REDUCTION OF CYCLOSPORINE-INDUCED NEPHROTOXICITY BY CILASTATIN FOLLOWING CLINICAL HEART-TRANSPLANTATION

The objective of this prospective, randomized, placebo-controlled, sin gle-blinded study in 28 heart-transplanted patients was to investigate whether the dehydropeptidase inhibitor cilastatin reduces cyclosporin e-induced nephrotoxicity. Cilastatin is available only in combination with imipenem, a beta-lactam antibiotic to which it is added for reduc tion of nephrotoxic side-effects of the antimicrobial agent. Patients received either 100 ml placebo (n=12) or 100 ml (500 mg) imipenem/cila statin (n=16) twice perioperatively, and 4 times daily for the first 7 postoperative days. Serum creatinine and urea, as well as urine conce ntrations of N-acetyl-beta-D-glucosaminidase, which is directly correl ated with tubular cell damage, were used as markers for renal function . Thromboxane B2 and 6-keto-prostaglandin F1-alpha serum concentration s were determined to investigate whether there is an imbalance in synt hesis of thromboxane A2 and prostacyclin as a possible mechanism for c yclosporine-induced nephrotoxicity. Two placebo patients and 6 patient s receiving imipenem/cilastatin had to be excluded from further analys is. Three of 10 placebo patients required hemofiltration, and 2 of the m even required hemodialysis, as compared with none in the imipenem/ci lastatin group. Creatinine concentrations increased significantly from the second to the fourth postoperative day in the placebo group, but remained nearly normal in cilastatin patients (P<0.05 for intergroup c omparison on postoperative days 2-4). The same trend was observed in u rea and N-acetyl-beta-D-glucosaminidase concentrations, without the di fference reaching statistical significance. For thromboxane B2 and 6-k eto-prostaglandin F1-alpha no differences between the groups could be found. These results suggest that imipenem/cilastatin can counteract a cute cyclosporine-induced nephrotoxicity, which appears to be associat ed with alterations of tubular cell function. The combined use of cycl osporine and imipenem/cilastatin appears to be advantageous in patient s following heart transplantation during the initial postoperative per iod.