Cardiovascular morbidity and mortality after liver transplantation: The protective role of mycophenolate mofetil.

Cardiovascular (CV) diseases are recognized longterm causes of death after liver transplantation (LT). The objective of this multicenter study was to analyze the prevalence and the evolution of CV risk factors and CV morbidity and mortality in 1819 LT recipients along 5 years after LT. The influence of baseline variables on survival, morbidity, and mortality was studied. There was a continuous and significant increase of the prevalence of all the CV risk factors (except smoking) after LT. CV diseases were the fourth cause of mortality in the 5 years after LT, causing 12% of deaths during the follow-up. Most CV events (39%) occurred in the first year after LT. Preexisting CV risk factors such as age, pre-LT CV events, diabetes, metabolic syndrome, and hyperuricemia, and mycophenolate-free immunosuppressive therapy, increased post-LT CV morbidity and mortality. The development of new-onset CV risk factors after LT, such as dyslipidemia and obesity, independently affected late CV morbidity and mortality. Tacrolimus and steroids increased the risk of posttransplant diabetes, whereas cyclosporine increased the risk of arterial hypertension, dyslipidemia, and metabolic syndrome. In conclusion, CV complications and CV mortality are frequent in LT recipients. Preexisting CV risk factors, immunosuppressive drugs, but also the early new onset of obesity and dyslipidemia after LT play an important role on late CV complications. A strict metabolic control in the immediate post-LT period is advisable for improving CV risk of LT recipients. Liver Transplantation 23 498-509 2017 AASLD.

Liver transplantation for adenomatosis: European experience.

The aim of this study was to collect data from patients who underwent liver transplantation (LT) for adenomatosis; to analyze the symptoms, the characteristics of the disease, and the recipient outcomes; and to better define the role of LT in this rare indication. This retrospective multicenter study, based on data from the European Liver Transplant Registry, encompassed patients who underwent LT for adenomatosis between January 1, 1986, and July 15, 2013, in Europe. Patients with glycogen storage disease (GSD) type IA were not excluded. This study included 49 patients. Sixteen patients had GSD, and 7 had liver vascular abnormalities. The main indications for transplantation were either a suspicion of hepatocellular carcinoma (HCC; 15 patients) or a histologically proven HCC (16 patients), but only 17 had actual malignant transformation (MT) of adenomas. GSD status was similar for the 2 groups, except for age and the presence of HCC on explants (P = 0.030). Three patients with HCC on explant developed recurrence after transplantation. We obtained and studied the pathomolecular characteristics for 23 patients. In conclusion, LT should remain an extremely rare treatment for adenomatosis. Indications for transplantation primarily concern the MT of adenomas. The decision should rely on morphological data and histological evidence of MT. Additional indications should be discussed on a case-by-case basis. In this report, we propose a simplified approach to this decision-making process.

Use of artificial intelligence as an innovative donor-recipient matching model for liver transplantation: results from a multicenter Spanish study.

BACKGROUND & AIMS: There is an increasing discrepancy between the number of potential liver graft recipients and the number of organs available. Organ allocation should follow the concept of benefit of survival, avoiding human-innate subjectivity. The aim of this study is to use artificial-neural-networks (ANNs) for donor-recipient (D-R) matching in liver transplantation (LT) and to compare its accuracy with validated scores (MELD, D-MELD, DRI, P-SOFT, SOFT, and BAR) of graft survival. METHODS: 64 donor and recipient variables from a set of 1003 LTs from a multicenter study including 11 Spanish centres were included. For each D-R pair, common statistics (simple and multiple regression models) and ANN formulae for two non-complementary probability-models of 3-month graft-survival and -loss were calculated: a positive-survival (NN-CCR) and a negative-loss (NN-MS) model. The NN models were obtained by using the Neural Net Evolutionary Programming (NNEP) algorithm. Additionally, receiver-operating-curves (ROC) were performed to validate ANNs against other scores. RESULTS: Optimal results for NN-CCR and NN-MS models were obtained, with the best performance in predicting the probability of graft-survival (90.79%) and -loss (71.42%) for each D-R pair, significantly improving results from multiple regressions. ROC curves for 3-months graft-survival and -loss predictions were significantly more accurate for ANN than for other scores in both NN-CCR (AUROC-ANN=0.80 vs. -MELD=0.50; -D-MELD=0.54; -P-SOFT=0.54; -SOFT=0.55; -BAR=0.67 and -DRI=0.42) and NN-MS (AUROC-ANN=0.82 vs. -MELD=0.41; -D-MELD=0.47; -P-SOFT=0.43; -SOFT=0.57, -BAR=0.61 and -DRI=0.48). CONCLUSIONS: ANNs may be considered a powerful decision-making technology for this dataset, optimizing the principles of justice, efficiency and equity. This may be a useful tool for predicting the 3-month outcome and a potential research area for future D-R matching models.

Tacrolimus pharmacokinetics in the early post-liver transplantation period and clinical applicability via Bayesian prediction.

PURPOSE: To define and validate a pharmacokinetic (PK) model for tacrolimus (TAC) that includes patient pathophysiology and has clinical applicability in the first 2 weeks post-liver transplantation (PLT). METHODS: Routine monitoring records [dose, trough levels (C(min)), demographics, biochemistry] from 75 patients treated with TAC (Prograf®) PLT were used to develop a population PK model (employing NONMEM®) testing for predictors of oral clearance (CL/F) according to bedside evidence and primarily with aspartate aminotransferase (AST), albumin (ALB), and hematocrit (HCT). Patients were catergorized into subgroups with above and below "normal" thresholds for AST (500 U/L), ALB (2.5 g/dL), and HCT (28 %), respectively. The model was validated with ten patients from the same period and 15 more recent patients. An empirical Bayes method was developed and applied to the prediction of individual profiles serving as a dose adjustment tool. RESULTS: The number of days PLT (Days PLT) was a key variable during the first 2 weeks, with a dichotomy in the mono-compartmental parameters for 0-3 Days PLT and 4-15 Days PLT. During 0-3 Days PLT, AST levels, indicative of allograft functionality (and TAC metabolism), were crucial predictors of elimination. Three groups were identified with the following clearances: CL/F0₋3 = 8.93 L/h for AST ≥ 500 U/L and CL/F0₋3 = 11.0 L/h for AST <500 U/L. During 4-15 Day PLT, low values of ALB (<2.5 g/dL) and HCT (<28 %) combined were determinant of a patient subgroup with a tendency to underexposure and complexity in empirical dose adjustment. The CL/F4₋15 = 25.1 L/h for this subgroup compared to CL/F4₋15 = 17.1 L/h for the others in that period. The elimination half-life for individual patients varied over tenfold so that a large number of subjects were not at steady state, making the use of a PK model necessary to achieve rapidly and safely the target concentration for TAC in LT. Validation of the model demonstrated that both bias and precision were within acceptable limits. CONCLUSION: For TAC therapy, covariate models using mixed effects methods are most useful when combined with patient-specific biochemical assays as well as clinical evidence. In such cases, the observed C(min) and Bayes methods can provide the most likely individual PK parameters, hence the optimal next dose to reach individualized target levels for each patient.

An open, randomized, multicenter clinical trial of oral tacrolimus in liver allograft transplantation: a comparison of dual vs. triple drug therapy.

Triple therapy combining an anticalcineurin agent, corticosteroids, and azathioprine (AZA) in liver transplantation has been frequently applied, particularly in Europe. Debates have arisen concerning the use of a third drug (AZA), mainly in patients receiving tacrolimus (TAC). An open-label, multicenter, prospective, and randomized trial was performed to assess the efficacy and safety of TAC and corticosteroids (dual therapy [D]) vs. TAC, corticosteroids, and AZA (triple therapy [T]) in liver transplantation. A total of 180 patients were randomized, 92 in D and 88 in T group. Patients were followed during 3 months for efficacy and safety and up to 24 months for patient and graft survival assessments. The rate of biopsy-proven acute rejection was higher in D than in T group (40.7% vs. 24.4%; P = 0.021). A higher incidence of positive HCV status in D group (55.6% vs. 40.7%; P = 0.049) may explain this difference, since significantly more patients of this HCV subpopulation experienced acute rejection when treated with D therapy (48% vs. 20%; P = 0.008). No treatment differences were apparent for HCV-negative patients. The 24-month graft survival tended to be inferior in T group, 69.8% vs. 75.8% (P = 0.283). Similar results were observed regarding patient survival at the same time point, with values of 72.9% vs. 76.9% (P = 0.573), favoring D group. Both regimens showed comparable safety profiles with the exception of hematological abnormalities, which were more frequently observed in T group. In conclusion, both regimens were shown to be effective although increased toxicity and a trend towards a lower graft and patient survival were observed in T group.