title: Experience with the use of sirolimus in liver transplantation--use in patients for whom calcineurin inhibitors are contraindicated.
abstract: Sirolimus (SRL) provides effective immunosuppression for kidney transplantation and may be useful in patients with delayed allograft function after kidney transplantation. We review our experience with SRL in liver transplant recipients for whom calcineurin inhibitors are undesirable. Fourteen patients with renal insufficiency or acute mental status impairment were administered SRL after liver transplantation (5- to 10-mg load, 1 to 4 mg/d). Immunosuppression also consisted of mycophenolate mofetil and corticosteroids. On resolution of neurological or renal dysfunction (return to baseline mental status or serum creatinine level), tacrolimus (TAC) therapy was initiated. Twelve patients received primary transplants, 1 patient received a combined liver-kidney transplant, and 1 patient received a third transplant. Follow-up was 2 to 7 months. Calcineurin inhibitors were initially withheld in 9 patients, and therapy was aborted because of toxicity in the remaining 5 patients. Mean times to the initiation of SRL and TAC therapy were 5.4 +/- 4.6 and 26.8 +/- 24.4 days, respectively. Serum trough levels of SRL did not correlate with dose or other patient variables. Two patients died after prolonged pretransplantation hospital courses in the intensive care unit. Six patients experienced acute rejection, but only 1 patient required antilymphocyte therapy. Serum creatinine levels at the start of SRL therapy were 2.2 +/- 1.1 and 1.2 +/- 0.6 mg/dL at 3 months. All 3 patients with neurological indications for SRL had a return to their baseline mental status. All patients had improved liver function chemistry test results and prothrombin times. No patients developed leukopenia or thrombocytopenia. SRL is safe after liver transplantation in patients with acute neurological or renal impairment. SRL is an attractive alternative when calcineurin inhibitors are undesirable, but serum trough levels of SRL should be monitored. A prospective randomized study of an SRL-based calcineurin inhibitor-avoiding regimen compared with standard therapy in patients with renal insufficiency will further evaluate the role for SRL in liver transplantation.
authors.affiliation: Department of Surgery, Division of Transplantation, University of California, San Francisco, CA 94143-0780, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Chang
authors.forename: H D
authors.initials: HD
authors.lastname: Mahanty
authors.forename: D
authors.initials: D
authors.lastname: Quan
authors.forename: C E
authors.initials: CE
authors.lastname: Freise
authors.forename: N L
authors.initials: NL
authors.lastname: Ascher
authors.forename: J P
authors.initials: JP
authors.lastname: Roberts
authors.forename: P G
authors.initials: PG
authors.lastname: Stock
authors.forename: R
authors.initials: R
authors.lastname: Hirose
mesh_terms: D000328:Adult; D001706:Biopsy; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D000075202:Contraindications; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use; D006084:Graft Rejection / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects; D016030:Kidney Transplantation / Q000473:pathology; D016031:Liver Transplantation / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives*; D011379:Prognosis; D011446:Prospective Studies; D020123:Sirolimus / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016559:Tacrolimus
chemical_list: D065095:Calcineurin Inhibitors; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D019703:Calcineurin; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus