Sirolimus and mycophenolate mofetil after liver transplantation

Abstract

Since the approval of sirolimus (SRL) as an immunosuppressive agent in renal transplantation, several liver transplant centres have introduced this agent to the immunosuppression regimen. We present here a retrospective followup study of late conversion to sirolimus and mycophenolate mofetil (MMF) as immunosuppressive agents after liver transplantation (LTX). From July 2001 to March 2002, seven liver transplant recipients (three female, 59 (41-66) years old) were enrolled in this study. Indications for liver transplantation were hepatitis B and/or hepatitis C (three), alcohol-induced cirrhosis (three) and Wilson's syndrome (hepatolenticular degeneration) (one). LTX was performed by standard (four) or piggy-back (three) technique. The switch to SRL was performed 62 (37-1 18) months after LTX; the reasons for the switch from cyclosporine or tacrolimus to SRL were renal (six) or neurological (one) impairment. As immunosuppressive therapy, SRL at trough levels of 4-10 ng/ml and MMF at trough levels of approximately 1 pg/ml were administered. Mean follow-up time under SRL per patient was 137 (26-258 days). Patient and graft survival was 100% during SRL therapy, and there were neither rejection episodes nor infections. Renal function improved in five of the six patients (83.3%) whom we had switched to SRL due to renal impairment. In the patient whom we switched to SRL due to neurological impairment, the neurological symptoms abated, and renal function improved. Side effects (hypertriglyceridaemia, hypercholesterolaemia, exanthema) became manifest in three patients (42.8%). Cessation of therapy due to side effects was necessary in two patients (exanthema: one, hypertriglyceridaemia: one). One patient refused to continue the therapy with SRL because he wanted tablets, and we only had SRL in fluid form. The data of our study suggest that SRL is a potent immunosuppressive agent of potential benefit in clinical LTX. SRL in combination with MMF provided sufficient immunosuppression of liver allografts in the late course after LTX. Side effects were reversible with dose reduction or cessation of therapy. We can thus conclude that SRL might offer an immunosuppressive therapy for patients with renal or neurological impairment after LTX.

Conversion to sirolimus-based immunosuppression in maintenance liver transplantation patients

“…In a large retrospective series of 175 patients, Montalbano et al20 described bilateral lower extremity edema (57.1%), dermatitis (25.3%), oral ulcers (24.2%), joint pain (23%), pleural effusion (16.5%), increase in abdominal girth (5.5%), general edema (5.5%), pericardial effusion (5.5%), facial edema (2.2%), and upper extremity edema (1.3%). Dyslipidemia was reported in up to 44% of patients 4, 8, 11, 19. In our study, hypercholesterolemia incidence increased from 32% before to 49% after conversion.…”

“…The great majority was treated with SRL alone (40%) or in association with MMF (35%). Other studies documented the safety of SRL without CNI4, 5, 7–9, 15 but to the best of our knowledge our report of 48 cases is one of the largest that has been published.…”

“…Randomized, controlled trials comparing SRL with conventional immunosuppressive drugs have not been yet completed in liver transplantation (LT) but several publications have documented the efficacy and safety of SRL in terms of graft and patient survival 1. Conversion from CNI to SRL or addition of SRL to achieve lower CNI target levels improved renal function in pediatric2–4 as well as in adult LT recipients 5–12. CNI‐related neurotoxicity also decreased or resolved after conversion to SRL 7, 13–15.…”

“…However, SRL is associated with frequent side effects such as anemia, thrombocytopenia, edema, dyslipidemia, joint pain, pulmonary disease, oral ulcers, and dermatitis 4, 7, 8, 11, 13, 19–21. These adverse effects often significantly affect the patient's quality of life, requiring SRL discontinuation in about 25% of cases (15–37%) 2, 7, 8, 10, 11, 13, 19…”

Switch to 1.5 grams MMF monotherapy for CNI-related toxicity in liver transplantation is safe and improves renal function, dyslipidemia, and hypertension

“…To our knowledge, the first work on the simultaneous use of MMF and sirolimus has been published by the Graz group, who reported no AR during the successful switch from CNI to MMF + sirolimus in 7 patients featuring CNI‐derived nephro‐ and neurotoxicity. Mean follow‐up; however, was only 137 days 30. Later, a Dallas team reported a trivial 2.8% incidence of AR in 35 patients converted from CNI+MMF+steroids to sirolimus+MMF+steroids 31.…”