Cyclosporine, a calcineurin inhibitor (CNI), changed the face of transplantation, and in a few years the survival rate of liver transplantation had reached 80% [7]. The search for new and safer immunosuppressants continued and in 1989, reports were published on the successful use of tacrolimus, another CNI, in liver mostly transplantation [8]. CNIs have been the cornerstone of maintenance immunosuppression in liver transplantation [9], but their nephrotoxic effects are an important source of morbidity [10�C13]. Several other factors are implicated in the development of renal dysfunction following liver transplantation, including increased age, diabetes mellitus, hypertension, and preexisting kidney disease [14]. Data from the United Network for Organ Sharing demonstrate that almost 20% of liver transplant recipients have chronic renal failure 5 years after transplantation [14].

High rates of renal dysfunction associated with the preexisting liver disease and with the use of CNIs are compounded by the use of the Model for End-Stage Liver Disease score for allocating transplants since it favors liver transplantation in individuals with renal dysfunction. In addition to renal dysfunction, long-term complications associated with liver transplantation include the development of de novo malignancies and the recurrence of HCV and HCC. Recurrence of HCC occurs in approximately 20% of liver recipients [15] and is associated with poor prognosis [16].

In patients who receive a transplant due to HCV-related end-stage liver disease, graft reinfection is almost universal and a significant percentage of patients develop chronic hepatitis in the graft [17�C19]; 5-year survival rates after primary liver transplantation are significantly reduced among HCV-positive patients compared to HCV-negative patients [19]. A four-fold greater risk of developing de novo malignancies posttransplant compared to the general population has also been reported [20]. Another concern relates to adverse effects of the immunosuppressants that are required to maintain the graft. For example, new-onset diabetes mellitus (NODM) has been estimated to occur in 5�C27% of liver transplant recipients [21�C23] and is associated with a negative impact on patient and graft survival [24]. CNIs, particularly tacrolimus, have been shown to increase the risk of developing NODM [21, 25, 26] and are also associated with an increase in the incidence of malignancies are transplantation [20, 27, 28] and with cases of neurotoxicity [28�C30]. In addition, metabolic syndrome, which refers to the combination of abdominal obesity, hypertension, hyperglycemia, Dacomitinib and hyperlipidemia, is common after liver transplantation and has been reported to affect 43�C58% of liver transplant recipients [31].