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HIV-Related Kidney Disease, ART Effects
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CROI, Feb 25-28, 2007, Los Angeles
Reported by
Christina Wyatt, Asst Professor of Nephrology
Paul Klotman, Chairman, Department of Medicine and Professor of Nephrology
Mt Sinai School of Medicine, NY, NY
At two poster sessions devoted to HIV-related kidney disease and antiretroviral nephrotoxicity, investigators provided new insights into the pathogenesis, epidemiology, and diagnosis of HIV-related kidney disease and tenofovir-associated kidney dysfunction.
Pathogenesis of HIV-associated nephropathy (poster 825)
Scientists at the Mount Sinai School of Medicine and the Institute Jacques Monod provided further insight into the pathogenesis of HIV-associated nephropathy. Previous data from mouse models have suggested a role for the HIV genes nef and vpr, but little is known about the pathogenic mechanisms associated with vpr expression in the kidney. In a series of in vitro experiments in a human tubular epithelial cell line, expression of HIV vpr, but not vif or tat, caused cell cycle arrest and cell death. Further experiments suggested that this effect is mediated by DNA repair mechanisms.
HIV-related chronic kidney disease (posters 826-828, 830)
Several groups explored the epidemiology of chronic kidney disease and end-stage renal disease in patients with HIV. Investigators from Washington University reported an increased prevalence of chronic kidney disease in their ambulatory HIV population, compared to matched controls from the National Health and Nutrition Examination survey (NHANES). Among 845 HIV-positive patients, almost 30% had proteinuria, 42.7% had a glomerular filtration rate (GFR) below 90 ml/min/1.73m2, and 7.3%* had a GFR below 60 ml/min/1.73m2 (*incorrectly reported as 4% in the published abstract). Factors independently associated with decreased GFR included hypertension, hypercholesterolemia, proteinuria, and tenofovir use. Of note, lower HIV viral load was also associated with a decreased GFR, and patients on combination antiretroviral therapy actually had a lower mean GFR.
Investigators from the EuroSIDA Study Group also reported an association between antiretroviral use and reduced GFR in their population, although only indinavir and tenofovir were independently associated with kidney disease in adjusted analysis. Other factors associated with kidney disease included older age, diabetes, hypertension, lower nadir CD4, and treatment of OI with potentially nephrotoxic agents. The rate of chronic kidney disease, only 3.5%, is lower than that observed in other studies, in part because the investigators required 2 consecutive GFR estimates below 60 ml/min/1.73m2. In addition, the authors do not report on the racial distribution in the EuroSIDA population, which has traditionally had a lower proportion of higher risk minority patients.
Data from the ACTG ALLRT cohort also demonstrated a non-significant decline in GFR among antiretroviral-treated patients with normal baseline GFR. In contrast, patients with a reduced baseline GFR or with a baseline CD4 count below 200 experienced a significant and sustained improvement in GFR associated with virologic suppression. Similar improvements in GFR with antiretroviral therapy were observed in African patients participating in the DART study, reported at the 2006 IAS in Toronto. These improvements may suggest underlying HIV infection of the kidney, a theory supported by a recently published study by Han and colleagues, who reported early pathologic changes of HIV-associated nephropathy in patients without clinically apparent disease.
Each of these epidemiologic studies used a creatinine-based estimate of GFR such as Cockcroft-Gault or MDRD GFR; however, these estimates have not been well-validated in patients with HIV or AIDS. A secondary analysis of data from the FRAM cohort suggested that cystatin C might be a more sensitive marker of kidney disease in patients with HIV. Unlike serum creatinine, cystatin C was not correlated with lean body mass in HIV-positive patients or controls, a characteristic that could prove useful in the setting of weight gain on antiretroviral therapy. While this report is promising, several studies presented at the 2006 American Society of Nephrology failed to find a significant improvement in GFR estimates using cystatin C in the general population.
End-stage renal disease in HIV (posters 824 and 829)
Investigators from Johns Hopkins reported an increase in the incidence of end-stage renal disease among HIV-positive African-Americans followed in two prospective cohort studies, with an incidence of 10.7 cases/1000 person-years between 2000-2005. After adjusting for age and history of AIDS, this reflected a greater than 2-fold increase compared to the period from 1990-1994. The observed increase in end-stage renal disease may reflect the contribution of kidney diseases other than HIV-associated nephropathy, since previous studies have shown a plateau in the number of new cases of end-stage renal disease caused by this disease during the study period.
On a more promising note, data from the Solid Organ Transplantation in HIV Multi-site Study provided further evidence in support of kidney transplantation as alternative therapy for end-stage renal disease in patients with well-controlled HIV. These investigators have previously reported an unexpected increase in acute rejection among HIV-positive kidney transplant recipients, but the current study did not find any association between acute rejection and transient episodes of detectable HIV viral load. Approximately one-quarter of kidney and liver transplant recipients experienced at least one episode of detectable HIV viral load in the first 2 years, often associated with stopping antiretroviral therapy. More intensive antiretroviral regimens were associated with a decreased risk of detectable viral load.
Tenofovir nephrotoxicity (posters 832-835)
Four posters explored the effect of tenofovir-containing regimens on the rate of decline in estimated GFR. Investigators from Johns Hopkins reported a greater decline in GFR among treatment-experienced patients initiating tenofovir compared to those initiating an alternative NRTI, a difference that was not observed in treatment-na•ve patients. The authors also reported that the observed decline in GFR occurred within the first 6 months and did not appear to be progressive. The Swiss HIV Cohort Study group also reported that declines in estimated GFR of >10cc/min or >10% were more common among patients initiating tenofovir-containing regimens. Declines of this magnitude are consistent with the literature on tenofovir, although it is interesting that the decline in GFR often occurred after more than 6 months of therapy in this cohort.
Investigators from UC San Diego and from CCTG 578 reported greater GFR declines in patients receiving both tenofovir and ritonavir, but no greater decline in patients receiving tenofovir alone. In CCTG 578, tenofovir clearance did not predict GFR decline, consistent with previous in vitro data showing that ritonavir does not interfere with renal tubular transport of tenofovir. While the mechanism of this previously reported interaction between ritonavir and tenofovir is not known, it has been hypothesized that ritonavir increases the GI absorption of tenofovir, resulting in increased exposure.
Note from Jules Levin: in poster 835/CCTG 578 authors find: "TDF-PI/r treated patients tended to have higher week 2 TFV plasma exposures (Cmax: 255 vs 225 ng/mL; p=0.34 and Cmin: 76 vs 63 ng/ml; p=0.18; TFV clearance 96 vs 108 L/hr; p=0.36). In mixed-effects models, week 2 TFV PK metrics were associated with baseline estimated GFR but did not predict renal function over time".
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