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

Our plain-English summary of Immune checkpoint inhibitor-induced nephrotic syndrome: a pharmacovigilance analysis of 404 FAERS cases and literature case series, by J. Ye, J. Huang, L. Shao, et al (Renal Failure, 2025).

The study

• Authors: J. Ye, J. Huang, L. Shao, Z. Wang
• Journal: Renal Failure
• Published: 2025;47(1):2569089
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This study examined reports of nephrotic syndrome, a kidney disorder with heavy protein loss in the urine, in cancer patients given immune checkpoint inhibitors. It analyzed the U.S. FDA Adverse Event Reporting System (FAERS) from early 2011 to early 2025 and reviewed 18 published cases. It did not study asbestos exposure. Malignant mesothelioma appeared as one of the cancers treated, not as an exposure outcome. The authors found 404 FAERS reports. Seven drug regimens showed a reporting signal, strongest for atezolizumab (reporting odds ratio 6.84; 95% CI 5.58 to 8.40). The authors state this measure is not a relative risk. Among reports naming an immune checkpoint inhibitor as a suspect drug and giving age and sex, nephrotic syndrome was more often the reported event for patients treated for malignant mesothelioma than for malignant pulmonary tumors (adjusted odds ratio 7.35; 95% CI 4.44 to 11.64). Age over 65, kidney cancer, and use of bevacizumab or lenvatinib were also associated. Median onset was 22.5 days in severe cases versus 96.5 days in others. The authors called these potential risk factors. They noted that a signal does not establish causality and reporting is incomplete.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective, cross-sectional disproportionality analysis of FDA adverse event reports (FAERS), with a case/non-case Firth logistic regression and a literature case series
• Who was studied: 404 FAERS reports of nephrotic syndrome linked to immune checkpoint inhibitors, from the first quarter of 2011 to the first quarter of 2025 (49.3% from Japan, 14.4% from the United States). The authors also reviewed 18 published patients from 16 publications.
• Exposure: Immune checkpoint inhibitor cancer drugs: anti-PD-1 (nivolumab, pembrolizumab, cemiplimab, dostarlimab), anti-PD-L1 (atezolizumab, avelumab, durvalumab), anti-CTLA-4 (ipilimumab), and nivolumab plus ipilimumab. Asbestos exposure was not studied.
• Main results:
  • Atezolizumab had the strongest reporting signal for nephrotic syndrome (ROR 6.84; 95% CI 5.58 to 8.40).
  • Nivolumab (ROR 4.37; 95% CI 3.64 to 5.25) and pembrolizumab (ROR 3.44; 95% CI 2.88 to 4.10) also showed signals.
  • Nivolumab plus ipilimumab showed a signal (ROR 4.56; 95% CI 3.56 to 5.83).
  • Cemiplimab had only two reports and no statistically significant signal (ROR 1.86; 95% CI 0.46 to 7.44). Dostarlimab had no reports. The authors said this should not be read as an absence of risk.
  • The regression used reports naming an immune checkpoint inhibitor as primary or secondary suspect, restricted to those with complete age and sex information. It compared nephrotic syndrome reports with reports of other adverse events. In that analysis, malignant mesothelioma as the treated cancer was independently associated with nephrotic syndrome reports, compared with malignant pulmonary tumor (aOR 7.35; 95% CI 4.44 to 11.64).
  • Age over 65 was associated with nephrotic syndrome reports (aOR 1.52; 95% CI 1.18 to 1.98).
  • Malignant renal neoplasm, compared with malignant pulmonary tumor, was associated with nephrotic syndrome reports (aOR 1.51; 95% CI 1.03 to 2.18).
  • Use of lenvatinib (aOR 2.5; 95% CI 1.6 to 3.8) and of bevacizumab (aOR 2.24, as given in the Results) was associated with nephrotic syndrome reports.
  • The E-value for malignant mesothelioma was 8.35. The authors interpreted this as robustness against unmeasured confounding.
  • Overall median time to onset in FAERS was 89 days.
  • Severe cases (death or life-threatening) had a median onset of 22.5 days, compared with 96.5 days for non-severe cases (p = 0.0479).
  • Of the 404 FAERS cases, 153 (37.9%) were hospitalized, 28 (6.9%) died and 29 (7.2%) had life-threatening events.
  • In the literature case series, 12 of 15 steroid-treated patients (80.0%) achieved complete or partial remission. The cancers in the series included malignant pleural mesothelioma.
• The authors' conclusion: The authors concluded that immune checkpoint inhibitors are broadly associated with a disproportionate reporting signal for nephrotic syndrome. They identified advanced age, renal malignancy, malignant mesothelioma, and concurrent bevacizumab or lenvatinib as potential risk factors.
• Limitations the authors state:
  • A positive disproportionality signal does not establish causality, and unknown confounders may affect the findings.
  • The reporting odds ratio measures signal strength, not relative risk.
  • FAERS relies on voluntary reporting and is subject to under-reporting, so report counts are not a measure of real-world incidence.
  • There were classification errors at the Preferred Term level, for example nephrotic syndrome reported without pathological subtype.
  • The regression models were limited by missing data such as age, indication and drug dosage.
  • The case series was too small to draw definitive conclusions about drug rechallenge.

Topics

Medical terms in this study, explained in our Lexicon: checkpoint inhibitors, Atezolizumab (Tecentriq), Nivolumab (Opdivo), Pembrolizumab (Keytruda), Durvalumab (Imfinzi), Ipilimumab (Yervoy), Neoplasm, Mesothelioma.

Related studies

• Nephrotic syndrome with acute kidney injury due to combination therapy of immune checkpoint inhibitors: a case report and review of the literature — R. Saiki, K. Katayama, et al. (2024)
• Dysautonomia and dysosmia associated with anti-Hu antibodies induced by immune checkpoint inhibitors: a case report — M. Fujimoto, K. Igari, et al. (2026)
• Nephrotic syndrome and mesenteric infarction secondary to metastatic mesothelioma — C.K. Farmer, D.J. Goldsmith (2001)
• An autopsy case of malignant pleural mesothelioma associated with nephrotic syndrome — S. Suzuki, M. Toyoshima, et al. (2014)
• Serum cytokines as a biomarker for immune checkpoint inhibitor toxicity in patients with pleural mesothelioma — S.J. Farooqi, Z. Zhao, et al. (2024)
• Celiac Disease After Administration of Immune Checkpoint Inhibitors: A Case Report — J. Leblanc, S. Hoibian, et al. (2021)

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