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

Sanders-Beer BE, Spano YY, Golighty D, Lara A, Hebblewaite D, Nieves-Duran L, Rhodes L, Mansfield KG - AIDS Res Ther (2011)

Bottom Line: 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 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).

View Article: PubMed Central - HTML - PubMed

Affiliation: Southern Research Institute, Frederick, MD, USA. bsanders@bioqual.com.

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.

No MeSH data available.


Related in: MedlinePlus

Correlation of BUN and phosphorus slope with composite ART nephropathy score. Correlation of BUN (r = 0.7234; p = 0.0003) and phosphorus (r = 0.4631; p = 0.0398) slope with composite ART nephropathy score reveals statistical significance. Black dots represent individual animals.
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Figure 6: Correlation of BUN and phosphorus slope with composite ART nephropathy score. Correlation of BUN (r = 0.7234; p = 0.0003) and phosphorus (r = 0.4631; p = 0.0398) slope with composite ART nephropathy score reveals statistical significance. Black dots represent individual animals.

Mentions: To determine whether longitudinal alterations in biochemical values were associated with morphologic evidence of ART nephropathy, linear regression was performed for serum chemistry values from individual animals, and the slope of change was compared to composite histologic scores. Positive correlations were observed between composite histologic scores and changes in BUN (r = 0.7234; 95% CI 0.4131 to 0.8832; p = 0.0003) and phosphorus (r = 0.4631; 95% CI 0.02575 to 0.7516; p = 0.0398) (Figure 6). No statistically significant correlation was observed between changes in serum creatinine and composite histologic score. In all, 9 of 21 animals had statistically significant positive slopes for BUN over time. For animals with no evidence of ART nephropathy 11.1% (1/9) had a positive slope compared to 66.7% (8/12) with evidence of ART nephropathy (p = 0.0244; Fischer exact test). These findings indicate that morphologic alterations resulted in biochemical changes consistent with progressive renal disease and suggest that over time some animals may have progressed to renal failure.


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

Sanders-Beer BE, Spano YY, Golighty D, Lara A, Hebblewaite D, Nieves-Duran L, Rhodes L, Mansfield KG - AIDS Res Ther (2011)

Correlation of BUN and phosphorus slope with composite ART nephropathy score. Correlation of BUN (r = 0.7234; p = 0.0003) and phosphorus (r = 0.4631; p = 0.0398) slope with composite ART nephropathy score reveals statistical significance. Black dots represent individual animals.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3038877&req=5

Figure 6: Correlation of BUN and phosphorus slope with composite ART nephropathy score. Correlation of BUN (r = 0.7234; p = 0.0003) and phosphorus (r = 0.4631; p = 0.0398) slope with composite ART nephropathy score reveals statistical significance. Black dots represent individual animals.
Mentions: To determine whether longitudinal alterations in biochemical values were associated with morphologic evidence of ART nephropathy, linear regression was performed for serum chemistry values from individual animals, and the slope of change was compared to composite histologic scores. Positive correlations were observed between composite histologic scores and changes in BUN (r = 0.7234; 95% CI 0.4131 to 0.8832; p = 0.0003) and phosphorus (r = 0.4631; 95% CI 0.02575 to 0.7516; p = 0.0398) (Figure 6). No statistically significant correlation was observed between changes in serum creatinine and composite histologic score. In all, 9 of 21 animals had statistically significant positive slopes for BUN over time. For animals with no evidence of ART nephropathy 11.1% (1/9) had a positive slope compared to 66.7% (8/12) with evidence of ART nephropathy (p = 0.0244; Fischer exact test). These findings indicate that morphologic alterations resulted in biochemical changes consistent with progressive renal disease and suggest that over time some animals may have progressed to renal failure.

Bottom Line: 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 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).

View Article: PubMed Central - HTML - PubMed

Affiliation: Southern Research Institute, Frederick, MD, USA. bsanders@bioqual.com.

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.

No MeSH data available.


Related in: MedlinePlus