remuzzi, G.Renal progenitors
in non-diabetic and diabetic nephropathies.
Trends Endocrinol. Metab. 24, 13–20 (2013).
38. Grahammer, F., Wanner, N. & Huber, T. B.
Podocyte regeneration: who can become a
podocyte? Am. J. Pathol. 183, 333–335 (2013).
39. Ray, P. E. et al. Human immunodeficiency virus
(HIV)-associated nephropathy in children from
the Washington D. C. area: 12 years’
experience. Semin. Nephrol. 18, 396–405
(1998).
40. Anochie, I. C., Eke, F. U. & Okpere, A. N. Human
immunodeficiency virus-associated nephropathy
(HIVAN) in Nigerian children. Pediatr. Nephrol.
23, 117–122 (2008).
41. Lanjewar, D. N., Ansari, M. A., Shetty, C. R.,
Maheshwari, M. B. & Jain, P. Renal lesions
associated with AIDS—an autopsy study.
Indian J. Pathol. Microbiol. 42, 63–68 (1999).
42. Williams, D. I. et al. Presentation, pathology,
and outcome of HIV associated renal disease
in a specialist centre for HIV/AIDS. Sex. Transm.
Infect. 74, 179–184 (1998).
43. Praditpornsilpa, K. et al. Renal pathology and
HIV infection in Thailand. Am. J. Kidney Dis. 33,
282–286 (1999).
44. Cove-Smith, A., Sheaff, M. T. & Ashman, N.
HIVAN is increasingly less common in HIV-
positive black Africans living in Europe.
Kidney Int. 70, 1662 (2006).
45. Mohan, S. et al. The changing pattern of
glomerular disease in HIV and hepatitis C
co-infected patients in the era of HAART.
Clin. Nephrol. 79, 285–291 (2013).
46. Foy, M. C. et al. Comparison of risk factors
and outcomes in HIV immune complex
kidney disease and HIV-associated
nephropathy. Clin. J. Am. Soc. Nephrol. 8,
1524–1532 (2013).
47. Stock, P. G. et al. Outcomes of kidney
transplantation in HIV-infected recipients.
N. Engl. J. Med. 363, 2004–2014 (2010).
48. Chandran, S., Jen, K. Y. & Laszik, Z. G.
Recurrent HIV-associated immune complex
glomerulonephritis with lupus-like features after
kidney transplantation. Am. J. Kidney Dis. 62,
335–338 (2013).
49. Mikulak, J. & Singhal, P. C. HIV‑1 and kidney
cells: better understanding of viral interaction.
Nephron Exp. Nephrol. 115, e15–e21 (2010).
50. Cohen, A. H., Sun, N. C., Shapshak, P. &
Imagawa, D. T. Demonstration of human
immunodeficiency virus in renal epithelium in
HIV-associated nephropathy. Mod. Pathol. 2,
125–128 (1989).
51. Eitner, F. et al. Chemokine receptor CCR5 and
CXCR4 expression in HIV-associated kidney
disease. J. Am. Soc. Nephrol. 11, 856–867
(2000).

158  |  MARCH 2015  |  VOLUME 11  www.nature.com/nrneph

© 2015 Macmillan Publishers Limited. All rights reserved

52. Hiramatsu, N. et al. Angiotensin II type 1
receptor blockade inhibits the development and
progression of HIV-associated nephropathy in a
mouse model. J. Am. Soc. Nephrol. 18, 515–527
(2007).
53. Simard, M. C. et al. Expression of simian
immunodeficiency virus nef in immune cells
of transgenic mice leads to a severe AIDS-like
disease. J. Virol. 76, 3981–3995 (2002).
54. Zuo, Y. et al. HIV‑1 genes vpr and nef
synergistically damage podocytes, leading to
glomerulosclerosis. J. Am. Soc. Nephrol. 17,
2832–2843 (2006).
55. Hatsukari, I. et al. DEC‑205‑mediated
internalization of HIV‑1 results in the
establishment of silent infection in renal tubular
cells. J. Am. Soc. Nephrol. 18, 780–787 (2007).
56. Singh, P. et al. Tubular cell HIV-entry through
apoptosed CD4 T cells: a novel pathway. Virology
434, 68–77 (2012).
57. Xie, X. et al. The basic domain of HIV-tat
transactivating protein is essential for its
targeting to lipid rafts and regulating fibroblast
growth factor‑2 signaling in podocytes isolated
from children with HIV‑1‑associated
nephropathy. J. Am. Soc. Nephrol. 25,
1800–1813 (2014).
58. Khatua, A. K., Taylor, H. E., Hildreth, J. E. &
Popik, W. Non-productive HIV‑1 infection of
human glomerular and urinary podocytes.
Virology 408, 119–127 (2010).
59. Bruggeman, L. A. et al. Nephropathy in human
immunodeficiency virus‑1 transgenic mice is due
to renal transgene expression. J. Clin. Invest.
100, 84–92 (1997).
60. Ray, P. E. et al. A novel HIV‑1 transgenic rat
model of childhood HIV‑1‑associated
nephropathy. Kidney Int. 63, 2242–2253 (2003).
61. Ray, P. E. et al. Infection of human primary renal
epithelial cells with HIV‑1 from children with HIV-
associated nephropathy. Kidney Int. 53,
1217–1229 (1998).
62. Ross, M. J., Bruggeman, L. A., Wilson, P. D. &
Klotman, P. E. Microcyst formation and HIV‑1
gene expression occur in multiple nephron
segments in HIV-associated nephropathy.
J. Am. Soc. Nephrol. 12, 2645–2651 (2001).
63. Zhong, J. et al. Expression of HIV‑1 genes in
podocytes alone can lead to the full spectrum
of HIV‑1‑associated nephropathy. Kidney Int. 68,
1048–1060 (2005).
64. Liapis, H., Romagnani, P. & Anders, H. J.
New insights into the pathology of podocyte
loss: mitotic catastrophe. Am. J. Pathol. 183,
1364–1374 (2013).
65. Snyder, A. et al. FAT10: a novel mediator of Vpr-
induced apoptosis in human immunodeficiency
virus-associated nephropathy. J. Virol. 83,
11983–11988 (2009).
66. Conaldi, P. G. et al. HIV‑1 kills renal tubular
epithelial cells in vitro by triggering an apoptotic
pathway involving caspase activation and Fas
upregulation. J. Clin. Invest. 102, 2041–2049
(1998).
67. Vashistha, H. et al. HIV‑1 expression induces
tubular cell G2/M arrest and apoptosis. Ren.
Fail. 30, 655–664 (2008).
68. Alpers, C. E., McClure, J. & Bursten, S. L. Human
mesangial cells are resistant to productive
infection by multiple strains of human
immunodeficiency virus types 1 and 2.
Am. J. Kidney Dis. 19, 126–130 (1992).
69. Tokizawa, S. et al. Infection of mesangial cells
with HIV and SIV: identification of GPR1 as a
coreceptor. Kidney Int. 58, 607–617 (2000).
70. Singhal, P. C. et al. HIV‑1 gp160 envelope protein
modulates proliferation and apoptosis in
mesangial cells. Nephron 76, 284–295 (1997).
NATURE REVIEWS | NEPHROLOGY VOLUME 11  |  MARCH 2015  |  159
FOCUS ON NEPHROLOGY IN THE DEVELOPING WORLD
71. Yamamoto, T. et al. Increased levels of
transforming growth factor-β in HIV-associated
nephropathy. Kidney Int. 55, 579–592 (1999).
72. Chen, G. et al. A protective role for kidney
apolipoprotein E. Regulation of mesangial cell
proliferation and matrix expansion. J. Biol. Chem.
276, 49142–49147 (2001).
73. Ahuja, T. S., Gopalani, A., Davies, P. & Ahuja, H.
Matrix metalloproteinase‑9 expression in renal
biopsies of patients with HIV-associated
nephropathy. Nephron Clin. Pract. 95, c100–c104
(2003).
74. Kaufman, L., Hayashi, K., Ross, M. J., Ross, M. D.
& Klotman, P. E. Sidekick‑1 is upregulated in
glomeruli in HIV-associated nephropathy. J. Am.
Soc. Nephrol. 15, 1721–1730 (2004).
75. Kaufman, L. et al. The homophilic adhesion
molecule sidekick‑1 contributes to augmented
podocyte aggregation in HIV-associated
nephropathy. FASEB J. 21, 1367–1375 (2007).
76. Conaldi, P. G. et al. Human immunodeficiency
virus‑1 tat induces hyperproliferation and
dysregulation of renal glomerular epithelial cells.
Am. J. Pathol. 161, 53–61 (2002).
77. Sunamoto, M., Husain, M., He, J. C.,
Schwartz, E. J. & Klotman, P. E. Critical role for
Nef in HIV‑1‑induced podocyte dedifferentiation.
Kidney Int. 64, 1695–1701 (2003).
78. Barisoni, L., Bruggeman, L. A., Mundel, P.,
D’Agati, V. D. & Klotman, P. E. HIV‑1 induces
renal epithelial dedifferentiation in a transgenic
model of HIV-associated nephropathy. Kidney Int.
58, 173–181 (2000).
79. Husain, M., D’Agati, V. D., He, J. C.,
Klotman, M. E. & Klotman P. E. HIV‑1 Nef
induces dedifferentiation of podocytes in vivo:
a characteristic feature of HIVAN. AIDS 19,
1975–1980 (2005).
80. Zerhouni-Layachi, B. et al. Dual tropism of HIV‑1
envelopes derived from renal tubular epithelial
cells of patients with HIV-associated
nephropathy. AIDS 20, 621–624 (2006).
81. Yadav, A. et al. HIVAN phenotype: consequence
of epithelial mesenchymal transdifferentiation.
Am. J. Physiol. Renal Physiol. 298, F734–F744
(2010).
82. He, J. C. et al. Nef stimulates proliferation of
glomerular podocytes through activation of Src-
dependent Stat3 and MAPK1,2 pathways. J. Clin.
Invest. 114, 643–651 (2004).
83. Feng, X. et al. Reduction of Stat3 activity
attenuates HIV-induced kidney injury. J. Am. Soc.
Nephrol. 20, 2138–2146 (2009).
84. Gu, L. et al. Deletion of podocyte STAT3
mitigates the entire spectrum of
HIV‑1‑associated nephropathy. AIDS 27,
1091–1098 (2013).
85. Yadav, A. et al. Sirolimus modulates HIVAN
phenotype through inhibition of epithelial
mesenchymal transition. Exp. Mol. Pathol. 93,
173–181 (2012).
86. Rai, P. et al. Rapamycin-induced modulation of
HIV gene transcription attenuates progression
of HIVAN. Exp. Mol. Pathol. 94, 255–261 (2013).
87. Sharma, M. et al. Activation of Notch signaling
pathway in HIV-associated nephropathy. AIDS 24,
2161–2170 (2010).
88. Sharma, M. et al. Inhibition of Notch pathway
attenuates the progression of human
immunodeficiency virus-associated nephropathy.
Am. J. Physiol. Renal Physiol. 304, F1127–F1136
(2013).
89. Barisoni, L. et al. Podocyte cell cycle regulation
and proliferation in collapsing glomerulopathies.
Kidney Int. 58, 137–143 (2000).
90. Shankland, S. J. et al. Differential expression
of cyclin-dependent kinase inhibitors in human
glomerular disease: role in podocyte
© 2015 Macmillan Publishers Limited. All rights reserved
proliferation and maturation. Kidney Int. 58,
674–683 (2000).
91. Rosenstiel, P. E. et al. HIV‑1 Vpr activates the
DNA damage response in renal tubule epithelial
cells. AIDS 23, 2054–2056 (2009).
92. Snyder, A. et al. HIV‑1 viral protein r induces ERK
and caspase‑8‑dependent apoptosis in renal
tubular epithelial cells. AIDS 24, 1107–1119
(2010).
93. Ross, M. J. et al. Role of ubiquitin-like protein
FAT10 in epithelial apoptosis in renal disease.
J. Am. Soc. Nephrol. 17, 996–1004 (2006).
94. Ross, M. J., Martinka, S., D’Agati, V. D. &
Bruggeman, L. A. NF‑κB regulates Fas-mediated
apoptosis in HIV-associated nephropathy. J. Am.
Soc. Nephrol. 16, 2403–2411 (2005).
95. Martinka, S. & Bruggeman, L. A. Persistent NF‑κB
activation in renal epithelial cells in a mouse
model of HIV-associated nephropathy. Am. J.
Physiol. Renal Physiol. 290, F657–F665 (2006).
96. Rai, P. et al. mTOR plays a critical role in p53-
induced oxidative kidney cell injury in HIVAN.
Am. J. Physiol. Renal Physiol. 305, F343–F354
(2013).
97. Doublier, S. et al. HIV‑1 Tat reduces nephrin in
human podocytes: a potential mechanism for
enhanced glomerular permeability in HIV-
associated nephropathy. AIDS 21, 423–432
(2007).
98. Cheng, K. et al. MicroRNAs in HIV-associated
nephropathy (HIVAN). Exp. Mol. Pathol. 94,
65–72 (2013).
99. Cheng, K. et al. Rapamycin-induced modulation
of miRNA expression is associated with
amelioration of HIV-associated nephropathy
(HIVAN). Exp. Cell Res. 319, 2073–2080 (2013).
100. Chandel, N. et al. HIV compromises integrity of
the podocyte actin cytoskeleton through
downregulation of the vitamin D receptor. Am. J.
Physiol. Renal Physiol. 304, F1347–F1357
(2013).
101. Stephens, E. B., Tian, C., Dalton, S. B.
& Gattone, V. H. 2nd. Simian-human
immunodeficiency virus-associated nephropathy
in macaques. AIDS Res. Hum. Retroviruses 16,
1295–1306 (2000).
102. Kopp, J. B. et al. Progressive glomerulosclerosis
and enhanced renal accumulation of basement
membrane components in mice transgenic for
human immunodeficiency virus type 1 genes.
Proc. Natl Acad. Sci. USA 89, 1577–1581
(1992).
103. Reid, W. et al. An HIV‑1 transgenic rat that
develops HIV-related pathology and immunologic
dysfunction. Proc. Natl Acad. Sci. USA 98,
9271–9276 (2001).
104. Genovese, G. et al. Association of trypanolytic
ApoL1 variants with kidney disease in African
Americans. Science 329, 841–845 (2010).
105. Tzur, S. et al. Missense mutations in the APOL1
gene are highly associated with end stage kidney
disease risk previously attributed to the MYH9
gene. Hum. Genet. 128, 345–350 (2010).
106. Limou, S., Nelson, G. W., Kopp, J. B. &
Winkler, C. A. APOL1 kidney risk alleles:
population genetics and disease associations.
Adv. Chronic Kidney Dis. 21, 426–433 (2014).
107. Behar, D. M. et al. Absence of APOL1 risk
variants protects against HIV-associated
nephropathy in the Ethiopian population. Am. J.
Nephrol. 34, 452–459 (2011).
108. Kopp, J. B. et al. APOL1 genetic variants in focal
segmental glomerulosclerosis and HIV-
associated nephropathy. JASN 22, 2129–2137
(2011).
109. Kasembeli, A. N. et al. APOL1 risk variants are
strongly associated with HIVAN in black South
Africans. J. Am. Soc. Nephrol. (in press).
REVIEWS
110. Lan, X. et al. APOL1 risk variants enhance
podocyte necrosis through compromising
lysosomal membrane permeability. Am. J.
Physiol. Renal Physiol. 307, F326–F336 (2014).
111. Nichols, B. et al. Innate immunity pathways
regulate the nephropathy gene apolipoprotein L1.
Kidney Int. 87, 332–342 (2015).
112. Lucas, G. M. et al. Clinical practice guideline for
the management of chronic kidney disease in
patients infected with HIV: 2014 update by the
HIV Medicine Association of the Infectious
Diseases Society of America. Clin. Infect. Dis.
59, e96–e138 (2014).
113. Berliner, A. R. et al. Observations on a cohort
of HIV-infected patients undergoing native
renal biopsy. Am. J. Nephrol. 28, 478–486
(2008).
114. Bohmart, A. & Burns, G. Renal disease in an
urban HIV population in the era prior and
following the introduction of highly active
antiretroviral therapy. J. Natl Med. Assoc. 103,
513–517 (2011).
115. Abraham, A. G. et al. End-stage renal disease
among HIV-infected adults in North America.
Clin. Infect. Dis. http://dx.doi.org/10.1093/cid/
ciu919.
116. Becker, S. et al. HIV-associated thrombotic
microangiopathy in the era of highly active
antiretroviral therapy: an observational study.
Clin. Infect. Dis. 39 (Suppl. 5), S267–S275
(2004).
117. Stohr, W. et al. Glomerular dysfunction and
associated risk factors over 4–5 years following
antiretroviral therapy initiation in Africa. Antivir.
Ther. 16, 1011–1020 (2011).
118. Peters, P. J. et al. Antiretroviral therapy improves
renal function among HIV-infected Ugandans.
Kidney Int. 74, 925–929 (2008).
119. Mpondo, B. C. et al. Impact of antiretroviral
therapy on renal function among HIV-infected
Tanzanian adults: a retrospective cohort study.
PLoS ONE 9, e89573 (2014).
160  |  MARCH 2015  |  VOLUME 11  www.nature.com/nrneph
120. Berns, J. S. & Kasbekar, N. Highly active
antiretroviral therapy and the kidney: an update
on antiretroviral medications for nephrologists.
Clin. J. Am. Soc. Nephrol. 1, 117–129 (2006).
121. Izzedine, H., Launay-Vacher, V., Baumelou, A. &
Deray, G. An appraisal of antiretroviral drugs in
hemodialysis. Kidney Int. 60, 821–830 (2001).
122. Eustace, J. A. et al. Cohort study of the
treatment of severe HIV-associated nephropathy
with corticosteroids. Kidney Int. 58, 1253–1260
(2000).
123. Ingulli, E. et al. Nephrotic syndrome associated
with acquired immunodeficiency syndrome in
children. J. Pediatr. 119, 710–716 (1991).
124. Gupta, S. K. et al. Guidelines for the
management of chronic kidney disease in HIV-
infected patients: recommendations of the
HIV Medicine Association of the Infectious
Diseases Society of America. Clin. Infect. Dis.
40, 1559–1585 (2005).
125. Bige, N. et al. Presentation of HIV-associated
nephropathy and outcome in HAART-treated
patients. Nephrol. Dial. Transplant. 27,
1114–1121 (2012).
126. Post, F. A. et al. Predictors of renal outcome in
HIV-associated nephropathy. Clin. Infect. Dis. 46,
1282–1289 (2008).
127. Fine, D. M. et al. APOL1 risk variants predict
histopathology and progression to ESRD in HIV-
related kidney disease. J. Am. Soc. Nephrol. 23,
343–350 (2012).
128. Kumar, D. et al. Inhibition of renin activity slows
down the progression of HIV-associated
nephropathy. Am. J. Physiol. Renal Physiol. 303,
F711–F720 (2012).
129. Kalayjian, R. C. The treatment of HIV-associated
nephropathy. Adv. Chronic Kidney Dis. 17, 59–71
(2010).
130. Ahuja, T. S., Grady, J. & Khan S. Changing trends
in the survival of dialysis patients with human
immunodeficiency virus in the United States.
J. Am. Soc. Nephrol. 13, 1889–1893 (2002).
© 2015 Macmillan Publishers Limited. All rights reserved
131. Macrae, J., Friedman, A. L., Eggers, P. &
Friedman, E. A. Improved survival in HIV-infected
African-Americans with ESRD. Clin. Nephrol. 64,
124–128 (2005).
132. Tourret, J. et al. Outcome and prognosis factors
in HIV-infected hemodialysis patients. Clin. J.
Am. Soc. Nephrol. 1, 1241–1247 (2006).
133. Vermeulen, A. MMed Thesis, University of
Witwatersrand (2014).
134. Meehan, S. M., Kim, L. & Chang, A. A spectrum
of morphologic lesions of focal segmental
glomerulosclerosis by Columbia criteria in
human immunodeficiency virus infection.
Virchows Arch. 460, 429–435 (2012).
Acknowledgements
The authors’ work is supported in part by the
Intramural Research Programs of the National Cancer
Institute, National Institute of Diabetes and Digestive
and Kidney Diseases, and National Institutes of
Health, USA, and by the Medical Research Council
and National Research Foundation of South Africa.
This project has been funded in whole or in part with
federal funds from the National Cancer Institute,
National Institutes of Health, under contract
HHSN26120080001E. Content of this publication
does not necessarily reflect the views or policies of
the Department of Health and Human Services, USA,
nor does mention of trade names, commercial
products, or organizations imply endorsement by
the US Government. The authors note with regret the
recent untimely death of Linda Kao, a pioneering and
generous researcher who made many important
contributions to the field of human genetics, in
particular to the discovery of the chromosome 22
locus that includes APOL1 as a risk factor for HIVAN.
Author contributions
All authors researched the data for the article, made
substantial contributions to discussions of the
content, wrote the article and reviewed and/or edited
the manuscript before submission.