1
Human Immunodeficiency Virus–Associated Renal Diseases
Since the beginning of the epidemic, a spectrum of renal diseases has been associated with acquired
immunodeficiency syndrome (AIDS) and HIV infection (17,294,295,296,297,298,299). Several welldefined clinicopathologic disorders have been reported in patients with HIV infection, including a number of
different forms of glomerular diseases and a variety of immune complex and vasculitic illnesses
(17,294,295,296,297,298,299). These disorders do not occur or are not detected with a frequency
commensurate with the prevalence of HIV infection, affecting at most 10% of the population at risk, in the
era before highly active antiretroviral drug therapy (HAART) (294,298,299,300). Therefore, the renal
diseases probably do not result from HIV infection alone, but from a combination of the infection and the
immunologic responses of the host (17,295,298,299,300,301). Renal complications affect specific subsets of
the HIV-infected population, primarily male African American patients in the United States
(294,295,296,297,298,299,300,301,302,303,304,305), suggesting that a host response or genetic component
may be associated with the incidence of the disease (294,295,296,297,298,299,300,301,302,303,304,305).
Factors linked to socioeconomic status may also be related to disease pathogenesis (305).
The common renal syndromes in HIV-infected patients include asymptomatic urinary abnormalities, acute
renal failure, chronic renal insufficiency, and nephrotic range proteinuria associated with focal
glomerulosclerosis, the classic HIV-associated nephropathy (HIVAN)
(294,295,296,297,298,299,300,302,303,306), and various proliferative glomerulonephritides, which may be
termed HIV-associated immune complex disease (HIVICD)
(294,295,297,298,299,302,303,307,308,309,310,311,312,313,314,315,316,317,318,319,320) (Table 59-9).
Over the past decade it has become clear that there are four syndromes of chronic renal disease intimately
associated with HIV infection. These are HIVAN, HIVICD, including HIV-associated IgA nephropathy, and
HIV-associated thrombotic microangiopathy (17,295,298,299). Other renal diseases in HIV-infected
patients, including cryoglobulinemia and vasculitis, may be related to host responses to the infection, or
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infections complicating the immunodeficiency state. Additionally, treatment effects may be associated with
adverse renal outcomes
(298,299,300,301,302,303,304,305,306,307,308,309,310,311,312,313,314,315,316,317,318,319,320,321).
TABLE 59-9 Glomerular syndromes associated with human immunodeficiency virus infection
HIV focal glomerulosclerosis (classic HIV-associated nephropathy)
HIV mesangial hyperplasia
HIV-associated immune complex disease
IgA nephropathy
Idiotypic
Other mechanisms
Immune complex proliferative glomerulonephritis
Postinfectious
Lupus-like
Mixed immune complex–sclerotic
Classic Human Immunodeficiency Virus–Associated Nephropathy
Epidemiology and Clinical Features
Classic HIVAN is the most commonly reported chronic renal disease associated with HIV infection
(17,294,295,296,297,298,299,300,322,323). This may be due in part to its association with the nephrotic
syndrome and the reluctance of performing biopsies in patients with HIV infection and mild urinary
abnormalities. The disease disproportionately affects men of African heritage
(294,296,297,298,299,300,302,305,322,323), which may also account for the relative frequency of HIVAN
reported in biopsy series from Europe and the United States. Clinical highlights of the disease are nephrotic
range proteinuria and renal insufficiency. In most reports, hypertension and edema are relatively uncommon.
2
This may be a consequence of the stage of disease or the presence of malnutrition in patients. The kidneys
are large and echogenic on ultrasonic examination (294,296,297,302,303,322,323).
Pathology
HIVAN has been termed a “pan nephropathy― because of characteristic involvement of the glomeruli,
tubules, and interstitium (324). Glomerular capillary wall collapse of varying severity is often noted
(296,297,298,299,324,325). Mesangial hyperplasia and other abnormalities may be an early stage of the
nephropathy (294), or this histologic variant may differentially involve children. Glomerular visceral
epithelial cells are characteristically abnormal, exhibiting hyperplasia, hypertrophy, and vacuolation.
Varying degrees of segmental or diffuse and global increased mesangial matrix are seen, as well as
obsolescent glomeruli (17). Tubular cells show marked degenerative changes, flattening, simplification,
brush-border abnormalities, and necrosis. Microcystic tubular dilation and hypertrophy are common. The
interstitium shows immune cell infiltration of mononuclear cells, primarily macrophages and T-lymphocytes
(17,325,326). Interestingly, T-lymphocytes are more prevalent than B-lymphocytes (326). Interstitial
fibrosis and edema of the interstitium are common. Results of immunofluorescent evaluations are variable
and nondiagnostic. Electron microscopy shows glomerular epithelial cell foot process effacement, wrinkling,
and abnormalities of glomerular basement membrane structure (294,325). Tubular reticular structures are
common, but not pathognomonic. They are found in glomerular and peritubular capillary endothelial cells
and are probably a concomitant of the action of IFN-α.
Although the individual features of HIV focal glomerulosclerosis are not specific, the concomitant findings
of glomerular collapse, glomerular and tubular epithelial cell abnormalities, increased mesangial matrix,
renal tubular atrophy or microcystic dilation, and interstitial immune cell infiltration, in combination with
tubular reticular structures are virtually diagnostic of classic HIVAN (17,299,324,325). The
clinicopathologic characteristics of HIVAN have been compared to those of the collapsing variant of focal
segmental glomerulosclerosis in the absence of HIV infection and found to be similar (327). Although it can
be suspected on clinical grounds, the diagnosis of HIVAN cannot be made reliably in the absence of a
biopsy, since other diseases such as diabetic nephropathy and HIV-associated immune complex renal
disease can have similar presentations and features.
Pathogenesis
Although early in the epidemic, HIVAN was thought by some to be an epiphenomenon, or a complication
secondary to intravenous drug use in patients, several lines of evidence suggest the renal disease is
intimately related to infection with HIV (17,294,295,299,322,323). The development of classic HIVAN in
the infant children of mothers with HIV infection (328) and the development of renal disease reminiscent of
HIVAN in transgenic murine models (29,296,329,330,331,332) and in primates infected with simian
immunodeficiency virus (SIV) (333,334,335) underscore the pathogenic relationship between the virus and
the renal disease. Expression of HIV proteins within renal tissue appears to be a prerequisite for the
development of renal disease (16,17,29,295,296,299,322,323,329,330). HIV proteins may affect renal cell
biologic responses in diverse ways (299). HIV peptides are toxic to many cell types (16,17). Apoptosis of
renal cells secondary to exposure to HIV peptides or as a result of their expression within renal tissue is a
probable cause of renal disease and a matter of current research interest
(16,17,295,296,299,322,323,329,330,336,337).
Abnormal proliferation and dedifferentiation of podocytes may be related to HIV infection of renal tissue
and the expression of Nef (299,338) on signal transduction pathways (338) and cyclin biology (338,339).
Stat3 and MAPK1,2 phosphorylation were increased in podocytes from kidneys of patients with HIVAN,
compared to those of uninfected patients with focal segmental glomerulosclerosis (FGS) and other renal
diseases, as well as kidneys from HIV-infected patients in the absence of renal disease, implicating these
pathways in HIVAN pathogenesis, however other mediators are involved (338). Kajiyama et al. showed, in
HIV-1 transgenic mice, that Nef is not necessary for induction of renal disease, but may rather potentiate
nephropathy dependent on the expression of other HIV-1 gene products (340). Dickie et al. showed, in
transgenic mice with mutations in either or both nef and vpr accessory genes, that proteinuria and FGS
developed only in animals carrying the vpr gene. In animals encoding Tat and Vpr, Vpr protein was
localized by immunostaining in glomerular and tubular epithelium. Breeding experiments produced mice
3
with increased severity of nephropathy without increase of Vpr expression, leading the authors to conclude
multiple genes must contribute to the development of renal disease in HIV-1 transgenic mice (341).
Inhibition of cyclin-dependent kinase improved urinary and histopathologic parameters of nephropathy in
HIV-1 transgenic mice (342,343). Dysregulation of podocyte biology may be an important mediator of the
development of HIVAN, and abnormal expression of glomerular epithelial cell proteins is associated with
the disease
(16,299,322,323,324,325,326,327,328,329,330,331,332,333,334,335,336,337,338,339,340,341,342,343,344,
345). Podocan expression was increased in podocytes of HIV-1 transgenic mice compared with controls
(346). Increased expression of transforming growth factor-β, perhaps as a result of viral infection, is also a
possible mediator of nephropathy (347,348,349,350). Interestingly, expression of transforming growth factor
beta has been linked to apoptosis of podocytes (350).
We compared tissue levels of transforming growth factor- β and chemokines from biopsies of patients with
HIV-associated nephropathy, HIV-associated glomerulonephritis and idiopathic focal glomerulosclerosis
without HIV infection (299,351). Transforming growth factor-beta, monocyte chemoattractant protein-1
(MCP-1) and RANTES levels were increased in renal glomerular and interstitial tissue from patients with
HIV infection, regardless of the type or presence of renal disease, suggesting chemokine expression might
be a nonspecific response. Renal chemokine expression could act to interfere with local HIV infection by
engaging renal chemokine receptors. These data are also consistent with renal deposition of circulating
chemokines. In contrast, proteins associated with antigen presentation and response to infection, such as
MHC-Class II proteins, interferon-α, and interferon-γ receptor protein were specifically increased in
glomerular and interstitial tissue of biopsies of patients with HIV-associated nephropathy, compared with
uninfected control tissue with and without renal disease, or renal diseases in the setting of HIV infection.
The findings suggest genetic susceptibility, host responses, and a immunologically activated
microenvironment may be critical to disease pathogenesis. High levels of tissue interferon-α are consistent
with the pathologic feature of tubuloreticular inclusions (299). The pathogenesis of HIVAN is probably a
concomitant of relationships between renal cellular infection and immune cell infiltration, effects on renal
and infiltrating cellular cytokine, growth factor, and chemokine responses, and host factors. In addition,
clinical and animal studies suggest an important role for genetic susceptibility in association with the
development of nephropathy (301,352). Socioeconomic status, including access to antiretroviral medications
may also be an important determinant of outcome (298,299,353).
Many of these processes depend on the presence of productive infection of renal cells by HIV. We showed
that HIV DNA was present in renal tissue of patients with and without nephropathy (23). Detection of HIV
RNA in renal tissue of patients with HIVAN has recently been confirmed
(322,323,324,325,326,327,328,329,330,331,332,333,334,335,336,337,338,339,340,341,342,343,344,345,34
6,347,348,349,350,351,352,353,354,355,356). Renal cells can be infected by HIV in vivo
(16,295,296,354,355,357). Tubular and glomerular epithelial cells can be infected by HIV in vitro
(337,358), but in some studies mesangial cells could not (359). Infection of the glomerular epithelial cell and
subsequent podocyte injury may be critical to the pathogenesis of HIVAN (16,299,322,323,330,344). The
infiltration of immune cells in renal tissue may be associated with progressive nephropathogenesis (326).
Preliminary evidence suggests chemokine receptors are not present on renal cells from biopsy tissue
(360,361,362), although they may be expressed in pathologic states in inflammatory cells in renal tissue
(360), and may be detected by molecular techniques in vitro (337). Differential expression of chemokine
receptors in renal tissue in different HIV-infected populations could be associated with different patterns of
susceptibility to renal disease. The role of expression of CD4 and coreceptors for HIV infection in renal cells
must be further investigated.
Prognosis and Treatment
Treatment studies have sharpened our understanding of the pathogenesis of HIV-associated diseases. In the
era before widespread availability of antiretroviral therapy, HIVAN was characterized as a disease with an
extremely rapid progression to its end stage (294,363,364). Several anecdotal studies suggested
antiretroviral therapy improved the course of HIVAN (reviewed in [16,363,364]). Four therapeutic
approaches have been used in patients with HIVAN. Limited data suggested cyclosporine ameliorated the
4
course of the renal disease (363), but few patients have been assessed with this therapy. In addition, concern
has been raised regarding the risk/benefit ratio of immunosuppression in patients with HIV infection.
Several of these reports are difficult to evaluate since treated patients were not always evaluated with renal
biopsies. Individual case reports (17,363,364,365,366,367) have suggested glucocorticoids may be effective
in slowing the progression of HIVAN. A case series of patients with HIV infection and renal disease, treated
with steroids, showed impressive diminution in urinary protein excretion and improvement in renal function
(368). These studies, unfortunately, were not performed in a randomized controlled manner. In addition,
there was a relatively high frequency of side effects such as psychosis, gastrointestinal bleeding, and
infections (368). Finally, since survival analyses were not conducted in this series, the long-term effects of
such treatments were poorly understood. More recently, Eustace et al. (369) found a salutary effect of
treatment of patients with HIVAN with CS. Almost a quarter of patients maintained sufficient renal function
to remain independent of need for renal replacement therapy for up to a year, in contradistinction to previous
findings. Patients treated with CS, however, had longer hospital stays. Concurrent therapy with antiretroviral
drugs and drugs which inhibit the renin-angiotensin system, as a result of advances in therapeutics, may
have influenced outcomes in this uncontrolled study.
The angiotensin-converting enzyme (ACE) inhibitors, captopril and fosinopril, have been used in patients
with HIVAN both to decrease urinary protein excretion and to halt progression of disease. Therapy with
captopril increased length of time before death or start of dialysis in a case-control study (17,363,364). Nine
patients with HIVAN were treated with captopril. Their course was compared to age, race, gender, CD4
count, and serum creatinine concentration versus matched control patients untreated with ACE inhibitors.
All patients in both groups had HIVAN evaluated on renal biopsy. Renal survival was longer in patients
treated with captopril. In another study, HIV-infected patients with proteinuria were treated with fosinopril
(370). Patients who refused fosinopril treatment had an increase in serum creatinine concentration compared
with those treated with fosinopril. These studies suggest a therapeutic effect of ACE inhibitors in patients
with HIVAN. Neither of these studies was randomized or placebo-controlled. Wei et al. recently reported
long-term results in the patients treated with fosiniopril, suggesting excellent outcomes (371). Twenty-eight
patients were treated with fosinopril, compared to 16 in an untreated comparison group, in this
nonrandomized, non–time-controlled study. Mean renal survival was 479.5 days in treated patients
compared with 146.5 days in the comparison group. All patients untreated with ACE inhibition went on to
ESRD, compared with one patient in the fosinopril group during a more than five year observation period.
The authors however could not show an independent effect of treatment with antiretroviral drugs in this
small uncontrolled study. Once again, the influence of change in clinical practice, especially regarding the
use of antiretroviral drugs and HAART must be considered as potential confounding factors.
These findings were corroborated in studies of Bird et al. (372), who showed administration of captopril to
HIV-transgenic mice that exhibited characteristics of HIVAN was associated with improvement of several
renal functional parameters, such as urinary protein excretion, azotemia, and histologic abnormalities,
despite the expression of HIV genes. A likely mechanism underlying the action of these drugs is the
decrease in the expression of transforming growth factor beta afforded by ACE inhibitors
(347,363,364,372).
Studies of treatment with antiretroviral drugs before the HAART era were inconclusive, because of small
size and lack of definitive controls (298,299), but often showed beneficial effects on the nephropathy, as
well as morbidity and mortality (298,299,322,323,354,373). Recent uncontrolled studies have suggested
improved outcomes in patients with HIV infection and renal disease treated with HAART (374,375,376).
Interpretation of the findings is often difficult because biopsies are often not performed in all patients
reported. In patients treated with captopril, use of antiretrovirals was independently associated with
improved renal survival (364).
A case report detailed improvement in the nephrotic syndrome in a child treated with HAART (377). Two
cases of patients with HIVAN complicating early stages of infection demonstrate treating patients with HIVassociated nephropathy with HAART may cause resolution of both functional and pathologic abnormalities
(354,378), although productive infection of kidney tissue may continue (354). Recent work in an
5
uncontrolled observational cohort of patients with HIV infection and renal disease who underwent renal
biopsy suggests treatment with antiretroviral drugs was associated with improved outcomes in patients with
HIVAN (353). Such data also bolster evidence for the causal relationship between viral infection and
nephropathy.
ACE inhibitors represent a safe, possibly effective long-term therapy for patients with HIVAN. Because
there is evidence that treatment with both HAART and ACE inhibitors is associated with improved
outcomes in patients with HIVAN, the field requires implementation of well-designed and powered
randomized controlled therapeutic trials of antiviral therapies and ACE inhibitors in patients stratified for
age, gender, and histologic parameters, in whom virologic and immune parameters, as well as side effects,
are carefully delineated. In some patients treated with both ACE inhibitors and HAART, in whom the
disease progresses, consideration may be given to the use of CS. The role of treatment with CS, however, is
unclear and awaits the performance of controlled clinical trials to determine its utility and safety. The
development of renal disease in a patient with HIV infection may be an indication for HAART, regardless of
stage of the viral illness, unless it is specifically contraindicated (298,299,322). Because not all renal disease
in HIV infected patients is HIVAN, consideration should be given to performing a renal biopsy if the
diagnosis is unclear (298,299,353).
Initial reports indicated survival of HIV infected patients with ESRD treated with dialysis was poor
(299,379). While the initial growth of HIV infection in the U.S. ESRD program was quite high, recently the
incidence has stabilized at 1.25% to 1.5% (298,299,380). The prevalence of HIV infected patients in the
ESRD program has increased dramatically, from 0.45% in 1995 to 0.83% in 2000, in part because of the
improved survival of patients with HIV infection (380,381,382). It is possible that trends in both incidence
and prevalence of ESRD since 1996 have been affected by the availability of HAART in the US (299,380).
HIV infection in the ESRD program is more common in men (380). Outcomes for patients treated with
peritoneal and hemodialysis have been equivalent (383,384). In contrast, very few HIV-infected children
have been treated for ESRD, and only 50% are male (385). Survival of children was better than for HIVinfected adults with ESRD (385). Girls with HIV infection and ESRD have better survival than boys (385).
Recent studies have concentrated on treatment of HIV infected patients with ESRD with renal
transplantation (298,299,386,387,388,389,390). Consideration for such experimental treatment currently
requires patients to be treated with HAART and have undetectable viral loads (298,299).
Human Immunodeficiency Virus–Associated Glomerulonephritis
Less common than classic HIVAN, HIVICD (13,298,299,312,317) comprises proliferative
glomerulonephritis, renal insufficiency, and proteinuria. Circulating immune complexes composed of
immunoglobulins, characteristically IgG or IgA, reactive with specific HIV antigens such as p24, gp41, and
gp120 are present, and identical complexes may be eluted in higher titer from renal tissue. HIV peptides
may also be demonstrated intracellularly in eluted glomerular tissue by laser-enhanced microscopy (317).
Three main types of clinically distinguishable HIV-associated immune complex renal disease may be
delineated: HIV-associated immune glomerulonephritis, a mixed sclerotic–immune complex nephropathy
(319), and HIV-associated IgA nephropathy (17,23,295,298,299,312). Mesangial hyperplasia may also be a
glomerulopathy associated with HIV infection (294,328,365,391), but it is most often considered a part of
the spectrum of FGS. A “lupus-like― appearance to the glomerulonephritis has also been noted in a
subset of cases (319,392)
Human Immunodeficiency Virus Immune Complex–Mediated Renal Disease
Circulating immune complexes, often identifiable as HIV-related, are common in HIV-infected patients at
all stages of the disease (393,394,395,396,397,398). MPGN, diffuse proliferative glomerulonephritis,
immunotactoid glomerulopathy, and MN have been reported in patients with HIV infection
(202,294,297,302,303,307,308,309,317,318,319,325,399,400,401,402,403,404,405,406,407). In several
studies of HIV-infected patients with nephrotic range proteinuria, more than one-fourth had
glomerulonephritis as opposed to HIV-associated focal glomerulosclerosis (13,23,353,408).
Epidemiology
6
Of 1 patients with HIV infection and nephrotic range proteinuria who underwent evaluation in our series
(23), 28.6% had a form of proliferative glomerulonephritis; 87.5% of the latter were African American. In
subsequent studies, 40% of patients with HIV infection and renal disease who underwent renal biopsy had
findings consistent with an immune-mediated glomerular disease (13). Excluding patients with IgA
nephropathy, 30% of patients with renal abnormalities and HIV infection evaluated by renal biopsy had a
type of proliferative glomerulonephritis. Nochy and co-workers (319) describe a population of European,
Caribbean, and African patients with HIV infection and renal disease evaluated in Paris. Approximately
37% of patients had immune complex glomerulonephritis. Twenty-one percent of black patients had
immune complex renal disease. Interestingly, only one black patient in that series had immune complex
glomerulonephritis alone; the remainder had mixed focal glomerulosclerosis and immune complex
nephropathy. Approximately half of the white patients had immune
P.1496
complex glomerulonephritis, commonly with a variable tubulointerstitial nephritis. The majority of these
patients were homosexual. Only one of the white patients, an intravenous drug user, had the “mixed―
nephropathy. Three other European studies from the United Kingdom and Italy emphasize a high proportion
of patients with nephrotic syndrome in the setting of HIV infection have glomerulonephritis (400,401,402).
A study from Thailand of HIV infected patients with renal disease reported a diverse set of
glomerulonephridites, but no cases of classic HIVAN (407). While in general, patients of African heritage
are more likely to have HIVAN, European and Asian populations more often appear to have
glomerulonephritis. HIVICD did occur in patients of African heritage in the European studies
(319,400,401). In the large Italian study (402), although there were a variety of glomerulonephritides
delineated, no patient of Italian heritage had HIVAN. In a recent U.S. multicenter study in which 89 patients
with HIV infection and renal disease underwent renal biopsy, 14.6% had immune complex
glomerulonephritis, 9% had MN, 5.6% had MPGN, and 1.1% had IgA nephropathy and MCD (353).
Clinical Features
All patients we studied with HIVICD were African Americans with renal failure and proteinuria (13,317).
Three had proliferative glomerulonephritis, crescentic and sclerotic changes, marked renal insufficiency, and
nephrotic proteinuria. One had a clinical constellation consistent with postinfectious glomerulonephritis,
with mild renal insufficiency. Most patients were homosexual, but one patient was thought to have acquired
HIV infection through heterosexual transmission. Clinical stage of HIV infection was not related to the
occurrence of disease (317,319). The patients with HIVICD usually had mild hypertension, in contrast to
those with HIVAN. All patients had proteinuria, often in the nephrotic range. Hematuria was not an
invariable finding. Red blood cell and granular casts were variably present on urinalysis. Renal insufficiency
and hypocomplementemia to a variable degree were encountered. All patients in our series had circulating
immune complexes composed of immunoglobulins reactive with HIV proteins, which, in most cases, were
eluted from renal tissue in higher titers than in the plasma. Circulating immune complexes were isolated in
all four patients, composed of IgA-p24, IgG-gp120, and IgG-p24. Identical complexes were eluted from
renal tissue in the first three cases; only p24 and complement were eluted from the fourth. Eluted antibodies
reacted with the HIV antigens isolated from the circulating immune complexes. We were not able to
demonstrate cryoprecipitation in any case.
Renal Pathology
Nochy and co-workers (319) describe several subtypes of HIV-associated immune complex
glomerulonephritis. These include a diffuse exudative endocapillary proliferative form termed
“postinfectious;― a second type that resembles lupus nephritis with diffuse endocapillary proliferative
changes, wire loops, hyaline thrombi in capillary lumina, and mesangial, intracapillary, and subepithelial
deposits of immunoglobulin, C3, and C1q; and a “mixed― type with features of both focal
glomerulosclerosis and immune complex nephropathy. Two of the patients in our series might be considered
of the mixed type (317). We found a spectrum of pathologic changes, including variable degrees of
mesangial expansion, segmental increase of mesangial cells and matrix, and segmental or diffuse
7
proliferation of glomerular tufts. Increased cellularity with lobular transformation, segmental condensation
or simplification of the glomerular tuft, and segmental or global proliferative and sclerosing changes were
seen. Visceral epithelial cells were often prominent, and fibrocellular crescents were often present.
Microcystic tubular dilation and atrophy and interstitial fibrosis or edema were often noted. Biopsies were
characterized by interstitial infiltration with mononuclear cells, primarily macrophages and lymphocytes,
and occasionally plasma cells, polymorphonuclear leukocytes, and eosinophils. Occasionally, infiltrating
cells disrupted the tubular basement membrane. The proportion of interstitial macrophages was higher in
tissue from patients with classic HIVAN compared with tissue from patients with HIVICD. On the other
hand, interstitial tissue from biopsies of patients with HIVICD had a higher percentage of B cells compared
with HIVAN tissue (326). Such findings are consistent with different populations of infiltrating immune
cells causing different histologic types of disease or different tissue chemokine profiles in different
nephropathies caused by the same virus, which attract different cell types to the site of injury.
Immunofluorescence microscopy demonstrated intramembranous and mesangial deposits of
immunoglobulins and complement (317). Electron microscopy usually reveals subendothelial,
intramembranous, and mesangial electron-dense deposits. Electron-dense deposits are found within
mesangial cells, and glomerular capillaries occasionally exhibit both subepithelial and subendothelial
deposits. Foot processes of visceral epithelial cells are approximated. Tubular reticular structures can be
detected in endothelial cells.
Diagnosis
Renal biopsy is important in determining the histologic diagnosis in patients with HIV infection and renal
disease, including those who present with nephrotic range proteinuria (13,23,317,353), and is the only
definitive way to diagnose HIVICD. Several of the patients in our series were thought to have HIVAN
before biopsy. Renal biopsy must show histologic evidence of glomerular inflammation, with
immunofluorescent microscopy confirming deposition of immunoglobulin and complement and electron
microscopy demonstrating mesangial or capillary deposits. More precise diagnosis may be achieved by
identifying HIV protein–immunoglobulin complexes in glomerular capillaries or the mesangium in higher
titer than in the circulation, although such studies are often primarily research techniques. The role of
specific therapeutic interventions could be evaluated in controlled trials in HIV-infected patients with renal
disease with defined clinical and histologic parameters.
An interesting subgroup is comprised of patients coinfected with HCV and HIV who have renal disease
(35,186,409,410,411). The majority of reported cases were intravenous drug users who had
glomerulonephritis, typically MPGN, rather than HIVAN. MN and immunotactoid and fibrillary
glomerulonephritis have also been reported (35,202,405). HCV RNA was detected in renal tissue in half of
the patients evaluated in the study by Stokes et al. (409). Etiologic relationships between the immune
complexes, the inciting antigen, and the renal disease have not often been reported. Renal biopsy is
necessary to make a clinical diagnosis.
Prognosis and Treatment
Prognosis depends, in part, on renal functional status and histologic findings. All patients we evaluated with
findings of “mixed― disease progressed to ESRD. Another patient with mild urinary abnormalities and
well-preserved renal function had relatively stable renal function for almost 2 years while the viral illness
progressed. Antiretroviral therapy had been instituted in some patients with HIVICD without obvious effect.
Its role in the treatment of HIV-related glomerulonephritis must be studied rigorously. One patient with
advanced renal insufficiency and nephrotic range proteinuria treated with steroids had transient
improvement in renal function of several months’ duration but later progressed to ESRD (317). Patients
in other studies have had variable outcomes, but follow-up has usually not been extensive. Patients with
glomerulonephritis and HCV and HIV infection appear to have a variable, but worse outcome than patients
with HCV-associated glomerulonephritis (353,409,410). In a recent U.S. multicenter observational study,
patients with renal diseases other than HIVAN had a longer course until the development of ESRD (731 ±
642 compared with 254 ± 331 days) and had better overall survival (353). No differential effect of
treatment with antiretroviral drugs was noted in the group of patients without HIVAN.
8
Human Immunodeficiency Virus-Associated IMMUNOGLOBULIN A NEPHROPATHY
IgA nephropathy has been described in several patients with HIV infection. IgA antibodies directed against
HIV antigens are part of the early response to HIV infection (412,413,414,415,416). Circulating
antigen–antibody complexes containing IgA are often present in HIV-infected patients. Rather than being
the chance association of two unrelated diseases, it appears that the renal disease is intimately associated
with the viral infection. In HIV-associated IgA nephropathy, we detected idiotypic IgA immunoglobulins
directed against anti-HIV antigen–antibody complexes, which were identical to those found in renal tissue
(312). Immunochemical analysis revealed circulating, idiotypic IgA antibodies, bound to IgG-gp41 and
IgM-p24 complexes (312). Identical immune complexes were eluted from biopsied tissue, in higher
concentration than the circulating immune complex. In addition, HIV gene sequences were amplified by
PCR from renal tissue. These data are similar to findings in IgA nephropathy in non-HIV-infected
populations (417), suggesting immune mediation and a genetic predisposition to a particular pathologic
outcome.
Epidemiology and Clinical Features
Almost all patients with HIV IgA nephropathy reported are white or Hispanic
(310,311,312,313,314,315,316). Hsieh and others reported a black patient with HIV infection and crescentic
IgA nephropathy (320). Two Southeast Asian patients with HIV infection and IgA nephropathy have been
reported (407). Most patients are homosexual men, although the disease has also been reported in boys.
Patients have hematuria and proteinuria, sometimes in the nephrotic range. Red cell casts are usually noted.
Renal insufficiency is common but is often stable and can improve. Serum IgA levels are increased, but this
is a common finding in HIV-infected patients in the absence of renal disease. Occasional patients have
hypertension. Katz et al. (311) evaluated three white homosexual men and a Hispanic boy with HIV
infection and IgA nephropathy. All patients had circulating immune complexes composed of
immunoglobulins, including IgA reactive with various HIV antigens and IgA rheumatoid factors (311). We
demonstrated the presence of circulating immune complexes composed of idiotypic IgA antibodies directed
against IgG or IgM antibodies reactive with HIV peptides in two patients (312). The IgA
antiimmunoglobulin response in both patients was specific both for types of immunoglobulin and for
immunoglobulin reactive with specific HIV antigens. The anti-HIV antigen response was also both viral
peptide-specific and patient-specific. Cryoprecipitation was demonstrated in one case.
The low reported prevalence of IgA nephropathy in HIV-infected patients may be related to a true low
incidence of the disease (312,418), perhaps related to host and genetic background in infected patients
(312,417,418,419). Alternatively, the low prevalence may reflect the reluctance to perform renal biopsies in
patients with urinary abnormalities and mild renal insufficiency, in the absence of perceived effective
treatment, and in the presence of a disease that is thought to be more linked to survival than the nephropathy
(312). A study from France, however, suggests almost 8% of postmortem cases show mesangial deposition
of IgA (420). In a recent U.S. multicenter study in which 89 patients with HIV infection and renal disease
underwent renal biopsy, only 1.1% had IgA nephropathy (353).
Renal Pathology
Light microscopy usually shows diffuse or segmental increase in mesangial matrix, with segmental
proliferative changes. Rarely, thrombi are seen in glomerular capillaries, and areas of segmental sclerosis
may be noted. Occasionally fibrocellular crescents are seen (311,312,316,320). IgA is the predominant
immunoglobulin in the mesangium and in glomerular capillary walls, along with C3, IgM, and less often
IgG. Electron microscopy shows increased mesangial matrix with mesangial and peripheral
(intramembranous, subepithelial) electron-dense deposits. Tubular reticular structures may be noted in
glomerular endothelial cells. Nuclear bodies may be seen in interstitial cells (311).
Prognosis and Treatment
Jindal et al. (316) used steroid therapy in a patient with renal insufficiency and IgA nephropathy before the
HIV infection was diagnosed. The level of serum creatinine decreased, suggesting a beneficial clinical
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response may have been related to this treatment. Most patients, however, have had mild, nonprogressive
renal insufficiency, and there are few data regarding treatment. The effects of CS and antiretroviral therapy
on the natural history of the disease are unknown. A patient with HIV infection treated with didanosine, and
IgA nephropathy with urinary protein excretion of 12 g/day was given captopril. Over 3.5 months, urinary
protein excretion decreased to 0.5 g/day, associated with an increase of circulating levels of serum protein
and albumin (421). Prospective, controlled studies are necessary to evaluate the role of inhibition of the
renin-angiotensin system and the use of HAART in HIV infected patients with IgA nephropathy.
Human Immunodeficiency Virus–Associated Thrombotic Microangiopathies
Both thrombotic thrombocytopenic purpura (TTP) and hemolytic–uremic syndrome (HUS) have been
reported in patients with HIV infection (422,423,424,425,426,427,428,429,430,431). A French study
suggests the thrombotic microangiopathies are a common cause for acute renal failure in HIV-infected
patients (423). Evidence suggests the disease can be caused in animal models by retroviral infection
(431,432), and that the virus might mediate dysfunction of endothelial cells (431,433,434,435,436,437). The
diseases manifest their common presentations, but because of the protean manifestations of HIV infection,
may prove difficult to diagnose. Abnormalities of the peripheral blood smear remain the criterion for making
the diagnosis (422). Although a variety of different therapeutic approaches have been employed
(298,299,431,438), plasmapheresis remains the safest and perhaps the most effective treatment for HIVinfected patients with TTP. The potential therapeutic role of antiretroviral therapy in such cases, while
attractive on theoretical grounds, has not been tested adequately in well-designed clinical studies (439,440).
Few studies exist on the treatment of HUS in the setting of HIV infection. Randomized controlled trials of
therapy in patients with HIV infection and the thrombotic microangiopathies have been lacking
(298,299,431).
Renal Disease Related to Treatment
The host response to ongoing viremia may include continued antibody synthesis, cell-mediated immune
responses, and cellular antiviral responses. Therapy with IFN-α has been associated with a variety of renal
disorders. We studied an HIV-infected patient treated with IFN-α who developed MPGN. An IFN-αimmunoglobulin immune complex was identified in the circulation and in higher titer in renal eluates,
demonstrating that glomerulonephritis in HIV-infected patients may be secondary to a host response to
treatment (239). Distinguishing the progression of disease from iatrogenic effects may be an important
clinical dilemma in patients treated with this immunomodulator who develop increased renal insufficiency.
The extent of renal disease related to therapy with IFN-α in patients with HIV, HBV, or HCV infection,
however, is unknown.
The newer antiretroviral drugs, especially the protease inhibitors, in particular indinavir (321,363,441,442)
and to a lesser extent, ritonavir (363,443) may cause reversible nephropathy by several mechanisms
(299,321,441,444,445,446). It is important to distinguish such effects from the progression of the underlying
renal disease. Rhabdomyolysis may be an increasingly common cause of acute renal failure as patients with
lipodystrophy induced by antiretroviral therapy are treated with statins (299,447,448,449,450). Adefovir,
cidofovir, abacavir and tenofovir have all been associated with the development of tubular injury
(299,451,452,453,454,455).
Renal Disease Indirectly Associated with Viral Infection
Glomerular diseases may occur in HIV-infected patients that are unrelated to the viral infection, are related
to coinfections, or reflect the immune dysregulation seen in HIV infection (13,16,17,294,297,456,457). A
patient with glomerulonephritis and HIV infection exhibited characteristics of poststreptococcal
glomerulonephritis (456). The biopsy, however, showed tubular reticular structures, which are a hallmark of
HIV-associated renal diseases. Therefore, this patient may have had two different glomerular diseases, or the
electron microscopic findings may have been nonspecific. The slow resolution of the renal disease in this
case may reflect the disordered immunoregulation seen in HIV-infected patients, compared with
immunologically normal hosts who develop glomerulonephritis after streptococcal infections. We evaluated
a white man with nephrotic syndrome in the presence of HIV and HBV infection. The renal biopsy was
10
suggestive of MN secondary to HBV infection, rather than an HIV-associated glomerulopathy (399). The
association of these two diseases was confirmed when the proteinuria remitted concurrently with the
clearance of HBeAg from the patient's circulation (458). There are a paucity of well-described cases of lupus
nephritis in the setting of HIV infection (392,459). It is possible that the disordered immunoregulation
associated with the viral infection mediates altered renal outcomes in such patients.