Efficacy of melatonin on drug- or contrast-induced acute kidney injury: a systematic review and GRADE-assessed meta-analysis of experimental and clinical studies

Objective: The objective of this systematic review and meta-analysis was to assess the efficacy of melatonin in drug- or contrast-induced AKI in preclinical and clinical studies.

Methods: PubMed, Embase, Scopus, Web of Science (WOS), the Cochrane Database of Systematic Reviews (CDSR), and clinical trials.GOV from the beginning until August 1, 2024. On the basis of the inclusion and exclusion criteria, the articles were included by two independent researchers. Data regarding study design, patient characteristics, the number of patients with and without AKI, and the means and SDs of the serum creatinine and BUN levels were extracted from relevant studies. STATA version 17.0 was used to compute pooled measures of standardized mean differences, standardized mean differences, risk ratios and risk differences. I2 and chi-square tests were used to assess heterogeneity between studies. Funnel plots, Egger tests and the trim-and-fill method were used to evaluate small study effects (publication bias). The risk of bias of the included clinical and preclinical studies was assessed via the Cochrane ROB tool and SYRCLE tool, respectively. The credibility of the results was evaluated via GRADE. Sensitivity analysis was performed via the one-out removal method.

Results: We identified 1,696 nonduplicate records, of which the full texts of 159 articles were examined. Twenty-nine animal experimental studies and 5 clinical trials met the inclusion criteria and were included in the review. The results of the meta-analysis confirmed that melatonin was significantly effective at reducing the serum creatinine level (standardized mean difference: - 3.04; 95% CI - 3.904 to - 2.183, with 95% prediction interval: - 7.201 to 1.163) and the BUN level (standardized mean difference: - 3.464; 95% CI - 4.378 to - 2.549, with 95% prediction interval: - 7.839 to 0.911) in drug-induced AKI animal studies. Melatonin did not have a significant effect on the serum creatinine level (standardized mean difference: - 2.67; 95% CI - 9.69 to - 4.35, with 95% prediction interval: - 42.618 to 37.278) or the BUN level (standardized mean difference: - 1.77; 95% CI - 5.533 to - 1.994, with 95% prediction interval: -22.943 to 19.404) in contrast-induced AKI animal studies. Furthermore, in clinical studies, melatonin had no significant effect on reducing the serum creatinine level (standardized mean difference: 0.183; 95% CI - 1.309 to 1.675, with 95% prediction interval: - 7.975 to 8.340), BUN level (standardized mean difference: 0.206; 95% CI - 0.0871 to 1.283, with 95% prediction interval: - 5.115 to 5.528) or risk of AKI incidence (risk ratio: 0.877; 95% CI 0.46 to 1.64, with 95% prediction interval: - 0.238 to 3.174; risk difference: - 0.06 mg/dl; 95% CI - 0.259 to 0.40 mg/dl, with 95% prediction interval: - 0.467 to 0.348). There were no significant publication biases, and after sensitivity analysis, no considerable changes were observed, indicating the robustness of the results.

Conclusion: This meta-analysis indicates that melatonin may protect against drug-induced AKI in animal models but is not effective in clinical studies and that melatonin has no significant effect on contrast-induced AKI. Owing to the inconclusive results in clinical trials and very low certainty of evidence, further research with higher methodological quality is needed to reach a more certain conclusion.