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

Abstract

ABSTRACTRationale & ObjectiveCilastatin is an inhibitor of drug metabolism in the proximal tubule that demonstrates nephroprotective effects in animals. It has been used in humans in combination with the antibiotic imipenem to prevent imipenem’s degradation. This systematic review and meta-analysis evaluated the nephroprotective effects of cilastatin in humans.Study DesignSystematic review and meta-analysis of observational (comparative effectiveness) studies or randomized clinical trials (RCTs)Setting & Study PopulationsPeople of any age at risk of acute kidney injury (AKI).Selection Criteria for StudiesWe systematically searched MEDLINE, Embase, Web of Science, and the Cochrane Controlled Trials registry from database inception to November 2023 for observational studies or RCTs that compared kidney outcomes among groups treated with cilastatin, either alone or as combination imipenem-cilastatin, versus an inactive or active control group not treated with cilastatin.Data ExtractionTwo reviewers independently evaluated studies for inclusionand risk of bias.Analytical ApproachTreatment effects were estimated using random effects models and heterogeneity was quantified using the I2statistic.ResultsWe identified 10 studies (five RCTs, n=531 patients; 5 observational studies, n=6,321 participants) that met the inclusion criteria, including 6 studies with comparisons of imipenem-cilastatin to an inactive control and 4 studies with comparisons to alternate antibiotics. Based on pooled results from 5 studies, the risk of AKI was lower with imipenem-cilastatin (risk ratio [RR] 0.53 [95% CI, 0.38 to 0.74]; I2=42.2%), with consistent results observed from randomized trials (two trials, RR 0.30 [95% CI, 0.09 to 1.00]; I2=62.8%) and observational studies (three studies, RR 0.55 [95% CI, 0.38 to 0.81]; I2=62.8%). Based on results from six studies, kidney function was also better with imipenem-cilastatin than comparators (weighted mean difference [WMD] in serum creatinine -0.14 mg/dL [95% CI, -0.21 to -0.07]; I2=0%). The overall certainty of the evidence was low due to heterogeneity of the results, high risk of bias, and indirectness among the identified studies.LimitationsClinical and statistical heterogeneity could not be fully explained due to a limited number of studies.ConclusionPatients treated with imipenem-cilastatin developed AKI less frequently and had better short-term kidney function than control groups or those receiving comparator antibiotics. Larger clinical trials with less risk of detection bias due to lack of allocation concealment and blinding are needed to establish the efficacy of cilastatin for AKI prevention.RegistrationInternational Prospective Register of Systematic Reviews (PROSPERO) database (ID: CRD42023488809)