HIV Nephropathy

Overview

Human
immunodeficiency virus (HIV) infection can cause a broad spectrum of
clinical manifestations, ranging from an asymptomatic carrier state to
severe immunodeficiency. Renal disease is a relatively common
complication in patients with HIV disease.^[1] Renal
disease can result from direct kidney infection with HIV or from the
adverse effects of medications used to treat the virus (see the image
below).^{[2, 3]} Further,
patients with HIV disease are at risk for developing prerenal azotemia
due to volume depletion resulting from salt wasting, poor nutrition,
nausea, or vomiting

.

Types
of electrolyte abnormalities observed with some of the drugs used to
treat opportunistic infections in patients with human immunodeficiency
virus (HIV). ARF stands for acute renal failure. HIV-associated nephropathy (HIVAN), formerly known as AIDS-associated nephropathy, is characterized by the following findings:

• Nephrotic range proteinuria
  
• Azotemia
  
• Normal to large kidneys on ultrasonographic images
  
• Normal pressure
  
• Focal segmental glomerulosclerosis (FSGS) on renal biopsy findings
  

Once
HIVAN was diagnosed, rapid progression to renal failure and end-stage
renal disease (ESRD), leading to the need for dialysis, was the norm in
the preantiretroviral therapy era. Highly active antiretroviral therapy
(HAART) has changed the natural course of this disease. Although FSGS is
the predominant glomerular lesion in HIVAN, other reported glomerular
lesions in patients with HIV include IgA nephropathy, cryoglobulinemia,
amyloidosis, and a lupuslike immune complex glomerulopathy. Physicians
must consider HIVAN in patients who are seropositive for HIV and have
proteinuria. For excellent patient education resources, visit eMedicine's Immune System Center and Sexually Transmitted Diseases Center. Also, see eMedicine's patient education articles HIV/AIDS and Rapid Oral HIV Test.

Epidemiology

According
to the US Renal Data System (USRDS), HIV-associated nephropathy (HIVAN)
accounts for approximately 1% of new ESRD cases in the United States.
HIVAN is observed in patients regardless of the route by which HIV was
contracted. HIVAN is observed predominantly among African Americans and
is the third leading cause of ESRD among black persons aged 20-64 years.^{[4, 5]} Most patients with HIVAN are young black males, and approximately 50% of patients with HIVAN are intravenous addicts.^[6] Overall,
HIVAN is observed more often in men than in women, with a male to
female ratio of 10:1. The mean age of persons with HIVAN is 33 years.
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Pathogenesis

Experiments
using transgenic mice have provided perhaps the strongest evidence for a
direct role by HIV type 1 (HIV-1) in the development of HIV-associated
nephropathy (HIVAN). Researchers created transgenic mice by inserting
HIV deoxyribonucleic acid (DNA) constructs into the mice's genomes. The
mice developed proteinuria and had a histologic picture similar to that
observed in patients with HIVAN. A genetic or environmental cofactor
that has not yet been identified is required for patients to develop
this disease, which may explain the racial predilection for HIVAN among
black persons.^[4] The
cellular target in the development of HIVAN is probably the renal
glomerular and tubular epithelium. Using in situ hybridization and
polymerase chain reaction assays to detect HIV-1 DNA and messenger
ribonucleic acid (mRNA), investigators have shown that renal glomerular
and tubular epithelial cells are productively infected by HIV-1 in
patients with HIVAN; this argues strongly for localized replication of
HIV-1 in the kidney and for the existence of a renal viral reservoir.
Further, circularized viral DNA, a marker of recent nuclear import of
full-length, reverse-transcribed RNA, has been detected in kidney biopsy
samples from patients with HIVAN, suggesting active replication in
renal tissue. However, the mechanisms of virus-induced renal injury
remain undetermined. Peculiar histopathologic features of HIVAN
are the enhanced proliferation and the loss of differentiation markers
of glomerular epithelial cells. In one study, HIV-1 infection was shown
to kill renal tubular epithelial cells in vitro by triggering an
apoptotic pathway involving caspase activation and Fas up-regulation,
suggesting that apoptosis of nonlymphoid cells can be directly induced
by HIV-1. The net and long-standing glomerular and tubular epithelial
cell damage leads to proteinuria, glomerulosclerosis, and
tubulointerstitial scarring. The role of cytokines has not been
established, and although their presence is not essential for the
development of HIVAN, cytokines may modify the progression of infection
or a patient's susceptibility to infection. The levels of cytokines are
increased in renal biopsy samples from patients with HIVAN. In one
study, mesangial and tubular cell production of interleukin-6 and tumor
necrosis factor – alpha was shown to be a potent stimulus for HIV-1
expression in HIV-1 – infected monocytes.^[7] Viral replication in response to cytokines may play an important role in the pathogenesis of HIVAN.
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Genetics

The reason behind the increased predilection among black persons for the development of HIV-associated nephropathy is not clear.^[4] In
general, black persons have a higher incidence of other renal diseases
(eg, diabetic nephropathy, lupus, abuse); therefore, they may have an
underlying genetic predisposition to severe renal disease, regardless of
the etiology. The type of host response to the HIV infection itself may
be what determines whether or not nephropathy develops in a specific
individual.Kopp et al studied genetic variants predisposing to
idiopathic and HIV-1–associated focal segmental glomerulosclerosis
(FSGS) by carrying out admixture-mapping linkage-disequilibrium genome
scan on 190 African American individuals with FSGS and 222 controls.^[8] They identified a chromosome 22 region centered on MYH9, a functional candidate gene expressed in kidney podocytes. They concluded that genetic variation at the MYH9 locus substantially explains the increased burden of FSGS and hypertensive kidney disease among African Americans.
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Histology

When
examined using ultrasonography or computed tomography (CT) scanning,
patients with HIV-associated nephropathy (HIVAN) have enlarged and
echogenic kidneys. This may result from prominent interstitial expansion
by cellular infiltrate and markedly dilated tubules containing
voluminous casts. Findings from light microscopy of kidney biopsy
tissue are diagnostic in most cases. The most common histologic light
microscopy finding is a collapsing form of focal segmental
glomerulosclerosis.^[9] The
glomerular capillary tuft is collapsed (see the first image below) and
may be segmentally or globally sclerosed. Visceral epithelial cells are
hypertrophied and form a characteristic pseudocrescent in the Bowman
space. Tubulointerstitial scarring, atrophy, and marked dilatation of
the tubules (microcystic dilatations) are usually present (see the
second image below).



Light
microscopy with trichrome staining showing the collapse of the
glomerular tuft, with segmental glomerular and interstitial sclerosis
(bluish staining). The renal tubules are dilated and filled with
proteinaceous material.



Light
microscopy showing prominent microcystic dilatation of renal tubules
filled with proteinaceous material; this finding is characteristic of
human immunodeficiency virus (HIV)–associated nephropathy, although it
may also be observed in chronic glomerulonephritis.Immunofluorescent
microscopy helps to identify positive staining for albumin and
immunoglobulin G in epithelial cells and for immunoglobulin M, C3, and
(occasionally) A in mesangial or sclerotic areas. Electron microscopy
reveals wrinkling of the basement membranes, epithelial cell
proliferation, and focal foot process effacement. Tubuloreticular
structures in the glomerular endothelial cells (see the image below),
consisting of ribonucleoprotein and membrane, the synthesis of which is
stimulated by alpha interferon, is highly predictive of

HIVAN.



Electron
microscopy showing a segment of the glomerular basement membrane; foot
process effacement (black arrow) and prominent tubuloreticular
inclusions (red arrow) are present.
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Clinical Features

Patients with HIV-associated nephropathy (HIVAN) typically present with a nephrotic syndrome consisting of nephrotic-range proteinuria (>3.5 g/d), azotemia, hypoalbuminemia,
and hyperlipidemia. Edema is uncommon in HIVAN, yet many authors think
that this is a characteristic of HIVAN. The salt-losing propensity and
high oncotic pressure contributed by marked hypergammaglobulinemia
in these patients have been suggested as possible explanations for this
puzzling observation. The CD4 count in patients with HIVAN is usually
depressed below 200 cells/µL, but HIVAN has been reported in patients
with higher CD4 counts. The prognosis for renal survival is worse in
patients with clinical acquired immunodeficiency syndrome (AIDS),
especially if their CD4 count is less than 50 cells/µL. Patients
with HIVAN are not typically hypertensive, even in the face of renal
insufficiency, and their kidneys are usually normal to large in size and
highly echogenic on ultrasonograms. Routine urinalysis may occasionally
reveal findings of nonnephrotic proteinuria in patients being evaluated
for other medical conditions. The urinalysis reveals microhematuria,
leukocytes, hyaline casts, and oval fat bodies, but no cellular casts.
Serum complement levels are normal. In one study, the rate of
progression from the initial presentation to ESRD was 2.5 months in the
pre-HAART era. With the introduction of HAART in 1996-1997, the
traditional natural history of rapid progression of HIVAN has been
slowed significantly. HAART therapy has been shown to retard the
progression of renal disease in persons with HIVAN. Electrolyte
abnormalities, such as hyponatremia and hyperkalemia, may be observed in
patients with HIVAN and may reflect an increase in total body water
(from nephrotic syndrome
or syndrome of inappropriate secretion of antidiuretic hormone [SIADH])
or from hyporeninemic hypoaldosteronism, respectively. SIADH may result
from concomitant pulmonary infection or from persistent nausea from
medications or gastrointestinal disease. Hyporeninemic
hypoaldosteronism, a cause of type IV renal tubular acidosis manifesting
as hyperkalemia with normal anion gap metabolic acidosis, is much more
common when renal insufficiency is present. Most HIV medications
are well tolerated, even in the presence of renal insufficiency. The
(potential) toxicity of the nucleoside reverse transcriptase inhibitors
(ie, zidovudine,^[10] didanosine,
zalcitabine, stavudine, lamivudine, abacavir, emtricitabine) uniformly
manifests as type-B lactic acidosis. However, didanosine may cause
electrolyte abnormalities, such as hypokalemia, hyponatremia,
hypermagnesemia, and hyperuricemia, and stavudine may cause
hyperuricemia. Tenofovir is a nucleotide reverse transcriptase inhibitor
with known renal toxicity and hypophosphatemia and therefore dose
adjustment is indicated when creatinine clearance is less than 50
mL/min. Except for nevirapine, which may cause lactic acidosis, the
nonnucleoside reverse transcriptase inhibitors (ie, nevirapine,
delavirdine, efavirenz, etravirine) have no reported significant renal
toxicity. As a class, the protease inhibitors (ie, saquinavir,
ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, lopinavir,
atazanavir, tipranavir, darunavir) may precipitate nephrolithiasis. A
classic form of this is indinavir crystalluria, which occurs
independently of renal function; however, the stones resolve after
cessation of indinavir therapy. Enfuvirtide (Fuzeon) is the first of a
newer class of fusion inhibitors that targets the gp41 protein on HIV's
surface and stops the virus from entering cells. Enfuvirtide has no
known renal effects for creatinine clearance of greater than 35 mL/min.Maraviroc
(Selzentry), approved in August 2007, is also a fusion inhibitor that
targets the CCR5 protein and stops the virus from entering cells.
Selzentry does not require dose adjustment for creatinine clearance
greater than 50 mL/min. Raltegravir (Isentress) is the first of a newer
class of integrase strand transfer inhibitors; it does not require dose
adjustment in patients with abnormal renal function.Dose
adjustment should be made in patients receiving nucleoside reverse
transcriptase inhibitors when the glomerular filtration rate falls below
50 mL/min. Patients receiving nonnucleoside reverse transcriptase
inhibitors may also receive a dose adjustment when the glomerular
filtration rate falls below 50 mL/min. No dose adjustment is required
for patients taking protease inhibitors. Some drugs used to treat
opportunistic infections in HIV disease may also cause nephrotoxicity or
electrolyte abnormalities (see the image below).



Types
of electrolyte abnormalities observed with some of the drugs used to
treat opportunistic infections in patients with human immunodeficiency
virus (HIV). ARF stands for acute renal failure.
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Indications for Biopsy

The
decision to obtain a biopsy sample is somewhat controversial in the
general medical community. Even if a patient presents with the classic
clinical features of HIV-associated neuropathy (HIVAN), clinical
consideration is predictive of the biopsy diagnosis in only 55-60% of
patients. Therefore, to distinguish HIVAN from other forms of renal
disease (eg, immune complex glomerulonephritis, immunoglobulin-A
nephropathy), patients who are seropositive for HIV require a renal
biopsy. The typical practice is to obtain a renal biopsy specimen if the
patient's daily protein excretion is greater than 1 gram.
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Next Section: Epidemiology

Treatment & Management

Antiretroviral therapy

The best course of treatment involves a collaborative effort between a nephrologist and an HIV disease specialist.^[3] The
current United States Public Health Service standard is to initiate
aggressive combination antiretroviral therapy (ie, HAART) for all
patients with advanced or symptomatic HIV disease, or advanced disease
defined as a CD4 count of fewer than 350 cells/µL. Other authorities and
guidelines also recommend therapy for an HIV plasma viral load of
greater than 100,000/ml. Although there are no guiding clinical studies,
some experts recommend consideration of therapy in all patients with
HIV-associated nephritis (HIVAN). A report from the USRDS shows that the
incidence of HIVAN appears to have declined since the introduction of
HAART.HAART is in constant evolution. The reader is referred to
other chapters in this text for specific information, including
recommendations for dosage adjustments for renal insufficiency.
Angiotensin-converting enzyme (ACE) inhibitors

In patients with advanced renal insufficiency, captopril was noted to improve renal survival for a mean length of 37-156 days.^[11] In
a subsequent prospective follow-up of 44 patients, the median length of
renal survival for patients who received fosinopril was 479.5 days,
with only 1 patient developing ESRD. All untreated control subjects
progressed to ESRD, with a median length of renal survival of 146.5 days
(P < 0.0001). The exact mechanism of action of this class of drugs
is unknown, but it may be related to a hemodynamic effect, a reduction
in the transglomerular passage of serum proteins, and an
antiproliferative effect mediated in part by the inhibition of
transforming growth factor beta. Use ACE inhibitors if patients do not
have hyperkalemia.
Corticosteroids

A number of case reports have suggested that corticosteroids offer some short-term benefit.^[12] In
one report, results from a pretreatment and posttreatment kidney biopsy
suggested that an improvement in renal function was associated with a
reduced number of lymphocytes and macrophages infiltrating the
interstitium. In another report, 20 patients were treated with
prednisone at 60 mg/d for 2-11 weeks, followed by a slow taper.^[13] After
a follow-up of 44 weeks, 8 patients required maintenance dialysis, 11
died from complications, and 7 were alive and no longer had ESRD.
Cyclosporine

Some
reports on pediatric populations suggest that cyclosporine can be
effective in reducing the proteinuria observed in persons with HIVAN.
The usefulness of cyclosporine therapy for HIVAN warrants further study.
Promising therapeutic strategies in animal studies

Animal
research shows promising results for retarding renal disease
progression in HIVAN. In one study, the use of a cyclin-dependent kinase
inhibitor decreased visceral epithelial cell proliferation in
HIV-infected mice.^[14] In
another study, blocking nuclear factor kappa beta (a cell signaling
pathway) in mice resulted in increased lifespan and kidney and lean body
mass preservation.^[15] These
benefits were associated with a reduction in the number of CD45(+)
cells infiltrating the kidneys, amelioration of the renal architecture,
and a reduction in the level of circulating inflammatory cytokines.
Further studies are needed to determine the role of these inhibitors on
human HIVAN.Dialysis and transplantation

Patients with
HIVAN who progress to ESRD remain a clinical challenge. Physicians must
anticipate progressive renal disease in patients with HIVAN and have as a
goal the placement of an arteriovenous fistula in a timely manner for
future use in hemodialysis. In current practice, hemodialysis is the
accepted modality of ESRD therapy in these patients.In one
long-term study looking at survival on dialysis in the HAART era, Ifudu
et al showed that during the 68-month observation period, 17 (50%) of
the 34 patients with HIV infection and ESRD died, compared with 65 (50%)
of the 131 patients with ESRD alone (p = 0.49).^[16] Mean
(± SE) survival was equivalent between patients with both HIV infection
and ESRD (47.4 ± 4.6 mo; 95% CI 39,56) and those with ESRD alone (50.2 ±
1.9 mo; 95% CI 46,54) (log-rank test, p = 0.49). The authors concluded
that the survival of patients with HIV infection and ESRD receiving
hemodialysis has improved significantly compared with the uniformly
dismal outcomes in the 1980s.Because of increased susceptibility
to infections, peritoneal dialysis has not been widely advocated. For
the same reason, the general theory is that immunosuppression after
kidney transplantation would pose a substantive risk of opportunistic
infections in patients with HIVAN.^[17] Consequently,
kidney transplantation in these patients is performed with caution in
compliant, stable patients with no prior opportunistic infections who
have an undetectable viral load and a CD4 count of more than 300
cells/µL. Anecdotal reports drawn from small samples of this selected
group of patients with HIVAN suggest no extra risk of opportunistic
infections; however, until larger studies are performed, transplantation
in persons with HIVAN should be focused on stable patients as mentioned
above. In one study, 1- and 2-year actuarial patient survival
was 85% and 82%, respectively, and graft survival was 75% and 71%,
respectively. Plasma HIV-1 RNA remained undetectable, and CD4 counts
remained in excess of 400 cells/µL with no evidence of AIDS for up to 2
years. These results were comparable to other high-risk populations
receiving kidney transplantation.In an analysis of the United
Network for Organ Sharing (UNOS) database, Locke et al evaluated 39,501
patients undergoing renal transplantation between January 1, 2004, and
June 30, 2006.^[18] No difference was found in patient survival among HIV-positive patients compared with HIV-negative patients (95.4% vs 96.2%; P = .32). However, death censored 1 year graft survival was significantly lower among HIV-positive patients (87.9% vs 94.6%; P
= .03). They concluded that with proper donor selection and transplant
recipient management, including the avoidance of prolonged cold ischemic
time, use of living donors, and determination of optimal
immunosuppression dosing before transplant, long-term graft survival
comparable to that in HIV-negative patients can be achieved.