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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

Relationship between serum sodium levels at 2 wks of ART and ongoing pathology within the proximal convoluted tubules at death.
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Figure 5: Relationship between serum sodium levels at 2 wks of ART and ongoing pathology within the proximal convoluted tubules at death.

Mentions: To determine whether serum chemistry values were predictive of the development of chronic ART nephropathy, values were compared to individual and composite histologic scores. No statistically significant correlations were observed at base line, initiation of ART, 2 weeks ART, or 4 weeks ART for BUN, creatinine, phosphorus, calcium, albumin, globulin, glucose or alkaline phosphatase. At discontinuation of ART a negative correlation was observed between histologic score and phosphorus (r = -0.5360; 95% CI -0.7964 to -0.1079; p = 0.018) and positive correlations were observed with Ca/P (r = 0.4826; 95% CI 0.324 to 0.7684; p = 0.0364) and Crea/P (r = 0.4631; 95% CI 0.1109 to 0.7579; p = 0.0459) (Figure 4). At study termination, a positive correlation was observed between creatinine and composite histologic score (r = 0.4947; 95% CI 0.0372 to 0.7817; p = 0.037). Examination of individual histologic parameters revealed an unexpected relationship between serum sodium levels at 2 wks of ART and ongoing pathology in the proximal convoluted tubules at death (slope = 2.308; p = 0.0009) (Figure 5). This suggests that factors influencing hydration during treatment regimen may impact disease course.


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)

Relationship between serum sodium levels at 2 wks of ART and ongoing pathology within the proximal convoluted tubules at death.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Relationship between serum sodium levels at 2 wks of ART and ongoing pathology within the proximal convoluted tubules at death.
Mentions: To determine whether serum chemistry values were predictive of the development of chronic ART nephropathy, values were compared to individual and composite histologic scores. No statistically significant correlations were observed at base line, initiation of ART, 2 weeks ART, or 4 weeks ART for BUN, creatinine, phosphorus, calcium, albumin, globulin, glucose or alkaline phosphatase. At discontinuation of ART a negative correlation was observed between histologic score and phosphorus (r = -0.5360; 95% CI -0.7964 to -0.1079; p = 0.018) and positive correlations were observed with Ca/P (r = 0.4826; 95% CI 0.324 to 0.7684; p = 0.0364) and Crea/P (r = 0.4631; 95% CI 0.1109 to 0.7579; p = 0.0459) (Figure 4). At study termination, a positive correlation was observed between creatinine and composite histologic score (r = 0.4947; 95% CI 0.0372 to 0.7817; p = 0.037). Examination of individual histologic parameters revealed an unexpected relationship between serum sodium levels at 2 wks of ART and ongoing pathology in the proximal convoluted tubules at death (slope = 2.308; p = 0.0009) (Figure 5). This suggests that factors influencing hydration during treatment regimen may impact disease course.

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