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. C urrently, calcineurin inhibitors are the mainstay drugs in regimens to prevent acute rejection in liver transplantation. In the past decade, the efficacy of calcineurin inhibitors has revolutionized solid-organ transplantation. However, both cyclosporine and tacrolimus are limited by their toxicities, most prominently nephrotoxicity and neurotoxicity. Unfortunately, both renal dysfunction and encephalopathy are often prominent features in the clinical presentation of many liver transplant recipients before transplantation. In these patients, the management of posttransplantation immunosuppression is particularly challenging because of the need to provide adequate immunosuppression without exacerbating renal dysfunction or causing neurotoxicity. In this setting, calcineurin inhibitors are often withheld, which may result in an increased risk for allograft rejection.Sirolimus (SRL; rapamycin; Wyeth-Ayerst, Philadelphia, PA), a macrocyclic lactone produced by Streptomyces hygroscopicus, has been shown to be a potent therapeutic agent in combination with cyclosporine (CsA). It resembles tacrolimus (TAC; Prograf; Fujisawa Healthcare, Deerfield, IL) structurally and binds the same immunophilin FK506 12-kd binding protein . Whereas CsA and TAC inhibit interleukin-2 gene transcription, SRL acts by blocking postreceptor signal transduction and interleukin-2-dependent proliferation. 1 SRL has been shown to be a powerful immunosuppressant in in vitro and animal models. 2,3 More recently, used in combination with CsA, it has been shown to be a potent therapeutic antirejection agent for kidney transplantation in humans. 4 The side-effect profile of SRL differs from that of the calcineurin inhibitors. Notably, no nephrotoxicity or neurotoxicity has been observed; however, leukopenia, thrombocytopenia, hypertriglyceridemia, and hypercholesterolemia have been noted. 5 We and others have used SRL in combination with anti-CD25 monoclonal antibody induction in a calcineurin-inhibitorsparing regimen for renal transplant recipients with delayed or impaired initial graft function. When therapeutic dosages of SRL were administered and titrated to maintain serum trough levels greater than 8 to

Pretransplant renal function predicts survival in patients undergoing orthotopic liver transplantation

“…In addition, we believe that patients with renal insufficiency should be considered for less nephrotoxic immunosuppressive regimens, including sirolimus and mycophenolate mofetil. 26,27 These drugs should be tested in controlled trials to determine safety and efficacy. In conclusion, approximately one third of patients undergoing OLT have evidence of pretransplant renal impairment.…”

Early Withdrawal of Calcineurin Inhibitors and Everolimus Monotherapy in de novo Liver Transplant Recipients Preserves Renal Function

“…(2,15,16) A potential concern with CNI withdrawal is the risk of under-immunosuppression and ensuing rejection, which has been described in several reports (6,17). (18)(19)(20)(21)(22)(23)(24)(25)(26) (23)(24)(25)(26), concurrent non-CNI-related renal disease (25) and interval from transplantation (25,26 in which there was little improvement in the renal function of LT recipients after nonnephrotoxic drug implementation maintenance (27). …”

Intrahepatic cholestasis after liver transplantation

“…77 Persistent cholestasis may be managed by conversion to an alternative immunosuppressive agent, such as mycophenolate mofetil or sirolimus (Table 2). 78,79 Azathioprine Azathioprine is a purine analogue that is metabolized in the liver to 6-mercaptopurine by the enzyme glutathione S-transferase. Azathioprine causes inhibition of nucleic acid synthesis during the S-phase of the cell cycle.…”