Biopsy-proven acute interstitial nephritis associated with immune checkpoint inhibitors: clinicopathological features, management, and outcomes — a systematic review

Immune checkpoint inhibitors (ICIs) have transformed the treatment of multiple malignancies but are associated with immune-related adverse events, of which acute interstitial nephritis (AIN) is the most frequent histologically confirmed renal complication. Comprehensive synthesis of clinicopathological features, severity, and outcomes of biopsy-proven ICI-associated AIN remains limited. We sought to systematically review the demographic profile, AKI severity, concurrent nephrotoxin exposure, extra-renal immune-related adverse events, histopathological spectrum, treatment strategies, and renal outcomes of biopsy-proven ICI-associated AIN. We searched PubMed, Embase, and Scopus from database inception until 31 January 2026 for case reports, case series, and retrospective cohort studies reporting biopsy-proven AIN in adults receiving ICIs. The full Boolean strategy is reported in the Methods. Rayyan was used for screening; data extraction was performed using a standardised spreadsheet. The risk of bias was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklists for case reports and case series and the Newcastle-Ottawa Scale for cohort studies. Pooled estimates with explicit denominators were computed for KDIGO AKI stage, baseline comorbidities, concurrent nephrotoxic medication exposure, extra-renal irAEs, plasma exchange use, histological pattern, treatment, and outcome. Of 774 records identified, 41 studies comprising 93 patients with patient-level data on biopsy-proven ICI-associated AIN were included; pooled cohort-level estimates were derived from an additional ~ 610 patients reported in the source literature. Hypertension was the most prevalent baseline comorbidity (60.5%), followed by diabetes mellitus (20.0%) and pre-existing chronic kidney disease (~ 13.0%). Pooled KDIGO AKI severity at presentation was Stage 1 in 16.5%, Stage 2 in 30.0%, and Stage 3 in 53.5%, with renal replacement therapy required in 8.6%. Concurrent proton pump inhibitor exposure was present in 47.4% of patients (range 22.0% to 83.0% across cohorts), NSAID exposure in approximately 14.0%, and antibiotic exposure in approximately 25.0%. Concurrent extra-renal irAEs were present in 48.8% (range 46.9% to 74.0%), most commonly involving the gastrointestinal tract (~ 18.0%), endocrine system (~ 15.0%), and skin (~ 12.0%). Plasma exchange was used in only 2 of approximately 620 pooled patients (0.3%), restricted to those with concomitant ANCA-associated glomerulonephritis or anti-glomerular basement membrane disease. AIN was the dominant histological lesion (82.7% to 92.0%), with granulomatous variants in 8.3% to 25.0%, concurrent acute tubular necrosis in 10.0% to 17.0%, and clinically significant glomerular co-pathology in approximately 8.0% to 17.0%. The modal time-to-onset was 3 to 6 months (46.6%). Corticosteroids were used in 91.6% of patients; mycophenolate mofetil was used in approximately 5.5%, rituximab in 4.0%, and infliximab in single-figure case counts. Complete or partial renal recovery exceeded 75.0% across most cohorts, while ICI rechallenge was attempted in 16.0% to 28.0% with recurrence rates of 16.5% to 40.0%. Dual immune checkpoint blockade was independently associated with severe AKI (100.0% Stage 3 in pooled analysis) and inversely with complete renal recovery (odds ratio 0.15, 95% confidence interval 0.03 to 0.7). Biopsy-proven ICI-associated AIN is predominantly a severe AKI syndrome occurring three to six months after ICI initiation, frequently against a background of concurrent PPI or other nephrotoxin exposure, and accompanied by an extra-renal immune-related adverse event in nearly half of cases. Although AIN is the modal histology, a clinically important spectrum of glomerular and tubular lesions coexists and requires biopsy for recognition. Corticosteroids remain the cornerstone of therapy, with selected use of mycophenolate mofetil, rituximab, infliximab, and — in the small subset with concomitant ANCA- or anti-GBM-associated glomerulonephritis — plasma exchange and cyclophosphamide. Renal outcomes are generally favourable; however, dual immune checkpoint blockade and KDIGO Stage 3 presentation independently predict incomplete recovery. Biopsy informs both prognosis and therapy and should be performed in any clinically eligible patient with significant ICI-associated AKI.