Optimal strategies for umbilical cord mesenchymal stem cell-derived exosomes in acute kidney injury: a network meta-analysis in rat models.

Background: Exosomes derived from umbilical cord mesenchymal stem cells (UCMSC-Exos) have emerged as a highly promising cell-free therapeutic strategy for repairing acute kidney injury (AKI). However, preclinical evidence regarding their efficacy and optimal administration strategy remains heterogeneous and has not been systematically synthesized. Methods: PubMed, Web of Science, Embase, and Scopus were systematically searched to identify randomized controlled experiments evaluating UCMSC-Exos in rat models of AKI. Conventional meta-analyses were performed to pool effect sizes, and frequentist network meta-analyses were used to compare the relative efficacy and ranking probabilities of different interventions. Results: Fourteen studies were included. Conventional meta-analysis showed that, compared with controls, UCMSC-Exos significantly reduced serum creatinine (Scr; SMD = -5.60, 95% CI: -7.61 to -3.60) and blood urea nitrogen (BUN; SMD = -6.33, 95% CI: -8.91 to -3.75), alleviated renal histological injury scores (SMD = -3.62, 95% CI: -4.91 to -2.), and decreased cell apoptosis (SMD = -4.35, 95% CI: -6.06 to -2.64). Network meta-analysis further indicated that, at a fixed dose of 100 μg, tail vein injection was significantly superior to subcapsular renal injection in reducing Scr (SUCRA: 94.2% vs. 55.8%) and showed a similar trend for BUN. Within each administration route, distinct dose-response patterns were observed. For tail vein injection, there were no significant differences in efficacy among 30 μg, 100 μg, and 250 μg, although 100 μg showed the most favorable trend. In contrast, subcapsular renal injection exhibited a dose-dependent pattern, with higher doses (200 μg, 400 μg) being more effective than the lower 100 μg dose. Methodological reporting quality was generally inadequate, and potential publication bias was detected; however, the adjusted effect size remained statistically significant (SMD = -2.59). Conclusion: UCMSC-Exos effectively improve renal function, histopathology, and cell survival in rat models of AKI. Tail vein injection, particularly at a dose of 100 μg, may represent the most effective strategy, whereas subcapsular renal injection may require higher doses to achieve adequate efficacy. These conclusions should be interpreted cautiously, and future studies should more rigorously control for and report potential confounders, such as animal sex and AKI induction methods.