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Differentiating HIV-associated Nephropathy from Antiretroviral Drug-

Induced Nephropathy: A Clinical Challenge

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 Author's personal copy
Curr HIV/AIDS Rep
DOI 10.1007/s11904-014-0209-9
COMPLICATIONS OF ANTIRETROVIRAL THERAPY (JM KILBY, SECTION EDITOR)
Differentiating HIV-associated Nephropathy from Antiretroviral
Drug-Induced Nephropathy: A Clinical Challenge
Neelja Kumar & Mark A. Perazella
# Springer Science+Business Media New York 2014
Abstract With the introduction of potent combination antire-
troviral therapy (cART) into clinical practice, HIV-infected
patients have garnered much benefit. However, kidney disease
continues to be a potential complication in this group. Where-
as HIV-associated nephropathy (HIVAN) was the major renal
complication prior to cART, co-morbid diseases and adverse
renal effects of various drugs, in particular cART, now com-
plicate the landscape. Clinicians now must differentiate
HIVAN from cART nephrotoxicity. While sometimes this is
easy and relatively straightforward, often the clinician faces a
difficult challenge distinguishing these two etiologies of kid-
ney disease. This review will discuss HIVAN and cART-
related kidney disease and review the clinical and laboratory
data that may be useful in differentiating these processes.
Often, however, kidney biopsy may be required to differenti-
ate HIVAN from cART nephrotoxicity as well as other kidney
lesions associated with concurrent co-morbidities, both infec-
tious and non-infectious.
Keywords Combination antiretroviral therapy (cART) .
HIV-associated nephropathy (HIVAN) . Atazanavir .
Tenofovir . Indinavir . Proteinuria . Crystalluria
Introduction
Over 30 years ago, HIV infection was considered a death
sentence for patients based on the dismal outcomes reported
from New York and California. Since that time, advances in
N. Kumar : M. A. Perazella (*)
Section of Nephrology, Department of Medicine, Yale University
School of Medicine, BB 114, 330 Cedar Street, New Haven,
CT 06520-8029, USA
e-mail: mark.perazella@yale.edu
combination antiretroviral therapy (cART) significantly im-
proved the course of HIV disease progression, ameliorating
end organ injury and remarkably improving overall survival.
Although the incidence of HIV-associated nephropathy
(HIVAN) decreased in the late 1990s, it remains a problem
as this renal lesion still accounts for significant morbidity
within the HIV population [1]. With improved life expectancy,
non-HIV-associated diseases also remain a clinical concern.
For example, drug-induced kidney injury becomes a more
common issue (Table 1) due to exposure to a myriad of
nephrotoxic agents, many of which are essential to the treat-
ment and control of the HIV disease. This increases the risk of
acute and chronic kidney disease in this vulnerable popula-
tion. Differentiating between HIVAN and antiretroviral drug-
induced nephropathy can be challenging for the clinician, but
is critical to guide appropriate management and optimize the
course of disease and overall outcomes.
HIV-associated Nephropathy
Epidemiology
Rao and colleagues first described kidney disease in 1984 in a
group of ten patients with advanced acquired immune defi-
ciency syndrome (AIDS), and it was initially designated AIDS
nephropathy [2]. The term was later changed to HIVAN,
which classically presents with high-grade proteinuria and
rapidly progressive renal failure, often resulting in end-stage
renal disease (ESRD) or death. Many of the initial cases were
ascribed to heroin nephrotoxicity and HIVAN was not initially
accepted as a true diagnosis [3]. Over time, however, HIVAN
was soon recognized as its own entity and the pathophysiol-
ogy, clinical course, and treatment have been more compre-
hensively described over the past two decades. HIVAN is a
leading cause of chronic kidney disease (CKD) among the
 Author's personal copy
Table 1 Spectrum of kidney disease in HIV patients
HIV-Associated direct kidney injury
• HIV-associated nephropathy (HIVAN)
• Immune complex disease
• Thrombotic microangiopathy (TTP/HUS)
• Immunotactoid glomerulopathy
• Fibrillary glomerulonephritis
Drug-induced kidney injury
• Combined antiretroviral therapy (cART) nephrotoxicity
• Antimicrobial agents (aminoglycosides, antiviral agents, antifungal
agents) nephrotoxicity
• Nonsteroidal anti-inflammatory drugs (NSAIDs) renal syndromes
• Radiocontrast-induced nephrotoxicity
Other non-HIV related kidney injury
• Hepatitis B or C co-infection (membranoproliferative disease,
membranous nephropathy, cryoglobulinemia)
• Diabetic nephropathy
• Hypertensive nephrosclerosis
• Focal segmental glomerulosclerosis
• Renal amyloidosis
• Post-infectious glomerulonephritis
HIV population with a significant racial predilection such that
up to 90 % of HIVAN cases occur in African Americans [4].
The associated racial disparity led to the search for genetic
determinants of this disease.
In 1999, HIVAN carried a huge disease burden as noted by
its notorious ranking as the third leading cause of ESRD
among blacks between the age of 20 and 64 years, lagging
behind only diabetes mellitus and hypertension [3]. Impor-
tantly, as noted in data from the United States Renal Data
System (USRDS) during the period of 1992-1997, HIVAN
was also associated with significant mortality [5]. For exam-
ple, 2-year survival was 36 % for patients with ESRD second-
ary to HIVAN as compared with 64 % for patients with all
other causes of ESRD [5]. However, the introduction of
effective antiretroviral therapy has dramatically changed the
evolution of HIV-associated kidney. Although the incidence
of ESRD attributed to HIVAN in the 1990s declined, it sub-
sequently plateaued at approximately 800-900 cases/year in
the United States, suggesting the disease remains clinically
relevant. The good news is that any apparent increasing prev-
alence of ESRD in patients with HIV infection recently is
likely a result of overall improved HIV survival [6••].
Following the widespread introduction of cART in 1996,
the natural history, epidemiology, and spectrum of kidney
disease has evolved such that other co-morbid causes of
kidney failure such as diabetic nephropathy and hypertensive
nephrosclerosis have become more prevalent. To this point, a
longitudinal study among HIV patients undergoing kidney
biopsy described a decline in the annual proportion of HIVAN
Curr HIV/AIDS Rep
from 80 % in 1997 to 20 % in 2004 [7]. Additionally, the
clinical course of HIVAN transformed from a very aggressive
and rapid decline in kidney function to one characterized by a
more indolent, slowly progressive form of CKD with lower
levels of proteinuria [6••]. One must be careful to consider and
exclude both pre-renal and post-renal causes of kidney disease
when evaluating a patient with HIV infection.
Pathophysiology
HIV-associated kidney disease can result from a variety of
mechanisms including direct viral injury to epithelial cells,
formation of immune complexes, or development of a throm-
botic microangiopathy from viral-associated endothelial inju-
ry. HIVAN occurs from viral infection and injury of renal
epithelial cells, which has been elegantly established through
murine models of disease. HIV-1 must be present in renal
epithelial cells for HIVAN to develop [4, 8•]. Local HIV gene
expression within the renal parenchyma has been confirmed
and is considered an essential part in the development of this
disease [8•]. The HIV virus is able to directly infect renal
tubular epithelial cells, which then become a reservoir of viral
replication [9]. Although the exact mechanism remains un-
clear, it is hypothesized that the transfer of HIV nucleic acid
occurs independently from interaction of the viral glycopro-
tein and CD4 [8•].
Both epithelial cell proliferation and apoptosis are thought
to play a central role in the development of disease. Factors
capable of promoting cellular proliferation, such as
transforming growth factor β and basic fibroblast growth
factor are upregulated in HIVAN. Markers of proliferation
(Ki-67) are also increased in HIVAN kidneys [10]. Apoptosis
is promoted by factors such as Fas, thereby supporting the
dual mechanism of epithelial cell injury. Epithelial cell apo-
ptosis and dysregulation of podocyte differentiation are affect-
ed by the production of various viral factors. Viral gene
products nef (negative effector) and vpr (viral protein r) in
experimental animals and tat (transactivating factor) genes in
humans are considered important. Nef produces podocyte
dysfunction and de-differentiation via multiple interactions
that ultimately lead to podocyte foot process effacement.
Similarly, vpr through interaction and production of various
factors, results in renal tubular epithelial cell apoptosis [11].
Importantly, HIV infection of renal epithelial cells is only a
piece of the puzzle as it appears that certain host factors also
play a role in HIVAN susceptibility [4].
Recent data suggest that the critical host susceptibility to
HIVAN is genetic. HIVAN has a significant predilection for
patients of African descent with prevalence in this group
ranging from 3 to 12 % [12]. These data support a genetic
component to the pathogenesis of this disease. Animal studies
suggest that genetic variations in the HIVAN-1 and -2 genes
lead to increased susceptibility to the development of HIVAN
 Author's personal copy
Curr HIV/AIDS Rep
[11]. In humans, population linkage studies describe that
certain genetic variations contribute including alleles on the
MYH9 locus on chromosome 22, which has also been linked
to idiopathic focal segmental glomerulosclerosis (FSGS) and
hypertensive ESRD in blacks [13]. MYH9 codes for a non-
muscle myosin chain IIA and is highly expressed in podocytes
[14]. Apolipoprotein L1 (APOLI) gene variants play a critical
role in the development of FSGS in African Americans and
contribute to their genetic susceptibility to HIVAN. It appears
that single-nucleotide polymorphisms in the APOL1 gene,
which are more common among individuals of West African
descent, are at least partly responsible for the increased sus-
ceptibility to HIVAN [15].
Clinical Diagnosis
Clinically, classic HIVAN presents with significant pro-
teinuria and a rapidly progressive decline in kidney func-
tion (Table 2). HIVAN is typically characterized by high-
grade or nephrotic range proteinuria, generally >3 gm/
24 hr [16]. Although proteinuria is considered a hallmark
in this disease, studies demonstrate that high-grade pro-
teinuria is not always a sensitive marker [17]. For exam-
ple, only 53 % of 55 HIV patients with nephrotic range
proteinuria were found to have biopsy-proven HIVAN, a
sensitivity of 73 % and positive predictive value of only
53 % [17]. Despite these data, non-nephrotic range pro-
teinuria, when considered in conjunction with CD4 counts
>200 cells/mm3 may be useful to exclude HIVAN in
certain patients [17], although again, not definitively.
Not unexpectedly, hypoalbuminemia accompanies heavy
proteinuria in the setting of HIVAN [4]. Urine microscopy
often reveals a bland urine sediment in the setting of
HIVAN. At times, hyaline and proteinacious casts may
be seen in the spun urine sediment, as well as renal
tubular epithelial cells and granular casts if ischemic or
nephrotoxic tubular injury is superimposed. Cellular casts
Table 2 Clinical and laboratory features of kidney disease
HIVAN
Systemic disease: weight loss, recurrent infections (specifically
opportunistic infections), loss of muscle mass
CD4 count<200 cells/mm3
Viral Load>400 copies/mL
Rapid decline of kidney function (more likely)
Proteinuria>300 mg/24 hr
-early stage- non-nephrotic
-late stage-nephrotic
Bland urinary sediment/ hyaline or proteinaceous Casts
Ultrasonography: large sized kidneys with intense cortical echogenicity
Abbreviations: HIVAN, HIV-associated nephropathy; cART, combination antiretroviral therapy
are extremely unusual in pure HIVAN and their presence
should raise the possibility of another diagnosis or
superimposed process. Finally, microalbuminuria has also
been described in biopsy-proven HIVAN, making high-
grade proteinuria a less specific marker for HIVAN [18].
Clinical makers such as CD4 count and HIV DNA viral
load are potentially useful non-invasive predictive markers of
HIVAN (Table 2). Estrella divided 86 patients with HIV based
on their HIV viral load and found that a viral load>400
copies/mL was seen most often with HIVAN (23/63 vs.
1/23), supporting active viral infection as useful in assisting
in diagnosing HIVAN [19]. Viral RNA>400 copies/mL was
95.8 % sensitive for HIVAN with a positive predictive value
of 95.7 %, although unfortunately the test lacked specificity
(35.5 %). Furthermore, there was no correlation between viral
RNA level and patient survival. Similarly, CD4 counts have
been found to be non-specific for HIVAN, as a significant
number of patients with CD4 cells counts <200 cells/mm3 had
other forms of kidney disease on biopsy [17].
Ultrasonography of the kidneys has also been evaluated
as a noninvasive diagnostic test for HIVAN. Atta and col-
leagues noted that very high scores of renal echogenicity
were a strong predictor for HIVAN and low echogenicity
scores were valuable in excluding this diagnosis. However,
the diagnostic utility of this test is limited by the fact that a
significant number of patients with HIVAN have
echogenicity scores that fall between these two extremes
[20]. Additionally, subsequent studies have yielded poor
results and our personal experience is that many different
forms of kidney disease appear as large and hyperechogenic
on renal ultrasound, making the test quite non-specific [20].
In the end, kidney biopsy is often required to definitively
diagnose HIVAN, which is important as it guides manage-
ment, which potentially slows loss of kidney function and
progression to ESRD when timely [21]. Classic HIVAN is
characterized by a collapsing form of FSGS with associated
podocyte effacement, microcystic tubular dilation, and tubular
cART induced nephropathy
Systemic disease: osteomalacia, lipodystrophy, skin rash, diarrhea, peripheral
neuropathy, lactic acidosis, hepatotoxicity
CD4 count>200 cells/mm3
Viral load<400 copies/mL
Chronic indolent decline of kidney function (or AKI less commonly)
Proteinuria<300 mg/24 hr
Hematuria or Leukocyturia
Crystals on urine microscopy– needle-like or rod-like crystals
Hypophosphatemia, glucosuria, proteinuria or evidence of Fanconi syndrome
Ultrasonography: normal or small sized kidneys with variable cortical
echogenicity
 Author's personal copy
atrophy (Fig. 1a and b). In addition, lymphocytic infiltration,
and interstitial edema and/or fibrosis may also be present.
Visceral epithelial cell hypertrophy forms ‘pseudocrescents’
and may be a prominent finding in HIVAN [22]. Interestingly,
the classic ‘collapsing FSGS’ of HIVAN has become less
common in the past decade or so, with an increase in non-
collapsing FSGS noted in HIV patients [7]. This histologic
finding may reflect partially treated HIVAN or idiopathic
FSGS in a susceptible population. Finally, electron microsco-
py often reveals endothelial tubuloreticular inclusions com-
posed of interferon, similar to those seen in patients with other
viral illnesses, autoimmune diseases, or those treated with
interferon [12].
Fig. 1 a HIV-associated nephropathy (HIVAN). Light microscopy dem-
onstrates global collapse of the glomerular tuft and prominent hyperplasia
of overlying epithelial cells with large intracytoplasmic protein resorption
droplets (Jones methenamine silver, 400x). b Tubulointerstitial changes
of HIVAN include microcystic dilatation of tubules as well as wide spread
cytoplasmic simplification of proximal tubules, along with mild intersti-
tial edema and mononuclear inflammation (H&E, 200x). Images provid-
ed by Leal Herlitz, MD, Columbia University
Curr HIV/AIDS Rep
Combination Antiretroviral Drug-induced Nephropathy
The introduction of cART in 1996 changed the clinical land-
scape of HIV infection. Medications were now available that
could reliably control HIV disease progression and over time
with discovery of more potent, yet tolerable drugs, patients
could enjoy a near normal life expectancy. As a result, non-
AIDS-related chronic conditions have surfaced and replaced
opportunistic infections and malignancies as the major causes
of disease [23]. To this point, acute and chronic kidney disease
is increasingly prevalent in this group and ranks as one of the
leading causes of death [24].
The actual etiology of intrinsic kidney disease in patients
with HIV is not always clear-cut and may be due to any one of
the following causes either alone or in some combination
(Table 1). HIV-related disease (HIVAN), co-morbid disease
(diabetes, hypertension, renovascular disease, etc.), non-
cART drug nephrotoxicity (acyclovir, aminoglycosides,
NSAIDs, radiocontrast, etc.), and cART-related kidney dis-
ease. Although this review places significant emphasis on
diagnosing the etiology of intrinsic renal disease, it is also
important to consider both pre and post-renal etiologies of
disease. Prerenal causes include volume deletion, and cardio-
and hepatorenal syndromes, and post-renal causes such as
urinary obstruction from malignancies, stones, and inflamma-
tory masses. Most often, the clinician is challenged in trying to
clinically differentiate these various causes of kidney disease,
as they can appear quite similar when the clinical data are
evaluated. In particular, differentiating HIVAN from cART
nephrotoxicity can be difficult. The next section will consider
cART nephrotoxicity, as the list of possible nephrotoxic drugs
is large, only the clinically important nephrotoxic cART med-
ications, indinavir, atazanavir, and tenofovir will be reviewed.
Indinavir
Indinavir is an antiretroviral of the protease inhibitor class
that, upon its release into clinical practice in 1996, was used
in combination with other drugs to effectively treat HIV
infection. However, its efficacy was somewhat countered by
a number of issues including frequent dosing, meal restriction,
and prominent adverse kidney effects [25]. The major renal
effect is due primarily to the drug’s insolubility in the urine
and its tendency to form intratubular crystals and stones [25].
Risk for indinavir crystallization in the urine relates to its
pharmacology and drug characteristics. The drug is
hepatically metabolized with 20 % excreted by the kidneys
[26]. Indinavir is most soluble in acidic urine and exceeds its
solubility limit in the urine with typical therapeutic doses.
Other risk factors for crystal formation include dehydration/
volume depletion, increased indinavir serum concentrations
(liver disease), and co-administration of the drug with acyclo-
vir, trimethoprim-sulfamethoxazole, and low dose ritonavir
 Author's personal copy
Curr HIV/AIDS Rep
[25]. A cohort study of 1219 patients receiving indinavir
determined risk factors for the development of crystalluria.
As noted above, risk factors included alkaline urine pH>6,
low body mass, dose of 1000 mg or more twice daily, and
warm weather [27].
Several different clinical presentations are described with
indinavir nephrotoxicity. These include isolated crystalluria,
AKI from intratubular crystal precipitation (Fig. 2),
nephrolithiasis, and papillary necrosis [25]. Isolated
crystalluria (needle-shaped and other shaped crystals
found in clusters with positive birefringence) can be asymp-
tomatic or associated with flank pain with hematuria and
dysuria. Sometimes the only clue will be sterile pyuria [28].
In a study of 240 HIV patients treated with indinavir, 20 %
developed indinavir crystalluria, and 3 % formed indinavir
uroliths [29]. Asymptomatic crystalluria was observed in up
to 20 % of patients, while symptomatic disease developed
in 8 % [29]. AKI is due primarily to intratubular crystal
precipitation with subsequent tubular obstruction and gen-
eration of an associated inflammatory reaction. Indinavir
crystals, white blood cells and red blood cells are seen on
urine microscopy while biopsy reveals intratubular crystals
with variable interstitial inflammation [30]. This process
has been associated with development of CKD and hyper-
tension, likely reflecting chronic tubulointerstitial injury.
Nephrolithiasis from indinavir is also a potential side effect
[31]. Flank pain and at times, AKI occur with stone for-
mation, requiring urologic interventions such as stent for-
mation or stone removal. Prevention hinges upon adequate
hydration to obtain a urinary output of at least 1500 mL
per day [25].
Fig. 2 Indinavir nephropathy. Indinavir crystals are deposited within
renal tubular lumens. There is an associated interstitial inflammatory
infiltrate (H&E, 400x). Images provided by Glen Markowitz, MD, Co-
lumbia University
Atazanavir
Atazanavir is a newer antiretroviral of the protease inhib-
itor class and is one of the agents that has largely replaced
indinavir in the treatment of HIV infection. This change
reflects better tolerability, dosing convenience, and re-
duced adverse effects, including renal effects. The drug,
however, does still have adverse kidney effects that clini-
cians must be aware of—primarily nephrolithiasis, with
lesser asymptomatic crystalluria, and AKI from
intratubular crystal formation and acute interstitial nephri-
tis. Like indinavir, atazanavir is metabolized by the liver,
~7 % of the drug is excreted unchanged by the kidneys,
and it is poorly soluble in alkaline urine with maximal
solubility at pH 1.9 [32].
Nephrolithiasis appears to be the major adverse kidney
effect of atazanavir therapy. Initial clinical registry data
did not observe this complication, but subsequent release
of the drug into clinical practice generated reports of stone
formation. Couzigou and colleagues noted nephrolithiasis
as a complication of atazanavir therapy [32]. Eleven pa-
tients (overall prevalence 0.97 %) of 1134 patients devel-
oped kidney stones with a median time of onset of
23 months. Importantly, infrared spectrophotometry dem-
onstrated that the stones contained atazanavir crystals
[32]. In this study, risk factors associated with
nephrolithiasis were alkaline urinary pH, previous history
of stones, and co-infection with hepatitis C. Underlying
liver and kidney disease may also enhance stone forma-
tion by increasing urinary atazanavir exposure. In addi-
tion, the US FDA Adverse Event Reporting System iden-
tified 30 cases of nephrolithiasis in HIV patients treated
with an atazanavir-based regimen [33]. Underlying liver
and kidney disease were risk factors, while 12 stones that
were analyzed revealed atazanavir (40-100 % concentra-
tion within stones). Hamada et al. noted kidney stones in
31 patients on an atazanavir-based regimen compared
with stones in four patients receiving another protease
inhibitor, again suggesting risk for nephrolithiasis with
atazanavir [34•].
Examination of the urine in stone formers will sometimes
reveal birefringent, rod-like atazanavir crystals alone or some-
times associated with white blood cells. In addition to
nephrolithiasis, AKI may develop from intratubular precipita-
tion of crystals, with an associated interstitial reaction, or
isolated acute interstitial nephritis. Currently, six cases of
AKI from atazanavir have been reported; four of the cases
described acute interstitial nephritis without intratubular crys-
tals [35, 36] and two cases with intratubular crystal deposition
with associated granulomatous interstitial reaction [37, 38].
CKD from a chronic tubulointerstitial injury can occur in this
setting [38]. A cohort study revealed that atazanavir treated
patients had an increased risk of developing CKD [39••].
 Author's personal copy
Tenofovir
Tenofovir is an antiretroviral of the nucleotide reverse tran-
scriptase inhibitor class that is a critical component of many
cART regimens. Several randomized clinical trials document-
ed the drug’s potent efficacy and excellent tolerability, leading
to widespread adoption as an effective therapy in clinical
practice. In fact, phase III registration trials confirmed the
drug’s efficacy and safety profile. A post-marketing surveil-
lance study demonstrated rare percentage (0.2 %) of severe
albeit undefined kidney injury [40].Several cohort studies
noted modest rates of kidney dysfunction with tenofovir ther-
apy [41]. However, despite these comforting data early on in
the development of tenofovir, nephrotoxicity has been con-
vincingly described with this drug in recent years. Case re-
ports note primarily proximal tubular injury with isolated
proximal tubular dysfunction (phosphate wasting or full
Fanconi syndrome), AKI from acute tubular injury/necrosis,
or a combined kidney lesion [42–44]. Rare nephrogenic dia-
betes insipidus has also been noted [44, 45]. Clinically,
Fanconi syndrome (FS) is characterized by hypokalemia,
hypophosphatemia, and proximal renal tubular acidosis with
glucosuria, and increased urinary concentrations of phosphate,
uric acid, bicarbonate, and amino acids. AKI is manifested as
rising blood urea nitrogen and serum creatinine concentrations
associated with electrolyte and acid-base disturbances, de-
pending on whether there is concomitant FS. Urinalysis re-
veals positive protein and glucose in the setting of FS, while
urine microscopy often demonstrates renal tubular epithelial
cells (RTECs), RTEC casts, and granular casts when AKI is
present [46].
As with other drug-induced nephrotoxicity, only patients
with certain characteristics develop kidney injury upon expo-
sure to tenofovir [47•]. While not definitive, likely risk factors
include underlying kidney disease, genetic predisposition
(proximal tubular transport mechanisms), co-administration
of didanosine or ritonavir (unclear), and older age/low body
weight [47•]. The potential mechanism of tenofovir-
associated nephrotoxicity is, in part, explained by the proxi-
mal tubular handling of the drug. Tenofovir enters proximal
tubular cells from the basolateral space via the human organic
anion transporter (OAT1/3) [48]. Once within the cell cyto-
plasm, it is transported by protein carriers to subcellular loca-
tions prior to transport out of the cell by efflux transporters in
the apical cell membrane [49]. The efflux transporters for
tenofovir are likely the multidrug resistant associated proteins
2 and 4 (MRP-2,4) [49]. Dysfunction of the efflux transporters
by a single nucleotide polymorphism (SNP) has also been
shown to increase risk for FS and AKI with tenofovir therapy
[50]. In addition, competition for efflux transport by endoge-
nous substances and exogenous drugs may also impair
tenofovir secretion into the urine, ultimately raising intracel-
lular concentrations [51]. It is hypothesized that excessive
Curr HIV/AIDS Rep
intracellular drug concentrations result in tubular cell damage
by disrupting mitochondrial function [51, 52]. In support of
this, proximal tubular cell mitochondria are swollen with loss
of cristae (Fig. 3) and decreased in number when examined
histologically on electron microscopy in patients with
tenofovir-associated AKI and FS [52]. Renal proximal tubular
cells are significantly injured on light microscopy, with find-
ings consistent with a ‘toxic nephropathy’ [52].
Several studies suggest that tenofovir has significant neph-
rotoxicity that warrants surveillance of patients taking the
drug. In a study of 174 patients, a lower GFR was noted in
tenofovir-treated patient as compared with controls (97 mL/
min vs. 107 mL/min), with 38 % of patients on tenofovir (vs.
29 %) having lower GFR [53]. Proteinuria also developed in
many of the patients in the tenofovir group. In another study of
122 patients, 4.1 % of patients on a regimen including
tenofovir had a significant rise in serum creatinine as com-
pared with 0.5 % of patients not taking tenofovir [54]. In
addition, CrCl decreased by 13.3 ml/min in tenofovir-treated
patient (vs. 7.5 ml/min). Low CD4 count, diabetes mellitus,
and decreased baseline CrCl were risk factors for nephrotox-
icity [54].
A Swiss HIV cohort study reported a decline in CrCl of 4.1
to 5.5 ml/min with tenofovir as compared with no decline in
those not treated with this drug [55]. The HIV Outpatient
Study cohort study found that 3.5 % of tenofovir-treated
patients developed serum creatinine elevations and reductions
in CrCl (-3.2 ml/min vs. 1.2 ml/min) as compared with non-
tenofovir treated patients [56]. The largest trial to date, con-
ducted within the Veterans Health Administration evaluated
over 10,000 HIV patients [57•]. A 34 % increased risk of
Fig. 3 Toxic mitochondrial effects of tenofovir. Electron microscopy
reveals an overall decrease in the number of mitochondria, which range
from small and shrunken to markedly enlarged. Mitochondrial cristae are
flattened and pushed to the edges of the enlarged mitochondria and are
disoriented in many of the smaller mitochondria (6000x). Image provided
by Leal Herlitz, MD, Columbia University
 Author's personal copy
Curr HIV/AIDS Rep
proteinuria, 11 % increased risk of rapid decline in renal
function, and 33 % increased risk of CKD was noted with
tenofovir exposure. Interestingly, preexisting CKD, diabetes
mellitus, and hypertension were not associated with increased
risk for proteinuria. When compared with other HIV drugs,
tenofovir was the only antiretroviral associated with all three
previously described adverse renal outcomes. Furthermore,
drug-induced kidney damage was not reversible as the risk
of future kidney disease events persisted on follow-up despite
drug discontinuation [57•]. Another risk factor for the devel-
opment of CKD in patients with tenofovir toxicity included
black race/ethnicity, which may be supported by the genetic
polymorphisms that increase susceptibility in this population.
An association between tenofovir induced renal toxicity and a
mutation of the ABC2 gene has been previously described
[58]. It is difficult to differentiate genetic predilection to
tenofovir toxicity as these mutations are confounded by the
racial predisposition to HIV as previously described.
HIVAN or cART Nephrotoxicity: Which is it?
In current times, kidney disease is quite common in patients
with HIV infection. The actual etiology of kidney disease is
not always clear-cut and may be due to one of the patient’s co-
morbid diseases such as diabetic nephropathy, hypertensive
nephrosclerosis, ischemic nephropathy from renovascular dis-
ease, or obstructive nephropathy, to name but a few. These
patients are also exposed to numerous non-cART medications,
which can cause kidney injury through multiple mechanisms
including direct tubular injury, acute or chronic
tubulointerstitial disease, or another drug-related process. Su-
perimpose into this mix both HIVAN and cART nephrotoxi-
city, and the task is even more challenging. Thus, non-
invasively differentiating these various causes of kidney dis-
ease using clinical data is very difficult. We shall focus on
differentiating HIVAN from cART nephrotoxicity.
Approaching a patient with HIV and kidney disease re-
quires the clinician to employ all of his or her clinical skills by
performing a thorough history and physical examination,
detailed review of medication history, focused laboratory re-
view for clues pointing to one of the processes, and consider-
ing the role of kidney biopsy for definitive diagnosis (Table 2).
Historical information and physical examination evidence to
support uncontrolled HIV infection is critical. Weight loss,
fever, recurrent infections, muscle wasting, and many other
features should tip one off that HIV infection is poorly con-
trolled, whether it is due to medication partial/non-adherence
or viral resistance to drug. This would have one lean toward
HIVAN as a strong possibility and higher on the differential.
Uncontrolled blood pressure or poor diabetic control may
favor a co-morbid cause of kidney disease. Thorough
medication review is critical to sort out non-cART nephrotox-
icity from HIVAN and cART nephrotoxicity. Recent hospital-
ization and exposure to the myriad of nephrotoxic medications
(and those causing acute interstitial nephritis) as well as
NSAID use and illicit substance abuse (cocaine and designer
drugs, etc.) must be evaluated.
Laboratory tests can be helpful and provide important clues
to the cause of kidney injury (Table 2). Kidney function, as
measured by BUN and serum creatinine, can be normal in the
setting of pure drug-induced tubulopathy or abnormal in the
setting of AKI and/or CKD. Both HIVAN and cART can
present as either AKI or CKD, so tempo of kidney dysfunction
will not be helpful to differentiate the two. It is worthwhile,
however, to calculate estimated GFR in those with CKD and
follow changes over time to help understand the process going
forward. Serum chemistries can be helpful. A proximal
tubulopathy with hypophosphatemia, or either a partial or
full-blown FS will point to cART nephrotoxicity, especially
if tenofovir is part of the regimen. While not perfect, the CD4
count and HIV viral load are helpful in understanding the
status of HIV therapy and whether disease is under control.
For example, adequate CD4 count and unmeasurable viral
load strongly suggests that HIVAN is unlikely the cause of
kidney disease and can be helpful when used along with other
clinical information.
Urinalysis is a critical part of any initial evaluation and
should include a thorough microscopic examination of the
spun urine sediment. The presence of high-grade proteinuria,
which should be quantified with either spot protein/creatinine
measurement or 24-hour urine collection, is more indicative of
HIVAN rather than cART nephrotoxicity. Low-grade or ‘tu-
bular’ proteinuria is more suggestive of cART kidney injury,
which can be reflective of an isolated proximal tubulopathy or
acute tubular injury/necrosis with or without tubulopathy.
Dipstick positive glucosuria in the setting of normal serum
glucose concentration supports FS and tenofovir-related inju-
ry. In this setting, collecting urine to calculate the fractional
excretion of phosphate may help sort out whether proximal
tubular phosphate wasting is present. Hematuria and
leukocyturia can be seen with indinavir or atazanavir-related
kidney injury, primarily due to crystal-related tubular injury,
acute interstitial nephritis, or nephrolithiasis. HIVAN rarely
has hematuria and leukocyturia in the absence of another
superimposed process (UTI, etc.). The appearance of needle-
like or rod-like crystals supports one of the crystal-forming
drugs as causative. In contrast, patients with HIVAN will
typically have bland urine sediment with possible hyaline/
proteinacious casts and scattered RTE cells on urine
microscopy.
Renal ultrasonography is often part of the evaluation of the
patient presenting with kidney disease. The degree of
echogenicity may be modestly helpful in the evaluation of
HIVAN as the cause of kidney disease. For example, very
 Author's personal copy
large and intensely echogenic kidneys in the HIV patient with
high-grade proteinuria and bland urine sediment makes
HIVAN a real possibility. In contrast, small kidneys that are
moderately echogenic make HIVAN less likely, but do not
definitely exclude this lesion. Ultrasound may demonstrate
stones and/or hydronephrosis during scanning, which can
point toward asymptomatic indinavir or atazanavir-related
nephrolithiasis. CT scan adds nothing to ultrasound except
that this imaging modality visualizes stones more accurately,
but is not otherwise helpful in differentiating HIVAN from
cART nephrotoxicity. Ultimately the gold standard for diag-
nosis of underlying kidney disease in HIV patients is kidney
biopsy. As such, it is recommended for patients where the
cause of kidney disease is unclear and appropriate manage-
ment requires the correct diagnosis. In addition, biopsy is
required with acute worsening of kidney function or increas-
ing level of proteinuria. In addition, biopsy is often carried out
when more than one cause remains possible.
Conclusion
HIV patients are living longer and benefitting from a near
normal lifespan due to the development and implementa-
tion of effective and potent antiretroviral agents. Howev-
er, more prolonged cumulative exposures to co-morbid
diseases and end-organ complications of medical therapy
represent one part of the price paid for this success.
Kidney disease is one such adverse effect that develops
in this group. Combination ART has reduced direct HIV-
related kidney injury, but it has not completely eliminated
this adverse kidney process. Antiretroviral drugs also
cause various forms of kidney injury. Thus, clinicians
must carefully dissect out the potential causes of kidney
disease in this group—often wrestling with the possibility
of HIVAN vs. cART nephrotoxicity in an individual.
Clinical parameters must be thoroughly evaluated along
with laboratory data to synthesize a logical differential
diagnosis, which yields the most likely cause of kidney
disease. However, a kidney biopsy may be required to
garner a final, definitive diagnosis and appropriate man-
agement plan. Thus, a detailed evaluation by a nephrolo-
gist is essential in diagnosis and management of kidney
disease in this patient population.
Compliance with Ethics Guidelines
Conflict of Interest Neelja Kumar and Mark A. Perazella declare that
they have no conflict of interest
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
Curr HIV/AIDS Rep
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