title: Reduction of cyclosporine-induced nephrotoxicity by cilastatin following clinical heart transplantation.
abstract: The objective of this prospective, randomized, placebo-controlled, single-blinded study in 28 heart-transplanted patients was to investigate whether the dehydropeptidase inhibitor cilastatin reduces cyclosporine-induced nephrotoxicity. Cilastatin is available only in combination with imipenem, a beta-lactam antibiotic to which it is added for reduction of nephrotoxic side-effects of the antimicrobial agent. Patients received either 100 ml placebo (n = 12) or 100 ml (500 mg) imipenem/cilastatin (n = 16) twice perioperatively, and 4 times daily for the first 7 postoperative days. Serum creatinine and urea, as well as urine concentrations of N-acetyl-beta-D-glucosaminidase, which is directly correlated with tubular cell damage, were used as markers for renal function. Thromboxane B2 and 6-keto-prostaglandin F1-alpha serum concentrations were determined to investigate whether there is an imbalance in synthesis of thromboxane A2 and prostacyclin as a possible mechanism for cyclosporine-induced nephrotoxicity. Two placebo patients and 6 patients receiving imipenem/cilastatin had to be excluded from further analysis. Three of 10 placebo patients required hemofiltration, and 2 of them even required hemodialysis, as compared with none in the imipenem/cilastatin 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 comparison on postoperative days 2-4). The same trend was observed in urea and N-acetyl-beta-D-glucosaminidase concentrations, without the difference reaching statistical significance. For thromboxane B2 and 6-keto-prostaglandin F1-alpha no differences between the groups could be found. These results suggest that imipenem/cilastatin can counteract acute cyclosporine-induced nephrotoxicity, which appears to be associated with alterations of tubular cell function. The combined use of cyclosporine and imipenem/cilastatin appears to be advantageous in patients following heart transplantation during the initial postoperative period.
authors.affiliation: Department of Cardiac Surgery, University of Munich, Grosshadern Hospital, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Markewitz
authors.forename: C
authors.initials: C
authors.lastname: Hammer
authors.forename: M
authors.initials: M
authors.lastname: Pfeiffer
authors.forename: S
authors.initials: S
authors.lastname: Zahn
authors.forename: J
authors.initials: J
authors.lastname: Drechsel
authors.forename: H
authors.initials: H
authors.lastname: Reichenspurner
authors.forename: B
authors.initials: B
authors.lastname: Reichart
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000118:Acetylglucosaminidase / Q000652:urine; D000293:Adolescent; D000328:Adult; D001806:Blood Urea Nitrogen; D015377:Cilastatin / Q000494:pharmacology*; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D005260:Female; D016027:Heart Transplantation; D006440:Hemofiltration; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D016037:Single-Blind Method; D013929:Thromboxane B2 / Q000097:blood
chemical_list: D015377:Cilastatin; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D016572:Cyclosporine; D003404:Creatinine; D000118:Acetylglucosaminidase