Download HIV associated nephropathy

Dr.
 Approximately
2.7 million people a year
are infected with HIV worldwide
 Kidney
disease is a relatively frequent
complication of patients infected with
HIV
Nephron Clin Pract 2011;118:c346–c354
 HIVAN
(HIV Associated Nephropathy)
• Defined on renal biopsy as collapsing focal
glomerulosclerosis,
• Is the most common cause of chronic kidney
disease (CKD) in patients with HIV and
overwhelmingly affects patients of African
descent
Nephron Clin Pract 2011;118:c346–c354
• First described by Rao et. al. in 1984: sclerosing
glomerulopathy in HIV+ patients in NYC
• It is the third leading cause of ESRD in african
americans, ages 20-64
• Most common cause of ESRD in HIV+ patients
• Nephrotic syndrome
• Collapsing focal glomerulosclerosis (FGS)
• Tubulointerstitial injury
 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
HIVAN
 Renal
Disease in HIV/AIDS often NOT HIVassociated nephropathy
 Always evaluate for reversible causes of RF
 Common
Causes of Renal Failure in HIV/AIDS
• ARF – infection, hypotension, nephrotoxic drugs
•
•
•
•
(HAART, antibiotics, antifungals)
Membranous nephropathy (Hep B, syphilis)
Membranoproliferative glomerulonephritis (Hep C)
Immune complex glomerulonephritis (IgA)
Interstitial nephritis (CMV, sulfa drugs)
Nephron Clin Pract 2011;118:c346–c354
• Mostly occurs in blacks; in US, blacks are 12.2 times
more likely to develop it than non-blacks
• Prevalence in blacks ranges from 3.5% (proteinuria
screening in clinics) to 12% (autopsy)
• In patients with HIVAN, 25% also have 1st or 2nd
degree relative with ESRD
• Most patients have low CD4 counts (<200)
• However, may be seen in primary HIV infection
 Biopsy-
proven HIVAN has been reported in
• >80% of 30 patients with HIV screened for
proteinuria in South Africa and in
• 53–79% of HIV-infected patients of African descent
in studies from the USA and Europe
• In African-Americans, HIVAN is associated with
younger age and lower estimated glomerular
filtration rate (eGFR)
Nephron Clin Pract 2011;118:c346–c354
While the rate of new cases of ESRD due to AIDS has fallen slightly
since the beginning of the decade—reaching 2.7 per million
population in the 2004–2005 period—prevalence has grown steadily,
reaching 8.9 in 2004–2005, and indicating that people are living longer
with the disease
USRDS 2008
 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
 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
 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
 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
HIVAN is defined by the presence of
characteristic morphologic
abnormalities on renal biopsy
Light microscopy:
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•
•
•
•
collapsing focal glomerulosclerosis
marked hypertrophy and hyperplasia of
overlying visceral epithelial cells
microcystic dilatation of tubules
lymphocytic infiltration of interstitium
Normal glomerulus
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).
Collapsing FGS
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.
www.uptodate.com
Light microscopy from human biopsy with
HIVAN.
A. Characteristic collapsing focal segmental glomerulosclerosis
with podocyte proliferation.
B. Microcystic tubular dilatation and inflammatory interstitial
infiltrates.
Lu T. The Mount Sinai Journal of Medicine 2005; 72 (3): 193-199
Renal biopsy characteristic of HIVassociated 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
 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
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
 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
 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
 In
the absence of randomized clinical
trials, the treatment of HIVAN is based on
• Small, uncontrolled studies, epidemiologic data,
and pathogenic insights
Adv Chronic Kidney Dis. 2010 ; 17(1): 59–71
 Antiretroviral
therapy
 ACEi
 Steroids
 No
proven effective therapy
 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
 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)
Impact of highly active
antiretroviral therapy on AIDSrelated mortality (A), incidence of
HIV-related ESRD (B), and
mortality in patients with HIV and
ESRD (C)
Wyatt, C. M. et al. Clin J Am Soc Nephrol 2007;2:S20-S24

Atta et al. Antiretroviral therapy in the treatment of HIVassociated nephropathy. Nephrol Dial Transplant.
2006; 21: 2809-2813.
• Retrospective chart review of 263 HIV patients referred to a
single center renal clinic from 1995 to 2004
• Patients included if they had biopsy-proven HIVAN and did not
require dialysis within 1 month of their kidney biopsy
• 53 patients had HIVAN, 36 met inclusion criteria; 26 treated with
antiretrovirals (at least 1 agent; group I) and 10 were not (group
II)
• Multivariate analysis and cumulative probablility of renal
survival calculated
Atta et al. Nephrol Dial Transplant. 2006; 21: 2809-2813.
Atta et al. Nephrol Dial Transplant. 2006; 21: 2809-2813.
Atta et al. Nephrol Dial Transplant. 2006; 21: 2809-2813.
 Data
from uncontrolled or retrospective
studies and from a randomized
controlled trial suggest that
• HAART (defined as combination therapy with 3
or more drugs) is beneficial in both preservation
and improvement of kidney function in patients
with HIV
Nephron Clin Pract 2011;118:c346–c354
 Kalayjian
et al. showed in an observational,
prospective, multicenter cohort study
involving 1,776 HIV patients that
• Suppression of plasma viremia with antiretroviral
therapy was associated with improvement in GFR in
subjects with both CKD stage ≥ 2 and low baseline
CD4+ cell counts ( <200 cells/ l)
• In this subset of patients, viral suppression was
associated with an average increase in GFR of 9.2
ml/min/1.73 m 2 from baseline over a median followup of 160 weeks
Nephron Clin Pract 2011;118:c346–c354
 There
is also data suggesting that HAART
may prevent the development of HIVAN
• Among patients with a prior diagnosis of AIDS,
HIVAN incidence was significantly reduced from
26.4 per 1,000 person-years in patients not receiving
antiretroviral therapy, to 14.4 per 1,000 person-years
in patients treated with nucleoside analogue therapy
only, and to 6.8, per 1,000 person-years in those
treated with HAART
• In multivariate analysis, HIVAN risk was reduced
60% by use of HAART, and no patient developed
HIVAN when HAART had been initiated prior to the
development of AIDS
Nephron Clin Pract 2011;118:c346–c354
 On
the other hand, limited information is
available regarding the incidence of
proteinuria in patients with HIV or its
relation to antiviral therapy
Nephron Clin Pract 2011;118:c346–c354
 Angiotensin-converting
enzyme
inhibitors and angiotensin II receptor
blockers are effective antihypertensive
agents that can
• Reduce proteinuria and slow progression of
renal disease in both diabetic and non-diabetic
chronic nephropathy patients, and for these
reasons
• they are indicated in any patient with proteinuria
regardless of the cause
Nephron Clin Pract 2011;118:c346–c354

Burns et al. Effect of angiotensin-converting enzyme
inhibition in HIV-associated nephropathy. J Am Soc
Nephrol 1997; 8:1140.
• 20 patients with HIVAN
• 11 patients had non-nephrotic range proteinuria; 7 patients
•
•
•
•
received fosinopril 10 mg daily, 4 did not
Average baseline creatinine for treated and nontreated patients
was 1.3 +/- 0.24 and 1.0 +/- 0.25, (P = 0.07)
At 24 wk, creatinine of treated and nontreated patients was 1.5
+/- 0.34 and 4.9 +/- 2.4 (P = 0.006).
Average baseline 24-h urine protein excretion for treated and
nontreated patients was 1.6 +/- 0.68 and 0.78 +/- 0.39 (P = 0.02)
At 24 wk, 24-h protein excretion of treated and non-treated
patients was 1.25 +/- 0.86 and 8.5 +/- 1.4 (P = 0.006).

Burns et al. J Am Soc Nephrol 1997; 8:1140.
• Of nine patients with nephrotic-range proteinuria, five were
•
•
•
•
treated with fosinopril 10 mg daily and four were not
Average baseline creatinine for treated and nontreated patients
was 1.7 +/- 0.46 and 1.9 +/- 0.42 (P = 0.4)
At 12 wk, creatinine for treated and nontreated patients was 2.0
+/- 1.0 and 9.2 +/- 2.0 (P = 0.02).
The baseline 24-h protein excretion for treated and nontreated
patients was 5.4 +/- 1.6 and 5.2 +/- 0.97 (P = 0.9)
At 12 wk, 24-h protein excretion for treated and nontreated was
2.8 +/- 1.0 and 10.5 +/- 3.5 (P = 0.008).
A
number of retrospective, observational
or uncontrolled studies conducted before
or during the initial phases of HAART
reported variable success with the use of
corticosteroids in patients with HIVassociated kidney diseases
Nephron Clin Pract 2011;118:c346–c354
 Smith
et al. Effect of corticosteroid therapy on
human immunodeficiency virus-associated
nephropathy. Am J Med 1994; 97:145.
• Prospective study of 20 patients with biopsy-proven
HIVAN (N=17) or clinical characteristics suggestive
of HIVAN (N=3)
• SCr >2.0 mg/dl or proteinuria >2.0 g/day or both
• Prednisone 60 mg/day for 2-11 weeks
• Followed for a median of 44 weeks (range 8 to 107)

Smith et al. Am J Med 1994; 97:145.
• 19 patients had SCr >2.0 mg/dl
 2 patients progressed to ESRD in 4-5 weeks
 17 patients serum creatinine levels decreased from 8.1 +/- 1.2
mg/dL to 3.0 +/- 0.4 mg/dL (P < 0.001)
 5 patients relapsed after prednisone was d/c’ed and were retreated
with serum creatinine declining 8.2 +/- 1.2 mg/dL to 3.9 +/- 0.5
mg/dL (P < 0.01) with the second course of steroids
 11 of 13 tested patients showed a decrease in 24-hour urinary
protein excretion with an average decrease from 9.1 +/- 1.8 g/day to
3.2 +/- 0.6 g/day (P < 0.005)
 11 died from complications of HIV disease 14 to 107 weeks after
institution of prednisone, none were receiving prednisone at the time
of death
 2 cases of MAC infection and 3 cases of CMV retinitis
 Recognizing
that randomized controlled
trials comparing ART to placebo are no
longer ethically tenable, recently
updated expert guidelines consider
HIVAN an indication for the initiation of
ART, regardless of CD4 cell count
Semin Nephrol. 2008 November ; 28(6): 513–522
 The
guidelines also recommend
adjunctive therapy with ACE inhibitors or
angiotensin receptor blockers as
tolerated
• based on evidence of benefit from cohort
studies in patients with HIVAN and from
randomized clinical trials in other glomerular
diseases
Semin Nephrol. 2008 November ; 28(6): 513–522
 The
addition of corticosteroids may be
considered in patients with
• Aggressive disease or a prominent interstitial
inflammatory component, based on uncontrolled
clinical studies and in vitro evidence that HIV
infection induces a local inflammatory reaction in
tubular epithelial cells
Semin Nephrol. 2008 November ; 28(6): 513–522
 With
improvements in the survival of HIVpositive dialysis patients, patients with
HIVAN who are approaching ESRD
should be offered a choice between
hemodialysis and peritoneal dialysis,
which offer similar survival in adults with
HIV infection.
 Selected patients with remote HIVAN and
well-controlled HIV infection may also be
candidates for kidney transplantation
Semin Nephrol. 2008 November ; 28(6): 513–522
 Concerns
• Overimmunosuppression leading to opportunistic
infections and progression to AIDS
• Drug interactions between immunosuppressive
agents and HAART
• Reports in the pre-HAART era of poor outcomes in
HIV-positive patients receiving transplants
• Perception that transplanting HIV patients is morally
and ethically inappropriate for fear of wasting a
limited supply of organs
 Swanson
et al. Impact of HIV seropositivity on
graft and patient survival after cadaveric renal
transplantation in the United States in the pre
highly active antiretroviral therapy (HAART)
era: an historical cohort analysis of the United
States Renal Data System. Transpl Infect Dis.
2004 Sep;4(3): 144-7.
• Historical cohort analysis of 63,210 cadaveric
solitary renal transplant recipients with HIV serology
entries in the USRDS from 1987 to 1997
• 32 (0.05%) were HIV+ at transplant
HIV+ CAD
(N = 32)
Male
18 (56%)
African-American
8 (25%)
Recipient age (mean years, SD)
37.5 (4.14)
Donor age (mean years, SD)
25.84
A
(14.32)
64.82
A
(19,52)
1990
(3,03)
Recipient weight
Year recipient transplanted
Cause of ESRD
USRDS CAD
(HIV confirmed
negative)
(N = 63,178)
37,038 (61%)
14,800 (23%)
A
A
43.1 (13,67)
31.80 (16.33)
71.67 (18.34),
1992.32 (2,82)
B
Diabetes
5 (15.6%)
13,737 (21.7%)
Donor CMV+/recipient CMV–
6 (18.8%)
11,608 (18.4%)
Rejection (treated or presumed)
16 (50%)
30,575 (48.4%)
Pre-transplant dialysis
29 (93.5%)
56,695 (91.8%)
Cold ischemic time (hours)
C
Mean number of HLA antigen matches
(0–6)
14.88 ± 11.8 15.97 ± 11.3
A
4.00 (1.41)
2.74 (1.62)
Swanson et al. Transpl Infect Dis. 2004 Sep;4(3): 144-7.
 Kumar
et al. Safety and success of kidney
transplantation and concomitant
immunosuppression in HIV-positive patients.
Kidney Int. 2005 Apr; 67(4): 1622-9.
• 40 HIV patients with ESRD transplanted between
2001 and 2004
• Selection criteria: adherence to dialysis and HAART,
plasma HIV-1 RNA<400 copies/ml, CD4 >200
cells/ul.
• Basiliximab induction; CSA (trough 150-200 ng/ml),
sirolimus (trough 5-10 ng/ml), and prednisone
maintenance
• Protocol biopsies at 1, 6, 12, and 24 months
Kumar et al. Kidney Int. 2005 Apr; 67(4): 1622-9.
Post-transplant
day
2
Number of
patients
1
Anaphylactic reaction to drug
Intractable gastrointestinal
bleeding
Sepsis
6
1
107
1
Chest infection
37
1
Necrotizing fasciitis
238
1
Infection of the lymphocele
285
1
Myocardial infarction
545
1
Cause of death
Pulmonary embolism
Kumar et al. Kidney Int. 2005 Apr; 67(4): 1622-9.

Cause of graft loss

Patient deaths from Table 2




Days of graft loss
2, 6, 37, 107, 238, 285 and 545
Acute vascular rejection
Bleeding at the transplant site
Hemolytic uremic syndrome
12
15
55
Steven Johnson syndrome due to Dapsone 152
Kumar et al. Kidney Int. 2005 Apr; 67(4): 1622-9.
Number of grafts lost
7
1
1
1
1
Kumar et al. Kidney Int. 2005 Apr; 67(4): 1622-9.
Kumar et al. Kidney Int. 2005 Apr; 67(4): 1622-9.
 Qiu
et al. HIV-positive renal recipients can
achieve survival rates similar to those of HIVnegative patients. Transplantation. 2006 Jun 27;
81(12): 1658-61.
• Retrospective analysis of UNOS Renal Transplant
Registry
• Primary kidney transplants between 1997 and 2004
• Duplicated kidneys from the same donor (N=38)
transplanted to one HIV-positive patient and one
HIV-negative patient
• Patient and graft survival and mean serum creatinine
at 6 months, 1, 3, and 5 years
Qiu et al. Transplantation. 2006 Jun 27; 81(12): 1658-61
Qiu et al. Transplantation. 2006 Jun 27; 81(12): 1658-61
Qiu et al. Transplantation. 2006 Jun 27; 81(12): 1658-61
Qiu et al. Transplantation. 2006 Jun 27; 81(12): 1658-61
 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
 The
differential diagnosis of renal failure in the
HIV patient is broad and includes medication
nephrotoxicity, HIV-associated TMA, and
immune complex glomerulonephritis,
collapsing FSGS
 There
has been a plateau in the incidence of
ESRD in HIV patients and a reduction in ESRDrelated mortality since the advent of HAART
 ACE-inhibitors
should be used in
patients with HIVAN and has been
associated with a reduction in proteinuria
and increased renal survival
 Kidney
transplantation is an acceptable
form of renal replacement therapy for
selected HIV patients
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Atta MG, Gallant JE, Rahman MH, et al. Antiretroviral therapy in the treatment of HIVassociated 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