HIV Associated

Nephropathy
Disease Review
Cheri X. Ye, MD
12/10/08
Introduction: HIVAN
Initially described in 1984
Renal disease found in HIV-1 patients
HIVAN is not the only cause of kidney
disease in HIV infection
Usually a late manifestation of HIV-1
infection
Especially prevalent among those of
African descent (majority of cases occur in
blacks)
Rates of ESRD due to AIDS
While the rate of new cases of ESRD due to AIDS has fallen slightly since
the beginning of the decadereaching 2.7 per million population in the
20042005 periodprevalence has grown steadily, reaching 8.9 in 2004
2005, and indicating that people are living longer with the disease
USRDS 2008
Clinical Presentation
Renal insufficiency with proteinuria,
usually nephrotic range
Peripheral edema, HTN are uncommon
Urinalysis typically bland, except for
proteinuria
Renal US generally shows echogenic
kidneys that are normal-to-large, unlike
most cases of chronic renal failure
Clinical Presentation
Lack of signs such as edema or HTN may
lead to delay in diagnosis of renal failure
Uremic symptoms (anorexia, fatigue etc)
may be attributed to underlying HIV
infection, thus further delaying diagnosis
Thus, timely diagnosis of HIVAN requires
close monitoring of chemistries/UA with a
high degree of suspicion in at risk
populations
Differential Diagnosis
Etiologies of renal failure in HIV positive
patients are similar to seronegative
patients
Prerenal 2/2 poor PO, diarrhea, vomiting
Medications causing ATN, AIN
Hypotension, sepsis in hospitalized pts
Rule out acute/reversible causes first
Ross MJ. Aids Patient Care and STDs 2000; 14 (12): 637-645

Differential Diagnosis
Suspected cases of HIVAN are often not
HIVAN on biopsy
MPGN, IgA nephropathy, amyloidosis,
minimal change, diabetic nephropathy,
AIN, cryoglobulinemia etc
Thus, a kidney biopsy is necessary to
make the diagnosis of HIVAN as the
diagnosis cannot be made on clinical
grounds alone
Pathology
HIVAN is defined by the presence of
characteristic morphologic abnormalities
on renal biopsy
Light microscopy:
collapsing focal glomerulosclerosis
marked hypertrophy and hyperplasia of
overlying visceral epithelial cells
microcystic dilatation of tubules
lymphocytic infiltration of interstitium
Normal glomerulus Collapsing FGS
www.uptodate.com
Light micrograph showing collapsing
glomerulosclerosis with few open loops in the
sclerotic areas (long arrows); these findings
are characteristic of HIV nephropathy but can
also be seen in idiopathic disease. The
degree of collapse can be appreciated by the
openness of Bowman's space. Vacuolization
and crowding of the glomerular epithelial cells
(short arrows) is also frequently seen and
reflects the primary epithelial cell injury in this
disorder.
Light micrograph of a normal glomerulus.
There are only 1 or 2 cells per capillary tuft, the
capillary lumens are open, the thickness of the
glomerular capillary wall (long arrow) is similar
to that of the tubular basement membranes
(short arrow), and the mesangial cells and
mesangial matrix are located in the central or
stalk regions of the tuft (arrows).
A. Characteristic collapsing focal segmental glomerulosclerosis
with podocyte proliferation.
B. Microcystic tubular dilatation and inflammatory interstitial
infiltrates.
Light microscopy from human biopsy with HIVAN.
Lu T. The Mount Sinai Journal of Medicine 2005; 72 (3): 193-199
Renal biopsy characteristic of HIV-
associated nephropathy:
glomeruli show collapsing sclerosis
(arrows) characterized by
a global glomerular basement
membrane wrinkling and collapse
with narrowing and early
obliteration of the capillary lumens.
Adjacent tubules demonstrate
marked microcystic dilation with
flatting of the tubular epithelial cells
(arrow heads) and are filled
with proteinaceous casts. The
interstitium shows an inflammatory
cell infiltrate composed primarily of
lymphocytes (periodic
acid-Schiff, 200X)
Yalavarthy R et al. International Journal of STD & AIDS 2008; 19; 789-790

Pathology
Electron microscopy: may show numerous
tubuloreticular structures in glomerular
endothelial cells
Immunofluorescence: may be staining for
IgM, C3 and less frequently, C1.
EM of a normal glomerular capillary
loop showing the fenestrated
endothelial cell (Endo), the
glomerular basement membrane
(GBM), and the epithelial cells with
its interdigitating foot processes
(arrow). The GBM is thin and no
electron dense deposits are present.
Two normal platelets are seen in the
capillary lumen.
EM in HIV-induced focal collapsing
glomerulosclerosis shows
numerous intraendothelial (End)
tubuloreticular structures (arrow).
These structures are not seen in
the idiopathic form of the disease.
The epithelial cell (Ep) has no
discrete foot processes, a
reflection of primary epithelial cell
injury.
www.uptodate.com
Pathogenesis
Pathogenesis not well understood
Animal models suggest pathogenesis is
due to viral infection of the renal cells
HIV-1 RNA/DNA has been detected in
human renal epithelial cells, suggesting
that renal cells may act as a reservoir for
HIV-1
Mechanism of cellular entry is unclear
In situ hybridization for HIV-1 mRNA in kidney biopsies. (A and B)
Kidney biopsy from an HIV-negative patient demonstrating no HIV-
1 mRNA in the sense control (A) or the antisense (B) hybridization
of a serial section. (C and D) Kidney biopsy from an HIV-positive
patient with kidney disease. No hybridization was observed in the
sense control (C). Antisense hybridization (D) demonstrates HIV-1
mRNA in the cytoplasm of tubular epithelial cells and in cellular
casts (CC) in the tubular lumen (TL) but not in protein casts (PC).
Wyatt, C. M. et al. Clin J Am Soc Nephrol 2007;2:S20-S24
Clinical Course
Without treatment with HAART or ACEi,
most cases progress to ESRD rapidly
(weeks to months), necessitating dialysis
Mortality usually a complication of AIDS
itself rather than the renal disease

Host Factors
Predisposition of pts of African descent
suggests that host genetic factors are
important in development of disease
Patients with HIVAN are more likely to
have a family history of ESRD
Yalavarthy R et al. International Journal of STD & AIDS 2008; 19; 789-790

Treatment
Antiretroviral therapy
ACEi
Steroids
No well controlled clinical trials regarding
treatment of HIVAN
No proven effective therapy
HAART
Decline nationally of incidence of HIVAN
since inception of HAART ~ 1996
HAART effective in slowing down
progression to ESRD in HIVAN patients
HAART also associated with reduction in
risk for developing HIVAN
Reduces HIV-1 viral replication
HAART
Atta et al. (2006), retrospective study,
36 patients with biopsy proven HIVAN, not
on dialysis yet.
26 treated with HAART; 10 were not.
Median renal survival was substantially longer
in the 26 pts who received treatment (18
months vs 4 months)
Wyatt, C. M. et al. Clin J Am Soc Nephrol 2007;2:S20-S24
Impact of highly active
antiretroviral therapy on AIDS-
related mortality (A), incidence of
HIV-related ESRD (B), and mortality
in patients with HIV and ESRD (C)
ACE inhibitors
Wei et al. (2003) studied 44 pts with bx-
proven HIVAN. Cr <2. All offered
fosinopril 10mg QD. 28 pts agreed (study
group); 16 refused (control group).
After 5.1 years, all except 1 on fosinopril had
maintained stable renal fxn (median Cr 1.55)
All pts in the control group reached dialysis
Study limited by self selection, other meds not
controlled for
Steroids
Smith et al. (1996), observational study,
the effects of prednisone in 20 pts (17 had
biopsy proven HIVAN.) Majority with
advanced renal insufficiency (Cr>2) and
proteinuria (>2 g/day.) Followed for
median 44 wks.
17 pts had a reduction in serum creatinine
and/or protein excretion
Relapse common after stopping therapy
6 had infections (MAC, CMV, Candidemia)
Conclusions
HIVAN is most common cause of CRF in
HIV-1 patients, especially blacks
Can occur at any stage of HIV, but
majority of published cases are in AIDS
Prognosis is poor
Definitive diagnosis requires renal biopsy,
since HIV patients can develop a wide
variety of renal diseases
Conclusions
HIV infection of the renal epithelium is a
critical component of HIVAN pathogenesis
HAART, ACEi, prednisone used in small
observational studies. Long term benefits
of steroids remains to be demonstrated.
Need for controlled prospective studies

References
Atta MG, Gallant JE, Rahman MH, et al. Antiretroviral therapy in the treatment of
HIV-associated nephropathy. Nephrol Dial Transplant 2006; 21; 2809-2813
Lu T, Ross M. HIV-associated nephropathy: a brief review. The Mount Sinai Journal
of Medicine 2005; 72 (3): 193-199
Rose BD, Appel GB. Collapsing FGS and other renal diseases associated with HIV
infection. www.uptodate.com
Ross MJ, Klotman PE, Winston JA. HIV-associated nephropathy: case study and
review of the literature. Aids Patient Care and STDs 2000; 14 (12): 637-645
Smith MC, Austen JL, Carey JT, et al. Prednisone improves renal function and
proteinuria in human immunodeficiency virus-associated nephropathy. Am J Med
1996; 101 (1):41-48
US Renal Data System Annual Data Report 2008
Wei A, Burns GC, Williams BA, et al. Long-term renal survival in HIV-associated
nephropathy with angiotensin-converting enzyme inhibition. Kidney Int 2003;
64(4):1462-1471
Wyatt CM, Klotman PE. HIV-1 and HIV-associated nephropathy 25 years later. Clin J
Am Soc Nephrol 2007; 2: S20-S24
Yalavarthy R, Smith ML, Edelstein CL. HIV-associated nephropathy in Caucasians:
case report and review of literature. International Journal of STD & AIDS 2008; 19;
789-790