Kidney Function and Injury Biomarkers in Immunocompetent Tumor-Bearing Mice Treated with Cisplatin

Background: Cisplatin is a common chemotherapy drug for solid tumors, including neuroblastoma, the most prevalent extracranial solid tumor in children. Its clinical use is often limited by nephrotoxicity. While biomarkers of tubulointerstitial injury have been used to detect and predict cisplatin-induced acute kidney injury, the impact of the tumor itself on kidney function and tubulointerstitial disease biomarkers following cisplatin remains poorly understood. This study aimed to evaluate changes in kidney function and tubulointerstitial injury biomarkers in an immunocompetent murine model of neuroblastoma treated with cisplatin, compared to a vehicle control. Methods: Eight–10-week-old male C57BL/6J mice were subcutaneously inoculated with NB6494D mouse neuroblastoma cells. After 26 days, mice were randomized to receive cisplatin (T-Cis, 8 mg/kg/dose) vs. vehicle (T-Veh) treatments (n=12-13 mice/group) on days 27, 34, and 41. Transdermal glomerular filtration rate (tGFR) measurements, urine, and blood collection were performed before tumor implantation (baseline), and one day after each cisplatin vs. vehicle dose (D28, D35, and D42). Mice were euthanized on D42. tGFR, kidney function, and tubulointerstitial injury biomarkers were compared between groups. Results: Survival rates were similar between groups. Tumor volume showed no significant difference between groups before cisplatin. However, tumor size significantly decreased in cisplatin-treated mice (T-Veh=940.4 mm3 vs. T-Cis=225.7 mm3, p=0.03) at the end of the study. Both groups showed changes in tGFR, blood urea nitrogen (BUN), serum Cystatin C (sCys C), and urine neutrophil gelatinase-associated lipocalin (uNGAL) after tumor inoculation compared to baseline levels. However, there was a significant difference between cisplatin and vehicle-treated mice in tGFR, BUN, and sCys C only on D42. In comparison, urine kidney injury molecule 1 (uKIM1) and urine epidermal growth factor (uEGF) were significantly different between cisplatin and vehicle-treated mice after each treatment. Conclusion: Tumor development and cisplatin therapy cause changes in tGFR and levels of kidney function biomarkers (BUN and sCys C). However, uEGF and uKIM were significantly different after each cisplatin therapy compared to vehicle control. Funding: NIDDK Support