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Pathogenesis and Treatment of HIV-Associated
Nephropathy
Paul Klotman, MD, Mt Sinai Medical Center, NYC
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Topics in HIV Medicine, Volume 9, Issue 2, 6/2001 (Intl AIDS Society/USA)
www.iasusa.org
ABSTRACT: Over 90% of patients with HIV related kidney problems are black. Preliminary studies in animals and humans suggest HIV can play a direct role causing this disease. There is evidence that HAART treatment has a beneficial effect on disease progression. In the absence of adequate studies, Dr Klotman has devised a model which suggests that the decrease in the prevalence of end stage renal disease can be explained by the introduction of potent antiretroviral therapy. Below Dr Klotman describes his experience with one patient who had acute HIV infection and end stage renal disease. The patient was given aggressive antiretroviral therapy, and plasma HIV RNA level was suppressed to levels below detection limits. After 3 months the patient's renal failure had completely resolved. Klotman suggests the kidney may be an HIV reservoir. He raises the question whether the kidney can be repopulated with HIV after HAART effectiveness in reducing HIV viral load is reduced or when HIV therapy is stopped or interrupted. Klotman reported on HIV in the kidney at Retrovirus 2001 (LB3). Clearly, there has been little research in this area.
HIV-associated nephropathy (HIVAN) has become the most common single diagnosis in HIV-infected patients with renal insufficiency. More than 90% of patients with HIVAN are black, with 50% having a history of injection drug use. Data from 1999 indicated that AIDS-associated end-stage renal disease (ESRD) was the third most common form of ESRD in blacks aged 20 to 64 years (after diabetes and hypertension), accounting for 8% of cases. As a clinical syndrome, HIVAN is characterized by significant proteinuria and a
rapid progression to ESRD; there is evidence, however, that potent antiretroviral therapy may slow the progression of the disease, and a greater number of patients with HIVAN are living longer following therapy. The disease has tended to occur in later-stage HIV infection, but cases of
early onset have been seen and there is considerable interest in identifying renal changes that are associated with HIVAN early in the course of HIV infection. The disease is characterized among other features by normal to
enlarged kidneys on gross appearance.
Biopsy in HIV-infected patients with proteinuria finds the typical features of HIVAN in about 60% of cases, and a variety of other disease entities are also found in association with factors such as hepatitis and drug use.
Pathogenesis: is HIV a cause
A central question in the pathogenesis of HIVAN is whether the disease can be attributed to direct viral effects or to HIV-related changes in the cytokine milieu. Increasing evidence supports a direct role of HIV. Studies in a transgenic mouse model (Tg26), in which HIV-1 envelope and regulatory genes are expressed but gag and pol genes are deleted to render the
virus noninfectious, have shown that renal disease in these animals closely resembles HIVAN; the resulting disease includes rapid progressive renal failure with the HIVAN features of microcystic changes and segmental sclerosis, including the collapsing variant. These findings that viral expression in the kidney is sufficient for the development of the disease suggest
a direct role of HIV in its pathogenesis. Such findings, however, do not explain the strong predilection for disease in blacks. To determine whether HIV is indeed present in the human kidney, Dr Klotman colleagues have studied biopsy specimens from patients with HIVAN.
HIV Found in Kidney: may be a reservoir for HIV
Studies with PCR for LTR circular DNA showed the presence of this marker for recent cellular infection in approximately half of samples tested, including samples from patients with no detectable HIV in the peripheral blood. Use of HIV-1 gag mRNA probes to determine whether such infection was occurring in renal cells (ie, rather than in T cells or macrophages within the samples) found HIV-1 mRNA in the perinuclear region of renal tubular epithelial cells and glomerular cells, with clustering of positive cells
apparently indicating efficient cell-to-cell transmission of the virus. In
situ PCR for HIV-1 DNA in these samples showed proviral infection of the nuclei of both tubular epithelial cells and podocytes in the glomerulus.
In subsequent studies, laser capture microscopy has been used to isolate renal epithelial cells shown to have integrated virus by in situ PCR to permit amplification of viral envelope V3 loop genetic sequences. These studies have found that the genetic variants of the virus in the kidney are distinct from the genetic variants in the peripheral blood of the same patient.
Treatment: HAART helps; what happens after HIV therapy interruption?
No standard therapy for HIVAN has been developed, but there is evidence that potent antiretroviral therapy has a beneficial effect on disease progression. Angiotensin-converting enzyme inhibitors are sometimes used in patients with HIVAN, but their effects have not been evaluated in controlled studies. Steroids have also been reported to be of benefit in some cases, but the rationale for using them in a disease that is not immune complex- mediated is not clear.
The effects of potent antiretroviral therapy on HIVAN have yet to be examined in a controlled study; protocols for investigating this are currently being reviewed by the AIDS Clinical Trials Group. In the absence of data from controlled trials, Dr Klotman's group has generated a mathematical model for assessing the impact that potent therapy may have had on the increase in prevalence of ESRD in HIV-infected black patients. In brief, this model
shows that the decrease in the prevalence of ESRD that can be attributed to HIVAN since 1995 can be explained by the introduction of potent antiretroviral therapy. The best fit of the existing data demonstrates
that potent therapy has had an estimated 28% efficacy in reducing the
increases in the number of HIV-infected black patients with ESRD. This model also predicts that, in the absence of drug treatment with 100% efficacy and with increases expected in the pool of patients at risk for developing HIVAN (ie, black patients who are HIV-seropositive or living with AIDS), the size of the population of HIV-infected patients with ESRD will continue to increase.
Anecdotal evidence of a beneficial effect of potent antiretroviral therapy on
very early onset HIVAN comes from the recent experience of Dr Klotman and colleagues in a patient who presented with ESRD during acute HIV seroconversion. Biopsy performed when the patient was about to undergo dialysis showed classic features of HIVAN, consisting of microcystic
disease and focal segmental glomerulosclerosis. The patient was given aggressive antiretroviral therapy, and plasma HIV RNA level was suppressed to levels below detection limits. After 3 months the patient's renal failure had completely resolved. Repeated biopsy showed reversal of the microcystic changes that were present before potent antiretroviral therapy
was initiated and resolution of collapsing glomerular disease with residual scarring. Collagen staining showed residual interstitial fibrosis, but it was markedly improved from the pretreatment condition. Assessing LTR circular viral DNA in biopsy samples found marked positivity before potent antiretroviral therapy, but not after. In addition, the resolution of
renal failure after potent therapy was accompanied by a restoration of podocyte differentiation (as indicated by increased synaptopodin staining) and normalized cell proliferation (as indicated by normal-ized
Ki67 marker positivity). In situ hybridization for viral mRNA, however, showed that some (low) level of viral transcription was ongoing. Observations in this patient suggest both that renal damage due to active infection may be seen early in the course of HIV infection and that potent antiretroviral
therapy may have a beneficial effect on the course of HIVAN by stopping such damage, thus making structural and functional reconstitution possible. In addition, the finding of ongoing viral transcription in the absence of active cellular infection during potent antiretroviral therapy supports the hypothesis that the kidney may be a viral reservoir; it remains unclear, however, whether the kidney might be a source of viral repopulation when the efficacy of potent antiretroviral therapy in suppressing viral replication is reduced or when drug pressure is removed.
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