Types of HIV-associated glomerular nephropathies Endothelial cell injury (apoptosis, infection) Glomerular microangiopathy, mesangiolysis 2–10 HIV-associated thrombotic microangiopathy HIV-associated immune complexes deposition, co-infections associated immune complexes deposition (HBV, HCV, intravenous drug use) Membranoproliferative GN, membranous nephropathy, IgA nephropathy, 'lupus like nephropathy', 20–50 HIV-associated immune complexes nephropathy HIV infection of renal cells (epithelial tubular cells, podocytes, mesangial cells) Focal glomerular sclerosis, 'collapsing nephropathy' Tubular atrophy, microcystic dilatation 40–80 HIV-associated nephropathy (HIVAN) Proposed pathogenetic links Histological renal lesions Average freq (%) Types of HIV associated glomerular nephropathies
The spectrum of tubulointerstitial lesions includes
acute tubular necrosis
drug-related interstitial nephritis, and
neoplasms including lymphoma and Kaposi's sarcoma.
Renal infections include pyelonephritis, and opportunistic infections
such as aspergillosis Pseudallescheria boydii , murcomycosis and adenoviruses
regardless of the specific histologic lesion or underlying cause, the presence of proteinuria and/or decreased renal function is associated with increased mortality and worse outcomes
HIVAN HIV-associated nephropathy
progressive renal failure with both tubulointerstitial and glomerular lesions.
exclusively in Blacks
up to 10% of HIV+ve Black adults and occasionally Caucasian
None of 239 autopsies on AIDS pts in Switzerland has HIVAN
none of 26 HIV-infected proteinuric patients from Thailand (greater than 1.5 g/day) had HIVAN by biopsy
it is possible that an inherited susceptibility to renal failure is present in many Blacks with HIV infection who subsequently develop nephropathy
HIVAN became the 3rd leading cause of ESRD in Blacks, ages 20–64, in 1995
HIVAN is a late, not early, manifestation of HIV-1 infection
(some time occur before seroconversion)
Hypertension is absent in most patients who are volume depleted.
present with proteinuria and progressive renal failure
The proteinuria ranges from moderate to nephrotic levels.
renal tubular epithelial cells in the urinary sediment with few red or white cells (vs post-infectious and Ig A)
normal or large echogenic kidneys despite significant renal insufficiency
biopsy confirmation is important in order to distinguish HIVAN from other forms of of renal disease (as many as 50% of patients have a different lesion in patients with presumed HIV-related FGS pre-biospy esp white patients ) > Mx
biopsy those with proteinuria> 1000 mg/day
The prognosis of patients with HIVAN is poor, particularly if interstitial changes are prominent.
end-stage renal disease frequently develops within 1 to 4 months
some clinicians place a hemodialysis access once a renal biopsy has verified HIV-related FGS
Among 89 HIV infected patients who underwent renal biopsy
HIV associated nephropathy was noted in (42)
immune complex glomerulonephropathy (13)
membranous nephropathy (8),
diabetic glomerulopathy (6),
membranoproliferative disease (5)
hypertensive nephrosclerosis (5).
Szczech USA (2004) Kidney Int 2004 Sep;66(3):1145-52.
podocyte proliferation and loss of differentiation markers, coexisting with glomerular collapses and tubular pathology including atrophy and microcystic dilations (This microcystic dilation is responsible for increased kidney echogenicity and size.)
The interstitium shows infiltration by leucocytes, primarily CD8 + T-lymphocytes and macrophages.
Interstitial oedema and fibrosis is frequently noted.
Diffuse mesangial hyperplasia associated with some degree of podocytes hypertrophy is more frequently observed in children and Caucasoids and has a less severe clinical presentation with non-nephrotic proteinuria and normal renal function
Collapsing glomerulosclerosis: light microscopy showing few open loops, large urinary space in glomerulus and severe tubulointerstitial injury with microcyst formation and tubular degeneration
Electron microscopy show tubular reticular inclusions in endothelial cells which is thought to be induced by IFN-a (also in SLE)
Physiopathology of HIV-associated nephropathy
The key role of the virus in HIVAN is now well established.
Several studies demonstrated that HIV-1 is able to infect renal tubular and glomerular epithelial cells or podocytes
blacks have an increased incidence of ESRF from a variety of different causes, including hypertensive nephrosclerosis, diabetic nephropathy, lupus nephritis, and heroin nephropathy, implying an underlying genetic predisposition to severe renal dysfunction independent of disease
enhanced risk among blacks appears in part to be familial (Compared to the control group, a much higher percentage of first and second degree relatives with ESRD was observed among those with HIV nephropathy (24 versus 6 percent, p = 0.004).
Treatment of HIV-associated nephropathy
no proven effective therapy
highly active antiretroviral therapy
angiotensin-converting enzyme (ACE) inhibitors
Corticosteroids, cyclosporine and other immunosuppressants have been tried.
longitudinal multivariate analyses demonstrated an highly significant association between prednisone and a slower decline in creatinine clearance and corticosteroid-related side-effects were not prohibitive ( Szczech et al . 2002 ).
Although not based on well-controlled trials, the efficacy of highly active antiretroviral therapy is almost certain since it had a beneficial effect on the incidence of HIVAN in the United States
By statistical model fit to data after 1995, it was estimated that HAART had reduced the rate of progression from HIV-associated nephropathy to ESRD by 38 percent .
In a case report , a patient with FGS and dialysis-dependent renal failure became dialysis free after 15 weeks of triple agent antiretroviral therapy. Repeat renal biopsy revealed histologic recovery with only infrequent glomeruli showing mild collapse and minimal fibrosis.
In a retrospective cohort study of 19 patients with HIV nephropathy, the use of protease inhibitors as part of a HAART regimen significantly slowed the rate of progression of renal dysfunction (-0.08 mL/min per month versus -4.30 mL/min per month for those not administered one of these drugs) Szczech et al . (2002)
HAART may also prevent the development of HIV nephropathy . In a retrospective study of 4000 patients with HIV infection followed between 1989 to 2001, the risk of nephropathy was 60 percent lower among patients treated with HAART, and no cases were reported among patients who began HAART therapy prior to overt AIDS Schwartz et al.(2005)
Kimmel et al . (1996) showed in a retrospective study, using a Cox regression analysis, that captopril and antiretroviral therapy were associated with enhanced renal survival , while age, serum creatinine, urinary protein–creatinine ratio, and CD4 count were not.
Burns et al . (1997) examined the effect of fosinopril (10 mg daily) in 20 patients with HIVAN and observed that treatment with ACE inhibitor stabilize serum creatinine and 24-h protein excretion ( vs untreated patients deteriorated)
HAART and corticosteroids
Navarrete J Am Soc Nephrol 2000
retrospective study of 31 HIVAN pts, the mean renal survival to end-stage renal disease was 26 , 6 , and 3 months for those treated with combination therapy , HAART alone , and neither HAART nor prednisone, respectively
Eustace et al . 2000
A retrospective cohort study of twenty one patients with biopsy-proven HIVAN and progressive azotaemia.Thirteen selected patients were treated with 60 mg of prednisone for one month , followed by a several-month taper whereas eight had not.
On long-term follow-up, there was no significant difference in the incidence of hospitalizations or of serious infections .
At six months, only one of the non-corticosteroid-treated patients but seven of the corticosteroid-treated group continued to have independent renal function. Three of the corticosteroid-treated group continued to have independent function at two years of follow-up.
Ingulli J Pediatr 1991 Nov;119(5):710-6.
all three children who were treated with cyclosporine had remission of the proteinuria and stable renal function
The proteinuria rapidly recurred in one child in whom cyclosporine was discontinued.
Summary and recommendations
HIVAN should be treated with HAART
ACEI/ARBs are also reasonable if creatinine < 2.0 mg/dL (177µmol/L)
blood pressure <130/80 mmHg
Calcium channel blockers be avoided in patients receiving protease inhibitors.
IS - the risk of infection must be balanced against possible improvement in renal function.
RENAL REPLACEMENT THERAPY
Hemodialysis and peritoneal dialysis appear to be equally effective
candidates must be on a stable HAART regimen, with undetectable viral load, CD4 cell count greater than 200 cells/mm3, and no recent opportunistic infection
sirolimus inhibits HIV replication (reversed by FK506 )
Mycophenolate, has inhibitory effects on HIV, is synergistic with many antiretroviral agents and is being used for multidrug-resistant cases of HIV
cyclosporine and its analogs have anti-HIV activity
HIV-associated immune-complexes nephropathies
deposition of immune complexes in multiple sites (mesangial, subendothelial, intra- and epimembranous)
The complexes contain HIV antigen and antibody to gp 120 HIV
characterized by endocapillary proliferation with parietal fibrinoid deposits in multiple sites.
Deposits may be so intense that it resembles lupus nephropathy ('lupus like' GN).
Interstitial infiltrates are frequent with a higher frequency of B cells than in HIVAN and the progression to renal failure is slower than in HIVAN
The prognosis was poor
HCV-associated glomerular disease
Renal presentations included renal impairment, microscopic haematuria, hypertension, and nephrotic syndrome
Hypocomplementaemia and cryoglobulinaemia were present > 1/3
MPGN and less frequently membranous glomerulopathy
clinical course was characterized by rapid progression to renal failure requiring dialysis mimic HIVAN.
renal biopsy is essential to differentiate from HIVAN (more HPT, low C3/C4, cryoglobulinaemia)
A systematic study of kidney in 116 deceased AIDS patients showed diffuse mesangial IgA deposits in nine (7.75 per cent).
Urinary abnormalities were mild in all cases.
Anti-idiotypic IgA reacting with anti-gp41 IgG were detected in circulating immune complexes in patients with HIV infection and IgA nephropathy
Optimal therapy in this disorder is uncertain. Spontaneous remission can occur and some patients may show at least a transient response to corticosteroid therapy
Fibrillary/immunotactoid GN in HIV-positive patients was observed in three cases ( Haas et al . 2000 ).
Renal amyloidosis is rarely observed in HIV-infected patients ( Joseph et al . 2000 ).
HIV-associated thrombotic microangiopathy
TMA is an unfrequent cause of renal lesions in HIV
But, retroviral infections represent a significant cause of TMA ( Ucar et al . 1994 11 of 50 serum samples collected from patients with a diagnosis of TMA, from 1979 to 1991, tested positive for antiretroviral antibodies. 7 had HIV, 4 had human lymphotrophic virus, type I (HTLV- I) infection )
Since the introduction of HAART, the incidence of TMA in HIV-infected patients had markedly diminished.
Haemolytic anaemia and thrombocytopaenia are present in all patients but shyzocytes are infrequently found
Severe hypertension is present in 50% of cases.
Neurological manifestations (convulsions, cerebellar signs, coma) are present in the majority of the cases.
Multiple causes may be involved such as drugs, lymphomas, neoplasias, or infections.
The pathogenesis is unknown, but is thought to be the result of endothelial injury.
The course of TMA in HIV-infected patients is severe.
20% required haemodialysis
Non survive after 2 years
Other renal manifestations
Acute renal failure
Acute renal failure
Peraldi et al . (1999) found the HUS to be the most frequent cause of ARF (35% of the cases), 15% of patients had HIVAN .
it was emphasized that acute elevation of serum creatinine was most frequently due to others factors: volume depletion due to salt wasting, poor nutrition, or vomiting, obstructive uropathy and acute tubular necrosis due to recurrent infections and toxicity of medication ( e.g. aminoglycosides, sulfamethoxazole/trimethoprim, amphotericin, pentamidine, and foscarnet, antiretroviral) or radiological contrast media.
Hyponatraemia is common occurring in 40% patients with AIDS or AIDS-related complex, and may be due to
gastrointestinal fluid loss,
inappropriate ADH secretion associated with pulmonary and central nervous system infections, and
acute renal failure.
Hyponatraemia is mild in the majority of patients, but in a few it is severe and symptomatic.
Hyperkalaemia is less common but may arise owing to adrenal insufficiency, pentamidine therapy, high-dose trimethoprim (acting like potassium-sparing diuretic) or acute renal failure
Symptomatic hypocalcaemia and hypomagnesaemia due to renal magnesium wasting have been reported in a patient with AIDS treated with pentamidine
Well known (ATN) - pentamidine, foscarnet, cidofovir, amphotericin B, high dose adefovir, or aminoglycosides
increasingly described- ritonavir (a protease inhibitor) and tenofovir (nucleotide reverse transcriptase inhibitor), which is also associated with Fanconi's syndrome
nucleoside reverse transcriptase inhibitors, have much less renal toxicity.
intratubular obstruction due to crystal precipitation following sulfadiazine or IV acyclovir, indinavir
Indinavir forms characteristic crystals in the urine and may be associated with dysuria and urinary frequency, with flank or back pain associated with intrarenal sludging, and with the classic syndrome of renal colic.
Kopp et al . 2002 ,Nineteen of the 240 patients receiving indinavir ( 8% ) developed urologic symptoms. Of these, seven ( 3%) had nephrolithiasis and the other 12 ( 5% ) had previously undescribed syndromes: crystalluria associated with dysuria and crystalluria associated with back or flank pain
Interstitial nephritis, often with nephrocalcinosis, that may reflect cytomegalovirus infection or a reaction to a drug such as trimethoprim-sulfamethoxazole
Screening and Initial Evaluations
At diagnosis , all HIV patients should be assessed for existing kidney disease with a screening urine analysis for proteinuria and a calculated estimate of renal function (C-III).
If there is no evidence of proteinuria at initial evaluation, patients at high risk for the development of proteinuric renal disease (i.e., African American persons, those with CD4+ cell counts <200 microL or HIV RNA levels >4,000 copies/mL, and those with diabetes mellitus, hypertension, or hepatitis C virus coinfection) should undergo annual screening (B-II) .
Renal function should be estimated on a yearly basis to assess for changes over time (B-II) .
Additional evaluations (including quantification of proteinuria, renal ultrasound, and potentially renal biopsy) and referral to a nephrologist are recommended for patients with proteinuria of grade > 1+ by dipstick analysis or glomerular filtration rate (GFR) <60 mL/min per 1.73 m2 (B-II) .
BP < 125/75 mm Hg (B-III)
ACEI/ARBs for those patients with proteinuria (B-II).
Calcium channel blockers should be avoided in patients receiving protease inhibitors (D-II).
Pts should be treated with HAART at diagnosis (B-II). HAART should not be withheld from patients simply because of the severity of their renal dysfunction (B-III).
Addition of ACE inhibitors, ARBs, and/or prednisone should be considered in patients with HIVAN if HAART alone does not result in improvement of renal function (B-II).
Dialysis and the placement of arteriovenous fistulae should not be withheld for patients solely because of HIV infection (A-II)
Renal transplantation may be considered for patients with end-stage renal disease (ESRD) if provided in a supervised clinical trial or at centers with adequate experience in this area (C-III).
Antiretroviral Dosing And Renal Toxicities
Appropriate reduction of dosing for antiretrovirals that are primarily renally eliminated is warranted (C-III) , with additional doses given after hemodialysis for those drugs that are readily removed by dialysis (B-II) .
Nucleoside analogues should not be withheld in patients with reduced renal function for fear of the development of lactic acidosis (D-III) .
Patients receiving indinavir should drink at least 1.5 L of water daily to prevent stone formation (B-III) . Periodic monitoring of renal function and pyuria should be performed during the first 6 months of indinavir therapy and biannually thereafter (B-II) , although routine screening for crystalluria is not warranted unless there is a suspicion of nephrolithiasis (B-II) . Indinavir need not be withheld from patients with reduced renal function (C-III) . In patients who develop indinavir nephrolithiasis, it would be reasonable to restart indinavir therapy once rehydration is achieved (B-III) . Patients who develop indinavir-induced hypertension, pyuria, rhabdomyolysis, or renal insufficiency (acute or chronic) should permanently discontinue use of this drug (B-III) .
Patients receiving tenofovir who have a GFR <90 mL/min per 1.73 m2, patients receiving other medications eliminated via renal secretion (e.g., adefovir, acyclovir, ganciclovir, or cidofovir), patients with other comorbid diseases (e.g., diabetes or hypertension), or patients receiving ritonavir-boosted protease inhibitor regimens should be monitored at least biannually for measurements of renal function, serum phosphorus, and urine analysis for proteinuria and glycosuria (B-III) .