Approaches to optimize immunosuppression after liver transplantation

Abstract

Since its advent 51 years ago, liver transplantation (LT) has progressed from an experimental treatment to an accepted therapeutic modality that has reversed the gloomy prognosis of end stage liver disease. The great success of LT is for the major part due to calcineurin inhibitors (CNI) like Cyclopsorin A and Tacrolimus. These are powerful immunosuppressants (IS), which prevent graft rejection and are the cornerstone of posttransplant patient management. The introduction of Cyclosporine in March 1980 marked great clinical advance for graft and patient survival. Following the introduction of cyclosporine in LT, one-year patient survival more than doubled (from approximately 33 to 68%), with an increment to above 80% nowadays. (www.eltr.org). Although immunosuppressive regimens are indispensible therapeutics for LT recipients, the downside is their major adverse effects on the long-term. The obligatory lifelong use of these drugs increases patients’ morbidity by increasing their susceptibility for infections, cancer, cardiovascular diseases, kidney failure and de-novo diabetes, which impair long-term survival and quality of life after transplantation. These adverse effects are largely caused by the non-specificity of the immunosuppressive medications. In addition CNI also exert undesirable side effects on vasoactive compounds resulting in vasculopathy, and on LDL receptor bile acid synthesis from cholesterol and lipoprotein lipase activity, resulting in dyslipidemia.