Cilastatin protection against cyclosporin A-induced nephrotoxicity: clinical evidence

Background: Several studies have documented the nephroprotective effect of cilastatin co-administered with imipenem in subjects treated with cyclosporin A. However, no large clinical studies are available to confirm this observation. Here the quality of the evidence on cilastatin nephroprotection against cyclosporin-induced nephrotoxicity is evaluated. Methods: The results of all studies where cyclosporin was used alone or combined with imipenem/cilastatin (Tienam*) on the same clinical setting were systematically reviewed. Primary outcome was the reduction in serum creatinine concentration. Secondary outcome included development of acute renal failure. Medline was searched using three different retrieval systems (Pubmed, Silver Platter, Knowledge Finder) from January 1966 to February 2006. Attempts were made to contact authors of relevant studies to obtain additional data. Five clinical studies were found, including 125 patients under cyclosporin plus imipenem/cilastatin and 104 under cyclosporin alone. Results: Cyclosporin increased serum creatinine in all the studies. Average reduction of serum creatinine in cilastatin-treated versus untreated patients was Delta = -0.53 mg/dL (95% Cl: -0.90 to -0.17) (Z = 2.84, p = 0.004). Variability between studies was large (from Delta = -0.21 to Delta = -1.59 mg/dL) and heterogeneity pronounced (chi(2) = 8.760, df = 4; p = 0.067). Meta-regression of serum creatinine reduction versus baseline serum creatinine explained 84% of this variability, by the variation in basal serum creatinine. When randomized and observational clinical studies were analyzed separately, conclusions were the same: serum creatinine in cilastatin treated patients was reduced by Delta = -0.98 mg/dL (95% Cl: -1.57 to -0.38) in randomized studies (Z = 3.213, p = 0.001) and Delta = -0.32 mg/dL (95% Cl: -0.63 to -0.01) in observational studies (Z = 2.013, p = 0.044). Odds Ratio for developing acute renal failure was 0.24 (95% Cl: 0.11-0.53, p < 0.0001) on patients simultaneously treated with cyclosporin plus imipenem/cilastatin compared to patients treated with cyclosporin alone. Conclusions: Administration of cilastatin may reduce acute cyclosporin nephrotoxicity.