Background Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but are complicated by immune-related adverse events, including acute kidney injury (AKI). As clinical experience matures and treatment durations lengthen, initial estimates of ICI-AKI incidence and the perceived risks of resuming therapy may become outdated. Objective We aimed to provide a compelling, contemporary synthesis of the epidemiology, management outcomes, and specifically the safety profile of ICI rechallenge following ICI-AKI, integrating recent large-scale, real-world evidence accumulated through 2025. Methods We conducted a cumulative systematic review and meta-analysis (PRISMA 2020) searching PubMed/MEDLINE, Embase, The Cochrane Library (CENTRAL), Web of Science, and Scopus databases from inception through December 1, 2025. We included clinical studies reporting incidence, renal recovery following corticosteroid treatment, or recurrence rates upon ICI rechallenge. Data were pooled using random-effects models, with pre-specified subgroup analyses stratified by age to identify susceptible populations. Results A total of 60,799 patients from 21 studies were included. The pooled incidence of ICI-AKI was 2.61% (95% CI: 1.95, 3.28). While corticosteroid treatment showed a potential association with renal recovery (OR, 0.55; 95% CI: 0.06, 1.04; p = 0.03). Notably, the pooled recurrence rate of AKI upon ICI rechallenge decreased to 14.07% (95% CI: 10.26, 17.89; p = 0.00). Subgroup analysis revealed an age paradox: patients 65 years demonstrated a higher incidence but a significantly lower risk of recurrence upon rechallenge compared to older patients (10.6% vs 19.1%, respectively). Meta-regression analyses indicated that higher baseline serum creatinine was independently associated with an increased risk of ICI-AKI, with each 0.1 mg/dL increment conferring a substantial rise in effect size (coefficient 0.42, 95% CI 0.15–0.69; P 0.01). Conclusions The landscape of ICI-related nephrotoxicity is evolving. Recent data indicate a manageable incidence and, crucially, a substantially improved safety profile for ICI rechallenge than previously feared, particularly in younger patients. These findings advocate for a more proactive consideration of resuming life-prolonging immunotherapy after renal recovery, guided by age-stratified risk assessment. Systematic Review Registration https://inplasy.com/inplasy-2025-12-0073/ , identifier INPLASY2025120073
Wang et al. (Tue,) studied this question.