Emerging Therapeutic Strategies for Renal Ischemia‐Reperfusion Injury in Kidney Transplantation: Progress and Challenges—A Systematic Review

ABSTRACT Introduction Ischemia‐reperfusion injury (IRI) contributes to delayed graft function (DGF) and long‐term allograft loss in kidney transplantation (KTx). Despite decades of investigation, no pharmacologic strategy has achieved clinical translation. This systematic review evaluates investigational therapies for renal IRI (RIRI) reported since 2000. Methods Following the PRISMA 2020 guidelines, a systematic search of PubMed, ClinicalTrials.gov, and the European Union Clinical Trials Register (EUCTR) was conducted for articles published between January 1, 2000, and March 31, 2025. Eligible records included preclinical and clinical investigations evaluating pharmacologic interventions for RIRI in KTx. Narrative reviews, pediatric‐only, in silico‐only, and in vitro‐only records were excluded. A total of 76 full‐text reports were assessed for eligibility, with 43 meeting the inclusion criteria. Meta‐analysis was not performed due to heterogeneity. Included reports were synthesized by the mechanism of action, developmental stage, and translational status. Risk of bias was qualitatively assessed. This review was not prospectively registered, no formal protocol was prepared, and no external funding was received. Results Legacy agents, Diannexin, YSPSL, and I5NP demonstrated initial promise but failed to achieve late‐phase clinical efficacy. More recent agents, particularly alkaline phosphatase, complement‐targeting biologics, and mesenchymal stem cell (MSC)‐derived exosomes, offer mechanistically diverse strategies to attenuate RIRI, though most remain in early development. Conclusion Most available data remain preclinical and are limited by inconsistent outcome measures and translational bottlenecks. Future efforts should prioritize harmonized animal models, biomarker‐defined endpoints, and strategic investment in promising candidates to integrate them into kidney transplant care.