Risk stratification for immune checkpoint inhibitor rechallenge after acute kidney injury: towards a precision medicine framework.

The decision to rechallenge a patient with immune checkpoint inhibitor-associated acute kidney injury (ICI-AKI) remains one of the most challenging dilemmas in onco-nephrology. Although major guidelines affirm that rechallenge may be considered in selected patients, they uniformly acknowledge a critical gap: no validated tool currently exists to estimate an individual's risk of recurrence. Reported recurrence rates range from 16.5% to 44%, and the survival benefit of rechallenge is inconsistent across studies. In this review, we synthesize recent evidence on risk factors for ICI-AKI recurrence, including clinical parameters (acute kidney injury (AKI) severity, renal recovery status, extra-renal immune-related adverse events (irAEs), concomitant medications, and immune checkpoint inhibitor (ICI) regimen), pathological findings (acute tubulointerstitial nephritis (ATIN) with Banff scoring, and glomerular diseases), emerging biomarkers (urinary C-X-C motif chemokine ligand 9 (CXCL9)-to-creatinine ratio with an optimal cutoff of 269.5 ng/g, and serum soluble interleukin-2 receptor alpha (sIL-2Rα) with a cutoff of ≥1.75× the upper limit of normal (ULN)), genetic markers (the propionyl-CoA carboxylase subunit alpha (PCCA) variant rs16957301), and acute kidney disease (AKD). We translate this evidence into a practical, stepwise risk stratification framework that classifies patients into low-, intermediate-, and high-risk tiers through the sequential integration of clinical, pathological, and biomarker information. The biomarker cutoffs included in this framework-derived from diagnostic studies-are hypothesis-generating in the context of recurrence prediction and require prospective validation before clinical application. For each tier, we provide corresponding recommendations regarding rechallenge decisions, monitoring intensity, and prophylactic immunosuppression, while acknowledging the limited evidence supporting prophylactic corticosteroids in this setting. Finally, we discuss current controversies-including the optimal timing of rechallenge, racial differences that challenge model generalizability, and the unresolved role of prophylactic glucocorticoids-and outline future research priorities organized around clinical validation, biomarker development, mechanistic exploration, and integration of emerging technologies. This framework is designed for immediate clinical application across diverse settings, ranging from resource-limited primary hospitals to tertiary centers. By transforming empirical decision-making into evidence-based, individualized risk assessment, this review aims to guide precision rechallenge management for patients recovering from ICI-AKI.