research University of Dayton Galena, Ohio, United States
Background: Cisplatin is a widely used chemotherapeutic agent, with nearly half of pediatric cancer patients exposed during treatment. A major dose-limiting side effect is nephrotoxicity, which can lead to acute kidney injury (AKI) and chronic kidney disease (CKD). While clinical data suggest sex may influence cisplatin-induced nephrotoxicity, preclinical mouse models show conflicting results. This study investigates sex differences in repeated low-dose cisplatin models, which are currently underexplored. Objective: Kidney injury biomarkers can identify comparable injury phenotypes in male and female mice exposed to cisplatin. Design/Methods: C57Bl6J littermate mice (8–10 weeks) were treated with cisplatin. Males received 8 mg/kg on days 0, 7, and 14 (8mgCis3x, n=5). Females received either 8mgCis3x (n=5) or a reduced dose of 6 mg/kg (6mgCis3x, n=5) on the same schedule. Mice were euthanized upon reaching endpoint (≥35% weight loss for 2 consecutive days) or one month after the final dose. Survival was analyzed via Logrank (Mantel-Cox). Serum Cystatin C was measured at baseline, day 1 (D1), day 8 (D8), and one-month post-final dose (1M). Urinary epidermal growth factor normalized to creatinine (uEGF/Cr), a marker of tubular reserve, was measured before and after each dose. Significance was determined by two-way ANOVA (p < 0.05). Results: Female mice treated with 8mgCis3x showed significantly greater weight loss than those receiving 6mgCis3x (p < 0.0001). All females in the 8mgCis3x group met euthanasia criteria within 6–8 days post-third dose (p=0.0002), while no mortality occurred in males (8mgCis3x) or females (6mgCis3x). No significant differences in Cystatin C were observed among groups on D1 and D8. At 1M, Cystatin C levels were comparable between female 6mgCis3x and male 8mgCis3x groups. On D8, uEGF/Cr was significantly lower in females treated with 8mgCis3x compared to 6mgCis3x. Both male and female 8mgCis3x groups showed significant uEGF/Cr reduction from baseline, which was not observed in the female 6mgCis3x group.
Conclusion(s): Female mice exhibit increased susceptibility to cisplatin-induced kidney injury. Kidney function and injury biomarkers can help identify comparable toxicity across sexes, supporting refinement of preclinical models for nephrotoxicity studies.
