Nephroprotective effects of cilastatin in people at risk of acute kidney injury: A systematic review and meta-analysis

Background: Cilastatin is an inhibitor of drug metabolism in the proximal tubule of the kidney that demonstrates nephroprotective effects in animal models. Cilastatin has been in clinical use since the 1980s in combination with the antibiotic imipenem to prevent imipenem degradation, which has enabled studies testing the effect of cilastatin on kidney outcomes in observational studies and clinical trials This systematic review and meta-analysis was undertaken to evaluate the nephroprotective effects of cilastatin among people susceptible to acute kidney injury (AKI). Methods: We systematically searched MEDLINE, EMBASE, Web of Science, and the Cochrane Controlled Trials registry to November 2023 for observational studies or trials that compared kidney outcomes with cilastatin, either alone or as combination imipenem-cilastatin, compared to an inactive or active control group not treated with cilastatin. Two reviewers independently evaluated studies for inclusion, extracted data, and assessed risk of bias. Treatment effects were estimated using random effects models and heterogeneity was reported using the I2 statistic. Results: We identified 10 studies (five RCTs, n=535 patients; 5 observational studies n=6,198 participants) that met the inclusion criteria, including studies with comparisons of imipenem-cilastatin to an inactive control as well as those with comparisons to alternate antibiotics among patients being treated for bacterial infections. Based on results from 5 studies, imipenem-cilastatin significantly reduced the incidence of AKI (pooled odds ratio [OR] 0.42 [95% CI 0.26 to 0.69]; I2 48%), with consistent results observed from randomized trials (two trials, OR 0.12 [95% CI, 0.02 to 0.73]; I2 0%) and observational studies (four studies, OR 0.46 [95% CI, 0.28 to 0.78]; I2 62%). Based on results from six studies, kidney function was also better with imipenem-cilastatin than comparators (weighted mean difference in serum creatinine -0.14 mg/dL [95% CI -0.22 to 0.07]; I2 0%). There was no statistically significant difference in all-cause mortality with imipenem-cilastatin treatment compared to comparators (pooled OR 0.60 [95% CI, 0.12 to 3.03]; I2 73%). The overall certainty of the evidence was low due to heterogeneity of the results, high risk of bias, and indirectness among the identified studies. Conclusion: Patients at risk of AKI treated with imipenem-cilastatin less frequently developed AKI and had better short-term kidney function than those receiving control or comparator antibiotics. Larger clinical trials with less risk of bias are needed to establish the efficacy of cilastatin for AKI prevention. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Protocols ### Funding Statement The study was funded by the Canadian Institutes of Health Research (CIHR) Team Grant: Intervention Trial in Inflammation for Chronic Conditions - Evidence to Impact; Funding Reference Number LI3 189373. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used only openly available aggregated information from published studies. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.