Sirolimus Monotherapy in Liver Transplantation
C. AlegreCarlos Jiménez RomeroManuel Abradelo de UseraAlejandro Manrique MunicioElfrid CifuentesFélix Cambra MoleroJorge CalvoÁlvaro García‐SesmaMaría García NebredaRebeca Sanabria MateosS. Olivares PizarroÓscar Caso MaestroSandra García ArozIago JustoE. Moreno González
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Background: Sirolimus is an antibiotic with antifungal, antifibrotic and immunosuppressant properties that has been used in orthotopic liver transplantation (OLT) as substitute of calcineurin inhibitors (CNI) in cases of de novo tumors, patients subjected to OLT for hepatocellular carcinoma (HCC) and nephrotoxicity due to CNI. We present our experience with sirolimus monotherapy in OLT Patients and methods: Between April 1986 and December 2010 we performed 1500 OLT, of whom 57 patients are receiving immunosuppressive treatment with sirolimus, and 39 of them are currently in monotherapy. We analized the clinical characteristics of patients, associated side effects, rejection rate, renal function and lipid profile, in patients treated with sirolimus monotherapy. Results: There were 31 males (79.5%), and 8 females (20.5%) with a mean age at OLT of 50.5 ±10.5 years. The mean follow-up period was 89.8 months. The main indications for OLT was alcoholic cirrhosis in 10 patients (25.6%), HCV cirrhosis in 5 (12.8%), and HCV cirrhosis+HCC in 5 (12.8%). Other causes were HBV cirrhosis, acute liver failure, autoimmune hepatitis. The most frequently immusosuppressive therapy used at discharge was tacrolimus+prednisone in 25 patients (64.1%). Premonotherapy immunosuppression most frequently used was tacrolimus+sirolimus in 21 patients (53.9%), and mycophenolate+sirolimus in 15 (38.5%). The mean time from OLT to sirolimus monotherapy treatment initiation was 65.3 months, and the mean follow-up after switching to sirolimus monotherapy was 22.8 months. Only 1 patient (2.6%) presented acute rejection, being with adequate drug levels, and treated with reintroduction of tacrolimus. The indications for conversion to sirolimus monotherapy were: de novo aerodigestive tract tumors in 11 patients (28.3%), HCC in 10 (25.6%), nephrotoxicity due to CNI in 5 (12.8%), skin malignacies in 4 (10.3%), lymphoproliferative disorders in 3 (7.7%), urologic tract tumors in 3 (7.7%), central nervous system tumors in 2 (5%) and gynecological in 1 patient (2.6%). Adverse effects developed in 35 patients (89.7%) and the most frequent were: dyslipidemia in 24 patients (61.5%), edemas in 8 (20.5%), and cytopenias in 8 (20.5%). The mean creatinine clearance rate (CCL) before sirolimus therapy was 69.9 ml/min (normal kidney function in 30.8% of patients, mild renal insufficiency in 48.7%, and moderate in 20.5%); and after monotherapy was 75.3 ml/min (normal kidney function in 38.5% of patients, mild renal insufficiency in 41%, moderate in 18%, and severe in 2.6%) (p=0.0001). Total cholesterol and trigliceride values increased significantly after switching: cholesterol 171 mg/dl vs 208 mg/dl (p=0.002); and trigliceride 108 mg/dl vs 158 mg/dl (p=0.015). Seventeen patients were treated with hypolipemiant drugs. Conclusions: Sirolimus monotherapy is a good immunosuppressive option in patients who underwent OLT for HCC or those who develop de novo tumors or nephrotoxicity due to CNI. Monotherapy is well tolerated and is associated with low rejection rate. Renal function improves after conversion to sirolimus monotherapy and dyslipidemia is pharmacologically well controlled.Keywords:
Sirolimus
Immunosuppression
Cyclosporine and tacrolimus are potent inhibitors of the calcineurin-dependent cytokine synthesis in activated lymphocytes. In renal transplant patients tacrolimus is more powerful in preventing severe and refractory rejections, even when compared with the new cyclosporine microemulsion formulation. Both drugs are equally nephrotoxic, but tacrolimus induces less hypertension and less pronounced hyperlipidaemia. Especially in some categories of patients, a higher incidence of de-novo diabetes mellitus is seen with tacrolimus therapy.
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Refractory (planetary science)
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Posttransplantation lymphoproliferative disorder (PTLD) is a well-described complication of the systemic immunosuppression required for successful organ transplantation. Lesions of PTLD often occur in the region of the head and neck and require otolaryngologic evaluations. Although the majority of reported cases of PTLD are associated with cyclosporine immunosuppression, recently, PTLD has been described in patients treated solely with the newer systemic immunosuppressive agent tacrolimus (FK 506). As an introduction to tacrolimus and to PTLD as one of its complications, a case of PTLD presenting as airway obstruction in a child treated solely with tacrolimus immunosuppression is described. In addition, a review of tacrolimus and PTLD in patients under tacrolimus immunosuppression is presented to familiarize the otolaryngologist with this important new immunosuppressive agent and a potential complication of its use. (Arch Otolaryngol Head Neck Surg 1995;121:1037-1041)
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A de novo calcineurin inhibitor avoidance regimen based on sirolimus has been successfully used worldwide; demonstrating improved renal function from 1 to 5 years. This includes use of an induction antibody followed by sirolimus, mycophenolate mofetil, and steroids. This combination has a somewhat different side effect profile and wider experience has revealed that the use of de novo sirolimus requires careful therapeutic drug level monitoring, especially the first 6 months posttransplant. Experience has also demonstrated that delaying the introduction of sirolimus in patients considered at high risk for early mammalian target of rapamycin associated complications will optimize these results. For such recipients, the initial use of a calcineurin inhibitor drug for 2 to 4 months is preferred, followed by conversion to sirolimus. The late withdrawal of steroids may be possible, but awaits further evaluation in randomized controlled trials.
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P649 Aims: Until recently, there has been no practical alternative to the use of calcineurin inhibitors as primary immunosuppressants in lung transplantation. Sirolimus is a novel powerful immunosuppresant without renal toxicity, a common post-transplant problem associated with calcineurin inhibitors therapy. Methods: In 11 patients (3 with cystic fibrosis, 10 with COPD, 1 with CTEPH and 1 with PPH) the indication for lung transplantation was set. After lung transplantation these patients developed chronic kidney failure (creatinine ≥ 2mg/dl) and were switched to a combined immunosuppressive regime with reduced calcineurin inhibitors and sirolimus. The serum levels of the calcineurin inhibitors and of sirolimus should be between 5 ng/ml to 7ng/ml. We documented the values of the kidney function parameters (creatinine, BUN), lung function parameters (VC, FEV1, MEF50, TLC), number of thrombocytes, cholesterol values, triglycerid values on the day of the switch to a combined immunosuppressive regime with calcineurin inhibitors and sirolimus and three month after this switch. Results: All patients had stable lung function parameters during the observed period. There was no significant improvement of all investigated parameters in the whole patient group. According to the time between manifestation of chronic kidney failure and the switch to a combined immunosuppressive regime with calcineurin inhibitors and sirolimus we divided the patients in two groups: group A (n=5) with an early (192 ± 121.12 days) and group B (n=6) with a later (1520 ± 1151.13 days) switch. In group A there was a trend to improvement of renal function (creatinine from 2.85±0.92m/dl to 2.18±0.42mg/dl, p=0.11; BUN from 45.94±19.26mg/dl to 42.06±12.46mg/dl, p=0.69) which however was not significantly (perhaps due to the small number of patients). The number of thrombocytes changed from 251±93.57G/l to 218.25±116.59G/l, p=0.19, cholesterol values from 200.00±1.41mg/dl to 256.5±58.6mg/dl, p=0.4, the triglycerides from 201.5 ±127.99mg/dl to 338.00±52.33mg/dl, p=0.23. In group B there was no improvement of chronic renal insufficiency. Two patients died in fact of chronic kidney failure; one patient is in a dialyses program with the option of a kidney transplantation. Conclusions: This investigation suggests that the early addition of sirolimus and the reduction of the calcineurin inhibitors could be a valuable alternative immunosuppressant in patients with chronic kidney failure.
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This review of immunosuppression in renal transplantation has allowed us to highlight the deleterious effect of calcineurin inhibitor nephrotoxicity and to emphasise the importance of sirolimus. Now, a whole new set of possibilities has opened up in immunosuppression: sirolimus-based immunosuppression without calcineurin inhibitors; sirolimus in combination with calcineurin inhibitors in reduced doses; early calcineurin inhibitor withdrawal from a regimen that combines sirolimus, calcineurin inhibitors and steroids; and calcineurin inhibitor conversion to sirolimus when the first signs of graft nephrotoxicity appear. These new strategies in immunosuppression in renal transplantation are associated with good results in graft and patient survival in year 1, and with better renal function. Therefore, we can hope for better long-term results in transplantation, with a significant increase in the graft half-life and in the patient survival.
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Objectives: The aim of this prospective pilot study was to investigate, for the first time since the introduction of cyclosporine, whether de novo calcineurin inhibitor free immunosuppression after HTx is efficacious and can prevent calcineurin inhibitor specific adverse effects.
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