Limits...
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

Alterations in serum chemistry values at defined time points during the course of treatment and disease. Alterations in blood urea nitrogen, creatinine, phosphorus, calcium, the Ca/P ratio and alkaline phosphatase were plotted at critical time points (1 = baseline, 2 = initiation of ART, 3 = 2 weeks ART, 4 = 4 weeks ART, 5 = ART end, 6 = study end). Grey dots represent individual animals and black lines represent the mean.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3038877&req=5

Figure 3: Alterations in serum chemistry values at defined time points during the course of treatment and disease. Alterations in blood urea nitrogen, creatinine, phosphorus, calcium, the Ca/P ratio and alkaline phosphatase were plotted at critical time points (1 = baseline, 2 = initiation of ART, 3 = 2 weeks ART, 4 = 4 weeks ART, 5 = ART end, 6 = study end). Grey dots represent individual animals and black lines represent the mean.

Mentions: Longitudinal changes in serum chemistry were examined at different stages of disease and treatment and revealed an initial increase in BUN and creatinine and decrease in phosphorus, which coincided with ART initiation (Figure 2). These values tended to normalize following PMPA dose reduction from 30 to 20 mg/kg. Following discontinuation of ART, phosphorus increased further, and there were upward trends in both creatinine and BUN. One-way analysis of variance (Anova) was used to compare values at base line, initiation of ART, 2 weeks of ART, 4 weeks of ART, termination of ART, and end of study (Table 2 and Figure 3). Differences were observed for calcium (p < 0.001), phosphorus (p = 0.0042), alkaline phosphatase (p < 0.0001), Ca/P (p < 0.001), creatinine/phosphorus (p < 0.0001), and BUN/phosphorus (p < 0.001). A post (ANOVA) test pairwise comparison was performed to examine differences at select time points with the result that statistically significant increases in the calcium/phosphorus ratio (p < 0.001), the creatinine/phosphorus ratio (p < 0.001), and alkaline phosphatase (p < 0.05), and a statistically significant decrease in phosphorus (p < 0.05) were present after 4 weeks of ART compared to values obtained at the initiation of ART (Table 2). Further differences were not observed at the termination of ART suggesting that only the higher dose of PMPA was associated with adverse outcomes or that compensatory mechanisms had come into play for reducing serum chemistry changes.


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)

Alterations in serum chemistry values at defined time points during the course of treatment and disease. Alterations in blood urea nitrogen, creatinine, phosphorus, calcium, the Ca/P ratio and alkaline phosphatase were plotted at critical time points (1 = baseline, 2 = initiation of ART, 3 = 2 weeks ART, 4 = 4 weeks ART, 5 = ART end, 6 = study end). Grey dots represent individual animals and black lines represent the mean.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Alterations in serum chemistry values at defined time points during the course of treatment and disease. Alterations in blood urea nitrogen, creatinine, phosphorus, calcium, the Ca/P ratio and alkaline phosphatase were plotted at critical time points (1 = baseline, 2 = initiation of ART, 3 = 2 weeks ART, 4 = 4 weeks ART, 5 = ART end, 6 = study end). Grey dots represent individual animals and black lines represent the mean.
Mentions: Longitudinal changes in serum chemistry were examined at different stages of disease and treatment and revealed an initial increase in BUN and creatinine and decrease in phosphorus, which coincided with ART initiation (Figure 2). These values tended to normalize following PMPA dose reduction from 30 to 20 mg/kg. Following discontinuation of ART, phosphorus increased further, and there were upward trends in both creatinine and BUN. One-way analysis of variance (Anova) was used to compare values at base line, initiation of ART, 2 weeks of ART, 4 weeks of ART, termination of ART, and end of study (Table 2 and Figure 3). Differences were observed for calcium (p < 0.001), phosphorus (p = 0.0042), alkaline phosphatase (p < 0.0001), Ca/P (p < 0.001), creatinine/phosphorus (p < 0.0001), and BUN/phosphorus (p < 0.001). A post (ANOVA) test pairwise comparison was performed to examine differences at select time points with the result that statistically significant increases in the calcium/phosphorus ratio (p < 0.001), the creatinine/phosphorus ratio (p < 0.001), and alkaline phosphatase (p < 0.05), and a statistically significant decrease in phosphorus (p < 0.05) were present after 4 weeks of ART compared to values obtained at the initiation of ART (Table 2). Further differences were not observed at the termination of ART suggesting that only the higher dose of PMPA was associated with adverse outcomes or that compensatory mechanisms had come into play for reducing serum chemistry changes.

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