Supplementary Material for: Evaluating urinary biomarkers for early detection of kidney damage in immune checkpoint inhibitors-treated patients

Introduction: Immune checkpoint inhibitors (ICIs) have improved cancer treatment, however, their use can be limited by immune-mediated adverse events, such as kidney damage. Diagnostic limitations of nephrotoxicity may lead to worsening of the patient's prognosis. This study aimed to validate a panel of urinary biomarkers as diagnostic tools for kidney damage in patients treated with ICIs.
Methods: A prospective study was conducted on patients scheduled to receive ICIs. Those who subsequently developed kidney damage were considered cases; and those who did not were considered controls. A battery of biomarkers was assessed in urine samples at PRE-1, before the first treatment cycle; PRE-3, before the third cycle; and POST-3, one week after the third treatment cycle.
Results: A total of 46 patients participated in the study. At PRE-1, increased urinary excretion of IGFBP7, NAG, TIMP-2 × IGFBP7, and transferrin was observed in the case group, suggesting that these markers could be useful for early risk stratification of developing kidney damage. Furthermore, increased urinary excretion of albumin and NGAL was observed at PRE-3, suggesting that these markers could be of diagnostic utility to identify patients that could develop kidney damage once treatment is initiated. All of the aforementioned biomarkers demonstrated significant discriminatory ability between cases and controls, as verified by ROC curve analysis.
Conclusion: The proposed biomarker battery could be used as a preventive tool for decision-making in the management of oncology patients at risk for kidney damage associated with ICIs. Furthermore, its use would allow personalized adjustment of therapy that would minimize the probability of renal complications even before starting the first cycle of treatment.

引言：免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）已显著改善了恶性肿瘤的治疗格局，但其临床应用常受限于免疫相关不良事件，其中包括肾损伤。肾毒性的诊断局限性可导致患者预后恶化。本研究旨在验证一组尿液生物标志物，将其作为接受免疫检查点抑制剂治疗患者发生肾损伤的诊断工具。
方法：本研究针对计划接受免疫检查点抑制剂治疗的患者开展了一项前瞻性队列研究。后续发生肾损伤的患者纳入病例组，未发生肾损伤者纳入对照组。分别于三个时间点采集尿液样本并检测一系列生物标志物：首次治疗周期前的PRE-1、第三次治疗周期前的PRE-3，以及第三次治疗周期结束后1周的POST-3。
结果：本研究共纳入46例患者。在PRE-1时间点，病例组患者尿液中IGFBP7、NAG、TIMP-2 × IGFBP7及转铁蛋白的排泄水平显著升高，提示上述标志物可用于肾损伤发生风险的早期分层。此外，在PRE-3时间点，病例组患者尿液中白蛋白与NGAL的排泄水平亦显著升高，提示上述标志物具备诊断价值，可用于识别治疗启动后存在肾损伤发生风险的患者。经受试者工作特征（Receiver Operating Characteristic, ROC）曲线分析验证，上述所有生物标志物均展现出了病例组与对照组之间的显著鉴别效能。
结论：本研究提出的尿液生物标志物组合可作为辅助临床决策的预防工具，用于伴免疫检查点抑制剂相关肾损伤风险的肿瘤患者的管理。此外，在首次治疗周期开始前即可通过该标志物组合实现治疗方案的个性化调整，从而最大限度降低肾脏并发症的发生概率。