Sex-Based Differences in Cisplatin-Induced Nephrotoxicity

Background: Cisplatin is a potent chemotherapeutic agent, but its efficacy is limited by dose-dependent nephrotoxicity, with 30% of patients developing kidney injury, subsequently increasing the risk of chronic kidney disease. Sex-based differences are implicated as a biological variable of cisplatin-induced nephrotoxicity (CIN) and in immunological responses, but are greatly understudied. Given the crucial role of the immune system in mediating CIN, we hypothesize that sex-based immunological variations contribute to differential susceptibility to CIN. Methods: Male and female B6:129 mice were administered weekly doses of vehicle or cisplatin (5 or 7 mg/kg) for four weeks. Kidney function (transdermal GFR measurements), and immunological differences in the kidney (flow cytometry) were assessed. Results: Males treated with cisplatin exhibited a significant increase in kidney leukocytes, specifically resident macrophages. Transdermal GFR measurements showed a trending decrease in treated male mice. Conversely, treated female immune response was not statistically different than vehicle treated. Transdermal GFR measurements showed no significant difference between vehicle treated females and cisplatin treated females. Conclusion: Data indicate sex differences in a repeated low dose cisplatin model. Data suggest that kidney function in females, but not males was preserved in this model and that this could be in part be due to differences in immunological responses to cisplatin. This study highlights the importance of considering sex as a biological variable in CIN and advocates for sex-specific strategies to mitigate its adverse effects. Further studies will aid in gaining mechanistic insight for these sex specific differences for the development of more effective treatments. Funding: NIDDK Support