clinical monitoring and correlates of nephropathy in siv-infected macaques during high-dose antiretroviral therapy

AIDS Research and Therapy Clinical monitoring and correlates of nephropathy in SIV-infected macaques during high-dose antiretroviral therapy Brigitte E Sanders-Beer^3,1, Yvette Y Spano⁴, Dawn Golighty¹, Abigail Lara¹, Diane Hebblewaite¹, Lourdes Nieves-Duran¹, Lowrey Rhodes¹ and Keith G Mansfield² ¹Southern Research Institute, Frederick, MD, USA; ²Harvard Medical School, New England Primate Research Center, Southborough, MA, USA; ³BIOQUAL, Inc., 9600 Medical Center Drive, Rockville, MD 20850, USA; ⁴Vaccine Research Program, Division of AIDS/NIAID/NIH, 6700B Rockledge Drive, Bethesda, MD 20817, USA AIDS Research and Therapy* 2011 Jan 21, 8:3 doi:10.1186/1742-6405-8-3
January 21, 2011

Background In many preclinical AIDS research studies, antiretroviral therapy (ART) is administered to experimentally simian immunodeficiency (SIV)-infected rhesus macaques for reduction of viral load to undetectable levels. Prolonged treatment of macaques with a high dose of PMPA (9-[2-(r)-(phosphonomethoxy) propyl] adenine or tenofovir; 30 mg/kg of body weight subcutaneously once daily) can result in proximal renal tubular dysfunction, a Fanconi-like syndrome characterized by glucosuria, aminoaciduria, hypophosphatemia, and bone pathology. In contrast, chronic administration of a low dose of PMPA (10 mg/kg subcutaneously once daily) starting at birth does not seem to be associated with any adverse health effects within 3 years of treatment. In contrast to PMPA, limited information on systemic toxicity in rhesus monkeys is available for FTC (5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine; emtricitabine) and stavudine (d4T). Results In this study, the clinical and biochemical correlates of tubular nephrosis in SIV-infected rhesus macaques associated with systemic administration of high-dose ART consisting of the three nucleoside analog inhibitors PMPA, FTC, and d4T were investigated. It was found that acute renal failure was uncommon (7.1% of treated animals) and that morphologic evidence of nephropathy, which persisted for more than 300 days following discontinuation of the drug cocktail, was more frequent (52.4% of treated animals). While parameters from single time points lacked predictive value, biochemical alterations in Blood Urea Nitrogen (BUN) and phosphorus were frequently identified longitudinally in the blood of ART-treated animals that developed evidence of nephropathy, and these longitudinal changes correlated with disease severity. Conclusions Recommendations are proposed to limit the impact of drug-induced renal disease in future SIV macaque studies. ^*Corresponding author: Brigitte E Sanders-Beer bsanders@bioqual.com CLICK HERE FOR FULL-TEXT PDF OF JOURNAL ARTICLE © 2011 Sanders-Beer et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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