Clinical monitoring and correlates of nephropathy in SIV-infected macaques during high-dose antiretroviral therapy.

Abstract

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.

• Authors: Brigitte E Sanders-Beer, Yvette Y Spano, Dawn Golighty, Abigail Lara, Diane Hebblewaite, Lourdes Nieves-Duran, Lowrey Rhodes, Keith G Mansfield
• Journal: AIDS research and therapy (AIDS Res Ther) Vol. 8 Issue 1 Pg. 3 (Jan 21 2011) ISSN: 1742-6405 [Electronic] England
• PMID: 21255437 (Publication Type: Journal Article)