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:c346c354
Slide 3
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:c346c354
Slide 4
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
Slide 5
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
Slide 6
Renal Disease in HIV/AIDS often NOT HIV- associated 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) HIVAN
Slide 7
Nephron Clin Pract 2011;118:c346c354
Slide 8
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 1 st or 2 nd degree relative
with ESRD Most patients have low CD4 counts (
Biopsy- proven HIVAN has been reported in >80% of 30
patients with HIV screened for proteinuria in South Africa and in
5379% 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:c346c354
Slide 10
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 20042005, and
indicating that people are living longer with the disease USRDS
2008
Slide 11
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
Slide 12
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
Slide 13
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
Slide 14
Ross MJ. Aids Patient Care and STDs 2000; 14 (12): 637-645
Slide 15
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
Slide 16
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
Slide 17
Normal glomerulusCollapsing 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).
Slide 18
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
Slide 19
Slide 20
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
Slide 21
Electron microscopy: may show numerous tubuloreticular
structures in glomerular endothelial cells Immunofluorescence: may
be staining for IgM, C3 and less frequently, C1.
Slide 22
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
Slide 23
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
Slide 24
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
Slide 25
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
Slide 26
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
Slide 27
Yalavarthy R et al. International Journal of STD & AIDS
2008; 19; 789-790
Slide 28
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):
5971
Slide 29
Antiretroviral therapy ACEi Steroids No proven effective
therapy
Slide 30
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
Slide 31
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)
Slide 32
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)
Slide 33
Atta et al. Antiretroviral therapy in the treatment of HIV-
associated 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
Slide 34
Atta et al. Nephrol Dial Transplant. 2006; 21: 2809-2813.
Slide 35
Slide 36
Slide 37
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:c346c354
Slide 38
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 (
Slide 39
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:c346c354
Slide 40
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:c346c354
Slide 41
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:c346c354
Slide 42
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).
Slide 43
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).
Slide 44
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 HIV- associated kidney diseases Nephron Clin Pract
2011;118:c346c354
Slide 45
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)
Slide 46
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/ced
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
Slide 47
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):
513522
Slide 48
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): 513522
Slide 49
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):
513522
Slide 50
With improvements in the survival of HIV- positive 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): 513522
Slide 51
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
Slide 52
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
Slide 53
HIV+ CAD (N = 32) USRDS CAD (HIV confirmed negative) (N =
63,178) Male18 (56%)37,038 (61%) African-American8 (25%)14,800
(23%) Recipient age (mean years, SD)37.5 A (4.14)43.1 (13,67) Donor
age (mean years, SD)25.84 A (14.32) 31.80 (16.33) Recipient
weight64.82 A (19,52) 71.67 (18.34), Year recipient
transplanted1990 A (3,03) 1992.32 (2,82) Cause of ESRD Diabetes5
(15.6%) B 13,737 (21.7%) Donor CMV+/recipient CMV6 (18.8%)11,608
(18.4%) Rejection (treated or presumed)16 (50%)30,575 (48.4%)
Pre-transplant dialysis29 (93.5%)56,695 (91.8%) Cold ischemic time
(hours) C 14.88 11.815.97 11.3 Mean number of HLA antigen matches
(06) 4.00 A (1.41)2.74 (1.62)
Slide 54
Swanson et al. Transpl Infect Dis. 2004 Sep;4(3): 144-7.
Slide 55
Slide 56
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 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
Slide 57
Kumar et al. Kidney Int. 2005 Apr; 67(4): 1622-9.
Slide 58
Cause of death Post-transplant day Number of patients Pulmonary
embolism21 Anaphylactic reaction to drug61 Intractable
gastrointestinal bleeding 1071 Sepsis Chest infection371
Necrotizing fasciitis2381 Infection of the lymphocele2851
Myocardial infarction5451 Kumar et al. Kidney Int. 2005 Apr; 67(4):
1622-9.
Slide 59
Cause of graft loss Days of graft loss Number of grafts lost
Patient deaths from Table 2 2, 6, 37, 107, 238, 285 and 545 7 Acute
vascular rejection 12 1 Bleeding at the transplant site 15 1
Hemolytic uremic syndrome 55 1 Steven Johnson syndrome due to
Dapsone 152 1 Kumar et al. Kidney Int. 2005 Apr; 67(4):
1622-9.
Slide 60
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Slide 62
Qiu et al. HIV-positive renal recipients can achieve survival
rates similar to those of HIV- negative 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
Slide 63
Qiu et al. Transplantation. 2006 Jun 27; 81(12): 1658-61
Slide 64
Slide 65
Slide 66
Slide 67
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
Slide 68
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 ESRD- related mortality since the advent of HAART
Slide 69
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
Slide 70
Slide 71
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.comwww.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