The Utility of a Rodent Model in Detecting Pediatric Drug-Induced Nephrotoxicity

Abstract

A multi-age rat model was used to identify potential age-related differences in renal injury following exposure to gentamicin (GM). In this study, 10-, 25-, 40-, and 80-day-old Sprague-Dawley rats were dosed with GM at 0, 50, or 100 mg kg(-1) body weight per day (mkd) sc for 6 or 14 days. Urine samples were collected up to 72 h after initial dosing. The maximum tolerated dose was lower in 10-day-old rats than for other ages (none survived 11 days of treatment). Eighty-day-old rats given the highest dose showed a diminished rate of growth and an increase in serum creatinine, blood urea nitrogen (BUN), urinary kidney injury molecule-1 (Kim-1), and renal pathology. Ten- and 40-day-old rats given 100 mkd of GM for 6- or 14 days also had increased levels of serum BUN and Cr and renal pathology, whereas only mild renal alterations were found in 25-day-old rats. After 6 days of treatment with 100 mkd GM, significant increases in Havcr-1 (Kim-1) gene expression were detected only in 10- and 80-day-old rats. In urine samples, nuclear magnetic resonance and ultra performance liquid chromatography/mass spectrometry analysis detected changes related to GM efficacy (e.g., hippurate) and increases in metabolites related to antioxidant activity, which was greatest in the 80-day-old rats. The magnitude of the genomic, metabonomic, and serum chemistry changes appeared to correlate with the degree of nephropathy. These findings indicate that an experimental animal model that includes several developmental stages can detect age-related differences in drug-induced organ toxicities and may be a useful predictor of pediatric drug safety in preclinical studies.

Beneficial Effects of Short-Term Calorie Restriction against Cisplatin-Induced Acute Renal Injury in Aged Rats

“…There are experimental data suggesting that nephrotoxic drugs may also change the levels of BUN and SCr [22,23,24], which are commonly used to monitor the development and extent of renal tubular damage due to DDP [25]. Therefore, in this study we examined the levels of BUN and SCr after the application of DDP.…”

Proximal tubular dysfunction as an indicator of chronic graft dysfunction

“…Moreover, Kim-1 co-localized with signs of inflammation and renal fibrosis. The potential of Kim-1 as a biomarker of proximal tubular injury was illustrated in several other models and in human studies of drug toxicity (43,44), heavy metal nephropathy (43,45), protein-overload nephropathy (46), and polycystic kidney disease (47).…”

Children's toxicology from bench to bed - Drug-induced Renal Injury (4): Effects of nephrotoxic compounds on fetal and developing kidney

“…A multiage rat model was used to identify potential age-related differences of renal injury following exposure to gentamicin (Espandiari et al, 2007). In this study, 10-, 25-, 40-, and 80-day-old rats received a subcutaneous injection of gentamicin at a dose level of 50 or 100 mg/kg once a day for 6 or 14 days.…”