Liver transplantation using sirolimus and minimal corticosteroids(3-day taper)

Abstract

At our center, we have performed liver transplantation since 1995 with a rapid-taper steroid protocol (weaning steroids by day 14 posttransplantation). Beginning in 2000, we further reduced the use of corticosteroids to 3 days and added sirolimus to our immunosuppressive regimen. We report our experience with 39 patients who underwent liver transplantation with either tacrolimus or cyclosporin A (Neoral; Novartis Pharmaceuticals Corp., Summit, NJ) and sirolimus, with a 3-day tapered dose of corticosteroids. Thirty-two patients received a cadaveric graft and 7 patients received a right hepatic lobe from a living donor. All patients initially were administered either tacrolimus (0.1 mg/kg/d) or cyclosporin A (10 mg/ kg/d) and sirolimus (6 mg/d for 1 day, followed by 2 mg/d), in addition to methylprednisolone on the first 3 days (1, 0.5, and 0.5 g/d) after transplantation. Patients were administered corticosteroids for presumptive or biopsy-proven evidence of acute cellular rejection (methylprednisolone, 1, 0.5, and 0.5 g on 3 successive days). Seventeen patients were administered tacrolimus and 22 patients were administered cyclosporin A. Six patients were excluded from analysis because they were administered sirolimus for less than 2 weeks. Mean duration of follow-up was 124 days. Patient survival was 36 of 39 patients (92%), and graft survival was 35 of 39 grafts (89%). Ten of 33 patients (30%) experienced 12 episodes of rejection (7 biopsy proven, 5 presumptive) compared with 70% in historical controls (P < .01). OKT3 was required in 1 of 33 patients (3%) compared with 37% in controls (P < .01). Twenty-six of 33 patients (79%) were not administered prednisone, and 7 of 33 patients (21%) were administered prednisone for reasons other than rejection. Posttransplantation, there was no significant change in values for creatinine, glucose, aspartate aminotransferase, bilirubin, cholesterol, and white blood cell counts. Platelet counts were significantly reduced, and hematocrits were significantly elevated (P < .05). Liver transplantation may be successfully performed with minimal use of corticosteroids by using sirolimus and either tacrolimus or cyclosporin A. Despite the absence of prednisone from our immunosuppressive protocol, the incidence of rejection and OKT3 use was lower than in historical controls. Patient and graft survival rates were identical to those of historical controls. The findings in this report will serve as the basis for a formal trial evaluating the efficacy of sirolimus in liver transplantation. I mmunosuppression for liver transplantation has evolved over the past decade. From the inception of our current liver transplant program in 1988 until 1995, the standard immunosuppressive regimen was double therapy with cyclosporin A and prednisone. Many patients also were administered azathioprine in the first few months posttransplantation. Using this regimen, our 1-year patient and graft survival rates were approximately 85% and 80%, respectively, and the rate of treated allograft rejection was app...

Sirolimus as primary immunosuppression in liver transplantation is not associated with hepatic artery or wound complications

“…4 Similar efficacy was reported by McAlister et al 2 in an open-label report of 56 patients administered low-dose tacrolimus and sirolimus with prednisone up to 6 months after transplantation. The acute cellular rejection rate was 14%, which was approximately 50% lower than the historic rejection rate.…”

“…OKT3 use was significantly lower in sirolimus-treated patients (14%) versus controls (39%), as reported previously. 4 Hepatic artery and wound complications are listed in Table 2. In sirolimus-treated patients, hepatic artery complications occurred in 9 of 170 patients (5.3%; P ϭ not significant [NS] compared with historic controls); 7 complications occurred early (Յ30 days after trans- In historic controls, hepatic artery complications occurred in 15 of 180 patients (8.3%); 10 complications occurred early (Յ30 days after transplantation) and 5 complications occurred late (Ͼ30 days after transplantation).…”

“…In addition, OKT3 use was far more common in the control group (39%) versus sirolimus-treated patients (14%) because of the significantly lower occurrence of steroid-resistant acute cellular rejection in the sirolimus-treated patients. 4 OKT3 use significantly increases the likelihood of surgical site infection in liver transplantation. In a study using the National Institute of Diabetes and Digestive and Kidney Disease Liver Transplantation Database of 777 liver transplant recipients, the odds ratio of surgical site infection was 1.49 (P Ͻ .05) if OKT3 was administered within the first 7 days after liver transplantation.…”

“…[1][2][3][4] Sirolimus and tacrolimus are structurally related macrolides that bind the same intracellular receptor (FK506-binding protein-12 [FKBP12]) and potently inhibit T-cell proliferation. 5,6 The tacrolimus-FKBP12 complex, like the cyclosporine-cyclophilin complex, binds to and inhibits the Ca 2ϩ -dependent serine-threonine phosphatase calcineurin, thereby inhibiting cytokine-induced T-cell gene transcription and G 0 to G 1 transition.…”

HSV infection and immunosuppression

“…The authors have previously documented the efficacy of the three-drug combination described here. 5 As in all opportunistic infectious events, a viable firstline response might have been reducing immunosuppression to monotherapeutic Tacrolimus or Sirolimus or low-dose Tacrolimus ϩ low-dose steroids. Despite known thrombotic risks of Sirolimus-based combinations, single center experiences suggest that Sirolimus monotherapy provides safe and effective rejection prophylaxis early after liver transplantation, when initiated as a rescue option.…”