Delayed CNI-based Immunosuppression With Advagraf After MELD-based Liver Transplantation

Overview

Prolonged-release low-dose Advagraf should better protect from CNI-side effects compared to standard immunosuppressive regiments while the rate of rejection is not increased and thus graft function is well maintained. We hypothesize that especially in high-MELD (MELD-score \>20) recipients who have a decreased immune competence the prolonged-release low-dose Advagraf concept would better protect from side effects of immunosuppression (i.e. infection). Nevertheless, we assume that also patients with a MELD-score ≤20 will benefit from this concept in regard to lower infection rates and less side effects of immunosuppression.

The MELD-score (model of end stage liver disease) was designed to estimate the prognosis after TIPS (transjugular intrahepatic porto-systemic shunt). Nowadays it is the key-score for patients awaiting a liver graft and consists of serum-creatinine, serum-bilirubine and the INR-ratio with values between 6-40. The MELD-based liver allocation follows the sickest patient first strategy which significantly decreased outcome after liver transplantation (LTx) in Germany. There is evidence that the immune competence of very sick patients is decreased. Monocytic HLA-DR status is a marker for the function of the immune system. A reduced monocytic HLA-DR expression is indicative for a suppressed immune system. Blood levels of Advagraf are slowly increased during the first week until the aimed tacrolimus trough levels are reached. Since therapeutic tacrolimus trough levels are reached not before the end of the first week after transplantation this is a concept for prolonged-release immunosuppression. We assume, that high-MELD patients (MELD \>20) undergoing LTx are immunosuppressed per se. Thus prolonged-release low-dose immunosuppression with Advagraf would decrease both- infection rate (CMV-reactivation, wound infection urinary tract infections, pneumonia, etc.) and side effects of immunosuppression. The immune capacity of patients will be determined by the measurement of monocytic HLA-DR status. To ensure that graft function is not impaired due to rejection episodes, liver function will be determined with the LiMAx-test, a routine procedure in our institution. After 13-C-Methacetin is given to the patient, it is metabolized to paracetamol and 13CO2 by the enzyme CYP1A2 which is localized in hepatocytes. The 13CO2/12CO2 ratio in the exhaled air correlates with liver function.