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

Abstract

Sirolimus is a new immunosuppressive agent increasingly being used in liver transplant recipients. There is concern that sirolimus may be associated with wound complications and hepatic artery thrombosis (HAT). We have used sirolimus as primary immunosuppression in 170 liver transplant recipients and therefore reviewed our experience with wound complications and HAT in our cohort of patients. Records of all 170 patients administered sirolimus as primary immunosuppression and 180 historic controls were reviewed. Numbers of wound and hepatic artery complications were recorded, as well as the prevalence of obesity, reoperation, diabetes, and OKT3 use, all of which are risk factors for wound complications. The prevalence of wound complications was 12.4% in sirolimus-treated patients compared with 13. S irolimus, a new immunosuppressive agent, is being used increasingly in liver transplantation. 1-4 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. Conversely, the sirolimus-FKBP12 complex inhibits the target of rapamycin kinase, thereby inhibiting protein synthesis, G 1 to S transition, and cytokinedriven T-cell proliferation.Sirolimus has shown benefit in renal transplant recipients and therefore was approved for use in renal transplantation by the Food and Drug Administration in 1999. In two recent studies, a fixed dose of 2 or 5 mg/d of sirolimus in combination with cyclosporine decreased the acute rejection rate in the first year by 50% without an increase in immunosuppressant-related side effects. 7,8 Wound infection rates were not increased with sirolimus.Two recent trials have shown that liver transplantation may be performed successfully with minimal use of corticosteroids by using sirolimus and either tacrolimus or cyclosporine A. Low-dose sirolimus in the absence of prednisone in liver transplant recipients at our center was associated with a 50% decreased incidence of rejection, and the incidence of steroid-resistant rejection was decreased by 90% (compared with historic controls). 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. None of the patients had steroid-resistant rejection.The well-established side-effect profile of sirolimus includes dose-dependent hyperlipidemia, thrombocytopenia, anemia, and leukopenia with an absence of neurotoxicity, nephrotoxicity, and diabetogenesis. There are anecdotal reports from some centers that sirolimus is associated with an increased incid...

Novel synergistic antitumor effects of rapamycin with bortezomib on hepatocellular carcinoma cells and orthotopic tumor model

“…The average proliferation index was dramatically decreased from 62.8 ± 12.7% in rapamycin treatment group to 29.8 ± 6.5% in the group that received both rapamycin and bortezomib. Rapamycin has showed antiangiogenic activities in vivo not only by decreasing the production of VEGF but also by inhibiting the response of vascular endothelial cells on stimulation by VEGF via inhibiting of mTOR [41]. One mechanism of bortezomib-induced tumor growth inhibition identified in previous studies is also angiogenesis inhibition [42].…”

The Role of mTOR Inhibitors in Liver Transplantation: Reviewing the Evidence

“…Two multicenter randomized studies in de novo liver transplant recipients suggested that the use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in HAT [38, 44]. In subsequent studies (a mixture of quality and trial designs) that reviewed the use of sirolimus in liver transplant recipients, increased rates of HAT have not been observed (Table 4(a)) [15, 45, 48, 53, 55, 57, 61]. In fact, two of these studies recorded significantly lower incidences of HAT among patients receiving sirolimus compared to controls [53, 57].…”

“…In seven studies, wound complications (described as either wound complications, wound dehiscence, wound infection, healing complications, or slow wound healing) were reported in 2.2–15% of liver transplant recipients receiving sirolimus (Table 4(b)) [15, 48, 53, 55, 61, 69, 78]. Six of these studies included a control group, of which five (a mixture of quality and trial designs) demonstrated no significant difference in wound complications between sirolimus and control groups [15, 53, 55, 61, 69, 78] and one small study demonstrated a significantly lower incidence of poor wound healing versus the CNI group ( P = 0.017) [48]. Two of the studies reported that the incidence of incisional hernia was also similar in liver transplant recipients receiving sirolimus or CNIs [48, 53].…”

“…This contrasted with a high quality case-control review of prospectively collected data among HCC patients in which the incidence of NODM was significantly higher in the tacrolimus + MMF group ( n = 106, 12.26%) versus the sirolimus group ( n = 121, 0%, P < 0.001) [55]. In two other retrospective studies (one late-conversion, medium quality and one de novo , low quality study), the incidence of diabetes reported in liver transplant recipients receiving sirolimus was similar to controls who had never received sirolimus [61] or did not change after conversion to sirolimus [75]. …”

583 Everolimus Immunosuppression Reduces Serum Expression of Fibrosis Markers in Liver Transplant Recipients

“…However, this drug has also been used off-label in liver and lung transplantation patients [24][25][26][27] . At our center, the use of everolimus in LT recipients is approved in situations such as renal dysfunction or adverse events like neurotoxicity due to CNI, development of de novo malignancies, recurrence of hepatocellular carcinoma, and the presence of predictors of a high risk of hepatocellular carcinoma recurrence in the explanted liver (satellitosis, vascular infiltration and multinodularity disease) [28,29] . Con- traindications for the use of everolimus are a prior history of hepatic artery thrombosis, proteinuria greater than 800 mg/d and/or surgery in the previous 4 wk [29,30] .…”