Summary The purpose of this registry study was to provide an overview of trends and results of liver transplantation (LT) in Europe from 1968 to 2016. These data on LT were collected prospectively from 169 centers from 32 countries, in the European Liver Transplant Registry (ELTR) beginning in 1968. This overview provides epidemiological data, as well as information on evolution of techniques, and outcomes in LT in Europe over more than five decades; something that cannot be obtained from only a single center experience.

Graphical abstract

The efficacy and safety of dual-therapy regimens of twice-daily tacrolimus (BID; Prograf) and once-daily tacrolimus (QD; Advagraf) administered with steroids, without antibody induction, were compared in a multicenter, 1:1-randomized, two-arm, parallel-group study in 475 primary liver transplant recipients. A doubleblind, double-dummy 24-week period was followed by an open extension to 12 months posttransplant. The primary endpoint, event rate of biopsy-proven acute rejection (BPAR) at 24 weeks, was 33.7% for tacrolimus BID versus 36.3% for tacrolimus QD (Per-protocol set; p = 0.512; treatment difference 2.6%, 95% confidence interval −7.3%, 12.4%), falling within the predefined 15% noninferiority margin. At 12 months, BPAR episodes requiring treatment were similar for tacrolimus BID and QD (28.1% and 24.7%). Twelvemonth patient and graft survival was 90.8% and 85.6% for tacrolimus BID and 89.2% and 85.3% for tacrolimus QD. Adverse event (AE) profiles were similar for both tacrolimus BID and QD with comparable incidences of AEs and serious AEs. Tacrolimus QD was well tolerated with similar efficacy and safety profiles to tacrolimus BID.

No abstract

Tacrolimus, a cornerstone immunosuppressant, is available as a twice-daily formulation (tacrolimus bid). A once-daily prolonged-release formulation (tacrolimus qd) has been developed. This 6-week, randomized, phase 2, multicenter, open-label, prospective trial in primary liver transplant recipients investigated and compared the pharmacokinetics (PK) of tacrolimus for qd and bid formulations. All patients received tacrolimus-based immunosuppression (tacrolimus qd, n ¼ 67; bid, n ¼ 62). PK data were available for 77 patients (tacrolimus qd, n ¼ 45; bid, n ¼ 32). Tacrolimus area under the curve (AUC) from 0 to 24 hours (AUC 0-24 ) at equivalent doses was approximately 50% lower for tacrolimus qd than for bid on day 1 (146 versus 264 ngÁh/mL, respectively), but by day 14 was comparable between treatments (324 and 287 ngÁh/mL, respectively) with higher tacrolimus qd doses. There was a strong correlation between AUC 0-24 and concentration at 24 hours for tacrolimus qd and bid (r ¼ 0.92 and r ¼ 0.76, respectively). Furthermore, the relationship between these 2 parameters (ie, the slope of the line) was also similar for the 2 formulations. Efficacy endpoints were comparable for both formulations at 6 weeks with Abbreviations: AE, adverse event; AUC 0-24 , area under the curve from 0 to 24 hours; AZA, azathioprine; bid, twice daily; BPAR, biopsy-proven acute rejection; C 24 , concentration at 24 hours; C max , maximum concentration; C min , minimum blood concentration; MMF, mycophenolate mofetil; NEC, not elsewhere classified; PK, pharmacokinetics; qd, once daily; SD, standard deviation; T max , time to maximum concentration. This study and statistical analyses, and the editorial and project management services of Acumed involved in the preparation of this manuscript, were supported by Astellas Pharma Europe, Ltd., Staines, UK. L. Fischer, B. Gridelli, A. Roy, A. Vitale, A. Valdivieso, E. Varo, D. Seehofer, B. Ericzon, and K. Boudjema have declared no conflicts of interest. P. Trunečka has acted as study investigator and advisory board member for Astellas and has received speaker's fees. S. Lynch has received honoraria for chairing and speaking at international meetings for Astellas and JanssenCilag,

DIAMOND: multicenter, 24‐week, randomized trial investigating the effect of different once‐daily, prolonged‐release tacrolimus dosing regimens on renal function after de novo liver transplantation. Arm 1: prolonged‐release tacrolimus (initial dose 0.2mg/kg/day); Arm 2: prolonged‐release tacrolimus (0.15–0.175mg/kg/day) plus basiliximab; Arm 3: prolonged‐release tacrolimus (0.2mg/kg/day delayed until Day 5) plus basiliximab. All patients received MMF plus a bolus of corticosteroid (no maintenance steroids). Primary endpoint: eGFR (MDRD4) at Week 24. Secondary endpoints: composite efficacy failure, BCAR and AEs. Baseline characteristics were comparable. Tacrolimus trough levels were readily achieved posttransplant; initially lower in Arm 2 versus 1 with delayed initiation in Arm 3. eGFR (MDRD4) was higher in Arms 2 and 3 versus 1 (p = 0.001, p = 0.047). Kaplan–Meier estimates of composite efficacy failure‐free survival were 72.0%, 77.6%, 73.9% in Arms 1–3. BCAR incidence was significantly lower in Arm 2 versus 1 and 3 (p = 0.016, p = 0.039). AEs were comparable. Prolonged‐release tacrolimus (0.15–0.175mg/kg/day) immediately posttransplant plus basiliximab and MMF (without maintenance corticosteroids) was associated with lower tacrolimus exposure, and significantly reduced renal function impairment and BCAR incidence versus prolonged‐release tacrolimus (0.2mg/kg/day) administered immediately posttransplant. Delayed higher‐dose prolonged‐release tacrolimus initiation significantly reduced renal function impairment compared with immediate posttransplant administration, but BCAR incidence was comparable.

Steatosis occurs frequently after liver transplantation (LT). We aimed to determine the prevalence of steatosis in adult LT recipients, to determine the effects of significant (>33%; grades 2-3) steatosis on patient survival, and to identify risk factors for the development of significant steatosis and its effect on fibrosis progression. We retrospectively examined 2360 posttransplant biopsies of 548 LT recipients. Survival was compared between patients with significant steatosis and those with grades 0-1 steatosis. Patients with significant steatosis were compared to controls without steatosis (grade 0) for clinical and laboratory factors and fibrosis progression. Steatosis was found in 309 (56.4%) patients, including 93 (17.0%) patients with significant steatosis. Steatohepatitis (nonalcoholic fatty liver disease activity score 5) was diagnosed in 57 (10.4%) patients. The prevalence of steatosis increased from 30.3% at 1 year to 47.6% at 10 years after LT (P < 0.001). Survival times did not differ between groups (P 5 0.29). On multivariate analysis of pretransplant factors and initial immunosuppression (IS), alcohol-induced cirrhosis (P < 0.001) and high body mass index (BMI; P 5 0.002) were associated with the development of significant steatosis, whereas increased levels of alkaline phosphatase (P 5 0.01) and mycophenolate mofetil given initially (P 5 0.009) appeared to protect against significant steatosis. On multivariate analysis of posttransplant factors, high BMI (P < 0.001), serum triglycerides (P < 0.001), alcohol consumption (P 5 0.005), and type 2 diabetes mellitus (P 5 0.048) were associated with significant steatosis, whereas high creatinine (P 5 0.02) appeared to protect against significant steatosis. Significant steatosis was not associated with a higher fibrosis stage (P 5 0.62). Posttransplant steatosis affects 56.4% of LT recipients, and the prevalence increases with time after LT. Recipient factors and types of IS affect the risk for significant steatosis, which is not associated with a higher fibrosis stage or worse patient survival.Liver Transplantation 22 644-655 2016 AASLD.

This study was a retrospective analysis of the European Liver Transplant Registry (ELTR) performed to compare long‐term outcomes with prolonged‐release tacrolimus versus tacrolimus BD in liver transplantation (January 2008–December 2012). Clinical efficacy measures included univariate and multivariate analyses of risk factors influencing graft and patient survival at 3 years posttransplant. Efficacy measures were repeated using propensity score‐matching for baseline demographics. Patients with <1 month of follow‐up were excluded from the analyses. In total, 4367 patients (prolonged‐release tacrolimus: n = 528; BD: n = 3839) from 21 European centers were included. Tacrolimus BD treatment was significantly associated with inferior graft (risk ratio: 1.81; p = 0.001) and patient survival (risk ratio: 1.72; p = 0.004) in multivariate analyses. Similar analyses performed on the propensity score‐matched patients confirmed the significant survival advantages observed in the prolonged‐release tacrolimus‐ versus tacrolimus BD‐treated group. This large retrospective analysis from the ELTR identified significant improvements in long‐term graft and patient survival in patients treated with prolonged‐release tacrolimus versus tacrolimus BD in primary liver transplant recipients over 3 years of treatment. However, as with any retrospective registry evaluation, there are a number of limitations that should be considered when interpreting these data.