Immune checkpoint inhibitor-induced nephrotic syndrome: a pharmacovigilance analysis of 404 FAERS cases and literature case series

Immune checkpoint inhibitor (ICI)-related nephrotic syndrome is a rare but increasingly reported adverse event, where early-onset severe cases warrant heightened vigilance. This pharmacovigilance study assessed this correlation by analyzing the U.S. Food and Drug Administration’s Adverse Event Reporting System (FAERS) database from Q1 2011 to Q1 2025. A total of 404 cases of ICI-related nephrotic syndrome were identified in the FAERS database, with 84.1% of cases related to programmed cell death protein 1 (58.9%) or programmed death-ligand 1 (25.2%) inhibitors. Disproportionality signals were observed for six ICI monotherapies and one combination therapy: atezolizumab (ROR 6.84; 95% CI: 5.58–8.40), avelumab (ROR 5.54; 95% CI: 2.64–11.63), nivolumab (ROR 4.37; 95% CI: 3.64–5.25), pembrolizumab (ROR 3.44; 95% CI: 2.88–4.10), durvalumab (ROR 2.03; 95% CI: 1.12–3.66), ipilimumab (ROR 2.05; 95% CI: 1.07–3.94), and the combination therapy of nivolumab and ipilimumab (ROR 4.56; 95% CI: 3.56–5.83). Firth multivariate logistic regression analysis identified several independent risk factors, including advanced age (>65 years), malignant renal neoplasm, malignant mesothelioma, and the concomitant use of bevacizumab or lenvatinib. The median onset time was significantly shorter for severe cases than for non-severe cases (22.5 vs. 96.5 days, respectively; p = 0.0479). Additionally, a literature review of 18 cases provided supplementary information on the clinical features. This study provides vital pharmacovigilance insights regarding nephrotic syndrome related to ICIs, enhancing the understanding of its clinical implications.免疫检查点抑制剂（immune checkpoint inhibitor, ICI）相关肾病综合征是一种罕见但报道日益增多的不良事件，早发性重症病例需加强临床警惕。本药物警戒研究通过分析2011年第一季度至2025年第一季度的美国食品药品监督管理局（U.S. Food and Drug Administration, FDA）不良事件报告系统（Adverse Event Reporting System, FAERS）数据库，对该相关性展开评估。研究从FAERS数据库中共筛选出404例ICI相关肾病综合征病例，其中84.1%的病例与程序性死亡受体1（programmed cell death protein 1, PD-1）抑制剂（58.9%）或程序性死亡配体1（programmed death-ligand 1, PD-L1）抑制剂（25.2%）相关。研究观察到7种治疗方案存在不成比例信号：6种ICI单药治疗方案及1种联合治疗方案，分别为阿替利珠单抗（报告比值比（reporting odds ratio, ROR）=6.84；95%置信区间（confidence interval, CI）：5.58~8.40）、阿维鲁单抗（ROR=5.54；95%CI：2.64~11.63）、纳武利尤单抗（ROR=4.37；95%CI：3.64~5.25）、帕博利珠单抗（ROR=3.44；95%CI：2.88~4.10）、度伐利尤单抗（ROR=2.03；95%CI：1.12~3.66）、伊匹木单抗（ROR=2.05；95%CI：1.07~3.94），以及纳武利尤单抗与伊匹木单抗的联合治疗方案（ROR=4.56；95%CI：3.56~5.83）。弗斯多元逻辑回归分析识别出多项独立危险因素，包括高龄（＞65岁）、恶性肾肿瘤、恶性胸膜间皮瘤，以及合并使用贝伐珠单抗或仑伐替尼。重症病例的中位发病时间显著短于非重症病例（分别为22.5天与96.5天；p=0.0479）。此外，本研究对18例病例的文献综述补充了其临床特征相关信息。本研究为ICI相关肾病综合征提供了重要的药物警戒研究见解，加深了对其临床意义的认知。