Nephroprotective Effects of Cilastatin in People at Risk of Acute Kidney Injury: A Systematic Review and Meta-analysis

Abstract

Rationale & Objective

Cilastatin 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 block imipenem’s renal metabolism. This systematic review and meta-analysis evaluated the nephroprotective effects of cilastatin in humans.

Study Design

Systematic review and meta-analysis of observational (comparative effectiveness) studies or randomized clinical trials (RCTs).

Setting & Study Populations

People of any age at risk of acute kidney injury (AKI).

Selection Criteria for Studies

We 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 Extraction

Two reviewers independently evaluated studies for inclusion and risk of bias.

Analytical Approach

Treatment effects were estimated using random-effects models, and heterogeneity was quantified using the I² statistic.

Results

We identified 10 studies (5 RCTs, n = 531 patients; 5 observational studies, n = 6,321 participants) that met the inclusion criteria, including 4 studies with comparisons to inactive controls and 6 studies with comparisons to alternate antibiotics. Based on pooled results from 7 studies, the risk of AKI was lower with imipenem-cilastatin (risk ratio [RR], 0.52; 95% confidence intervals [CI], 0.40-0.67; I² = 26.5%), with consistent results observed in RCTs (3 RCTs, RR, 0.26; 95% CI, 0.09-0.77; I² = 44.4%) and observational studies (4 studies, RR, 0.54; 95% CI, 0.41-0.72; I² = 44.4%). Based on results from 6 studies, serum creatinine concentration was lower following treatment with imipenem-cilastatin than comparators (weighted mean difference 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.

Limitations

Clinical and statistical heterogeneity could not be fully explained due to a limited number of studies.

Conclusions

Patients treated with imipenem-cilastatin developed AKI less frequently and had lower serum creatinine concentration following treatment than control groups or those who had received 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.

Plain-Language Summary

Cilastatin, used with the antibiotic imipenem, has shown kidney-protective effects in animals and preclinical studies of acute kidney injury (AKI). This systematic review and meta-analysis identified 10 studies (5 randomized controlled trials and 5 observational studies) of imipenem-cilastatin involving people at risk of AKI. Pooled estimates of treatment effects indicated that patients who received imipenem-cilastatin had a lower incidence of AKI and lower serum creatinine concentrations following treatment compared to comparator groups. Despite these promising findings, the overall certainty of the evidence was low due to heterogeneity among studies, high risk of bias, and indirectness of the data. Although cilastatin appears to be a promising medication for preventing AKI, larger, well-designed trials are needed to establish its effectiveness.