Guarding the kidneys in the immunotherapy era: Pooled incidence and severity of immune-related nephritis in renal-cell carcinoma treated with PD-1/PD-L1–based regimens.

489 Background: Immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, and CTLA-4 have redefined renal-cell carcinoma (RCC) management. However, immune-related nephritis (IRN) remains an uncommon but clinically relevant toxicity that can lead to treatment interruption or irreversible renal injury. The true pooled incidence and severity of IRN across modern phase III RCC trials have not been systematically quantified. Methods: A systematic review and single-arm random-effects meta-analysis was performed according to PRISMA guidelines. Eligible studies included phase III RCC trials evaluating PD-1/PD-L1–based immunotherapy alone or combined with VEGF-targeted therapy. Any-grade and grade ≥3 IRN data were extracted from peer-reviewed publications and supplementary materials ( NEJM , Lancet ). Pooled incidence estimates were calculated using a random-effects model with the Paule–Mandel estimator for between-study variance (τ²) and Hartung–Knapp adjustment for confidence intervals. Statistical heterogeneity was quantified using I². Results: Four trials (KEYNOTE-426, CLEAR, CheckMate-9ER, CheckMate-214) encompassing 1,535 patients in experimental arms were included. Any-grade IRN occurred in 1.1% (95% CI 0.7–1.7; I² = 34%), and grade ≥3 IRN in 0.4% (95% CI 0.2–0.7; I² = 29%). Incidence was highest with ICI + VEGF-TKI combinations (1.5–1.7%) and lowest with dual-ICI therapy (~0.8%). The estimated τ² was 0.00016, indicating modest between-study variance. No dialysis-requiring events were reported, and > 85% of cases resolved with corticosteroids. Conclusions: Immune-related nephritis occurs in approximately 1% of RCC patients receiving PD-1/PD-L1–based therapy and is rarely severe. Most events are grade 1–2, steroid-responsive, and reversible. These data provide the first pooled benchmark for renal immune toxicity in RCC and support routine renal monitoring from treatment initiation. Findings are particularly relevant to older adults, who represent the majority of RCC patients and often have reduced baseline renal reserve.