Early steroid withdrawal after liver transplantation: The canadian tacrolimus versus microemulsion cyclosporin a trial: 1-year follow-up

Abstract

Corticosteroid therapy contributes significant toxicity to liver transplantation. The safety and efficacy of early steroid withdrawal were determined in patients treated with either tacrolimus or microemulsion cyclosporin A (microCsA). The primary outcome was the proportion of patients who were steroid-free 1 year posttransplantation. From the seven Canadian adult liver transplant centers, 143 patients were randomly allocated oral treatment with either tacrolimus (n ‫؍‬ 71) or micro-CsA (n ‫؍‬ 72), together with corticosteroids and azathioprine. Eligibility criteria for steroid withdrawal included freedom from acute rejection for a minimum of 3 months, and prednisone <0.15 mg/kg/d. In eligible patients, the daily steroid dose was reduced by 2.5 mg each month until complete discontinuation was achieved. At 1 year after transplantation, 75% of the tacrolimus patients and 63% of the micro-CsA patients were steroid-free (P ‫؍‬ .20). Of all of the patients who became eligible for steroid withdrawal, steroid discontinuation was achieved in over 80%. One-year patient survival was 97% with tacrolimus and 89% with micro-CsA (P ‫؍‬ .052) . Graft survival was 97% and 86%, respectively (P ‫؍‬ .017). The overall incidence of acute rejection during the first year was 35% with tacrolimus and 43% with micro-CsA (P ‫؍‬ .26). There was no difference in survival, acute rejection, or rate of steroid withdrawal when adjusting for hepatitis C. All acute rejection episodes experienced during steroid withdrawal were steroid-responsive. Steroid-resistant rejection occurred in 5.6% of the tacrolimus and 9.7% of the micro-CsA patients. One patient, in the micro-CsA group, experienced refractory rejection. Chronic rejection was not observed in either group. The toxicity profiles were similar. Postoperative serum creatinine levels were similar, and dialysis was required in less than 10% of patients in each group. Infectious complications were similar in both groups. Neurotoxicity was a serious adverse event in 13% and 10% of patients receiving tacrolimus and micro-CsA, respectively. Early steroid withdrawal is safe and effective after liver transplantation using either tacrolimus plus azathioprine or micro-CsA plus azathioprine immunoprophylaxis. (Liver Transpl 2003;9:587-595.)T he calcineurin inhibitors tacrolimus and cyclosporin A are considered the immunologic foundation for liver transplantation; however, effective immunosuppression in the perioperative period seems to require the administration of corticosteroids, and most patients are maintained on prednisone for the long term. 1 The toxicities of corticosteroids, many of which are additive to those of tacrolimus or cyclosporin A, include increased susceptibility to infection (particularly opportunistic organisms), hypertension, hyperlipidemia, diabetes mellitus, osteoporosis and aseptic necrosis, cushingoid facies, acne, and growth retardation in children. Because the cumulative toxicities of immunosuppressive agents remain a major source of morbidity and mortality after liver transp...

Overview of immunosuppression in liver transplantation

“…Currently, intravenous corticosteroids are predominantly used as first-line therapy for the treatment of acute cellular rejection. Regarding maintenance therapy, they are often successfully withdrawn within 36 mo post transplantation in patients without evidence of rejection or liver disease attributed to autoimmune disorders [64] . The primary concern with corticosteroid use is exacerbation of hepatitis C virus (HCV) recurrence and liver fibrosis with highdose pulsed therapy [65] ; however, this has not been evident with low, gradually tapered doses [66,67] .…”

Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy

“…As with kidney transplantation, very early steroid withdrawal after liver transplantation results in an increase in the incidence of rejection though without increased graft loss [55]. However, in recipients free from acute rejection at 3 months, early steroid withdrawal is safe and effective [58]. …”

Inmunodepresión en el período postoperatorio inmediato del trasplante hepático

“…De estos estudios, 4 destacan por su trascendencia [45][46][47][48] (tabla III). En todos ellos la incidencia de rechazo agudo, rechazo corticorresistente y rechazo crónico fue similar.…”

“…Sin embargo, en este estudio la mayor mortalidad y la menor supervivencia del injerto en el grupo de Neoral no estuvieron relacionadas con la inmunodepresión y sí con una miscelánea de procesos no relacionados. En el estudio canadiense 48 se demostró que era posible la retirada de los esteroides a partir del cuarto mes en igual proporción en los pacientes que tomaban tacrolimus y Neoral. Por último, el perfil de seguridad de ambos fármacos fue similar, pero con una mayor incidencia de diabetes 45 y diarrea 46 en el grupo con tacrolimus y mayor incidencia de hipertensión e hiperuricemia en el grupo de Neoral en uno de los estudios 46 .…”