A Decade of Experience Using mTor Inhibitors in Liver Transplantation.

Division of Transplant Surgery, Department of Surgery, School of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
Journal of Transplantation 01/2011; 2011:913094. DOI: 10.1155/2011/913094
Source: PubMed

ABSTRACT Some studies suggest that Sirolimus (SRL) is associated with an increased risk of death in liver transplant recipients compared to treatment with calcineurin inhibitors (CNIs). We compared patients who received SRL or CNI in the first year after liver transplant. Our database included 688 patients who received a liver transplant. The patients were divided into groups. (1) CNI + MPS (mycophenolate sodium) at time of discharge. (2) CNI + MPS at time of discharge; SRL was added within the first 6 months and continued through the first year. (3) CNI + MPS at time of discharge; SRL was added within the first 6 months and discontinued before the first year. (4) SRL as primary immunosuppression. (5) SRL as primary immunosuppression and discontinued before the first year. We used mortality and graft loss as the primary measures of outcome. We also quantified renal function using the change in glomerular filtration rate (GFR), the presence of biopsy proven acute cellular reject (ACR), and steroid-resistant rejection (SRR). There were no significant differences in mortality or graft loss. There was no difference in patient or graft survival. Patients that received SRL as primary immunosuppression had 50% less rejection compared to controls.

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    ABSTRACT: Posttransplant malignancies, which occur either de novo or as cancer recurrences, are due to chronic exposure to immunosuppressive agents and are often more aggressive than those that develop in the nontransplant setting. Mammalian target of rapamycin (mTOR) inhibitors have antitumor and immunosuppressive effects. The dual effects of this class of agents may provide adequate immunosuppression to prevent organ rejection while simultaneously reducing the risk of posttransplant malignancy. mTOR inhibitors have become established approved agents for treating renal cell carcinoma and other cancers and, as reviewed herein, accumulating experience among organ transplant recipients collectively points toward a potential to prevent the development of de novo malignancies of various types in the posttransplant period. To date, most research efforts surrounding mTOR inhibitors and cancer control in the transplant population have been in the area of skin-cancer prevention, but there have also been interesting observations regarding regression of posttransplant Kaposi's sarcoma and posttransplantation lymphoproliferative disorder that warrant further study. This article is protected by copyright. All rights reserved.
    Clinical Transplantation 03/2014; DOI:10.1111/ctr.12357 · 1.49 Impact Factor
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    ABSTRACT: We studied whether the use of sirolimus with reduced-dose tacrolimus, as compared to standard-dose tacrolimus, after liver transplantation is safe, tolerated and efficacious. In an international multicenter, open-label, active-controlled randomized trial (2000-2003), adult primary liver transplant recipients (n = 222) were randomly assigned immediately after transplantation to conventional-dose tacrolimus (trough: 7-15 ng/mL) or sirolimus (loading dose: 15 mg, initial dose: 5 mg titrated to a trough of 4-11 ng/mL) and reduced-dose tacrolimus (trough: 3-7 ng/mL). The study was terminated after 21 months due to imbalance in adverse events. The 24-month cumulative incidence of graft loss (26.4% vs. 12.5%, p = 0.009) and patient death (20% vs. 8%, p = 0.010) was higher in subjects receiving sirolimus. A numerically higher rate of hepatic artery thrombosis/portal vein thrombosis was observed in the sirolimus arm (8% vs. 3%, p = 0.065). The incidence of sepsis was higher in the sirolimus arm (20.4% vs. 7.2%, p = 0.006). Rates of acute cellular rejection were similar between the two groups. Early use of sirolimus using a loading dose followed by maintenance doses and reduced-dose tacrolimus in de novo liver transplant recipients is associated with higher rates of graft loss, death and sepsis when compared to the use of conventional-dose tacrolimus alone.
    American Journal of Transplantation 01/2014; 14(2). DOI:10.1111/ajt.12543 · 6.19 Impact Factor
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    ABSTRACT: Despite the success of liver transplantation, long-term complications remain, including de novo malignancies, metabolic syndrome, and the recurrence of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC). The current mainstay of treatment, calcineurin inhibitors (CNIs), can also worsen posttransplant renal dysfunction, neurotoxicity, and diabetes. Clearly there is a need for better immunosuppressive agents that maintain similar rates of efficacy and renal function whilst minimizing adverse effects. The mammalian target of rapamycin (mTOR) inhibitors with a mechanism of action that is different from other immunosuppressive agents has the potential to address some of these issues. In this review we surveyed the literature for reports of the use of mTOR inhibitors in adult liver transplantation with respect to renal function, efficacy, safety, neurological symptoms, de novo tumors, and the recurrence of HCC and HCV. The results of our review indicate that mTOR inhibitors are associated with efficacy comparable to CNIs while having benefits on renal function in liver transplantation. We also consider newer dosing schedules that may limit side effects. Finally, we discuss evidence that mTOR inhibitors may have benefits in the oncology setting and in relation to HCV-related allograft fibrosis, metabolic syndrome, and neurotoxicity.
    Journal of Transplantation 02/2014; 2014:845438. DOI:10.1155/2014/845438

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