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Background. The aim of this study was to determine the long-term efficacy and safety of tacrolimus (Tac) and cyclosporine immunosuppression in pediatric liver transplantation (LTx). Methods. One hundred fifty-six patients who had taken part in a multicenter, randomized, open, parallel study of Tac and corticosteroids versus cyclosporine A microemulsion (CyA-ME), corticosteroids, and azathioprine. Patients were assessed at regular intervals up to 14 y after LTx. Analysis was conducted descriptively. Results. In a long-term follow-up, there was a similar incidence of acute rejection (Tac versus CyA-ME, 5 versus 8) and graft loss (5 versus 10). There were 11 deaths in the cohort, which were from infectious complications/malignancy in the Tac group (n = 2/5) and from chronic rejection/liver failure in the CyA-ME group (n = 3/6). A similar incidence of Epstein-Barr virus and posttransplant lymphoproliferative disease was observed (8 versus 8, 3 versus 3). However, there was a greater incidence of cosmetic adverse events in the CyA-ME cohort, with higher incidences of hypertrichosis (8 versus 27) and gum hyperplasia (20 versus 6). Growth improved equally in both groups. Overall, 81% of patients randomized to Tac remained on Tac therapy at study end, compared with 31% of patients randomized to CyA-ME. Common reasons for switching from CyA-ME included steroid-resistant/acute rejection (n = 12/8) and cosmetic changes (n = 8). Conclusions. This study is the first prospective, observational follow-up study of pediatric patients randomized to Tac and CyA-ME to evaluate long-term outcomes. Our analysis was limited by the degree of switchover between the cohorts; however, there were fewer deaths from chronic rejection/liver failure and reduced adverse events with Tac. Long-term use of Tac and Tac combination therapy appears to be safe and effective immunosuppression for pediatric LTx recipients.

Background and Aims: The European Liver Transplant Registry (ELTR) has collected data on liver transplant procedures performed in Europe since 1968. Approach and Results: Over a 50-year period (1968–2017), clinical and laboratory data were collected from 133 transplant centers and analyzed retrospectively (16,641 liver transplants in 14,515 children). Data were analyzed according to three successive periods (A, before 2000; B, 2000–2009; and C, since 2010), studying donor and graft characteristics and graft outcome. The use of living donors steadily increased from A to C (A, n = 296 [7%]; B, n = 1131 [23%]; and C, n = 1985 [39%]; p = 0.0001). Overall, the 5-year graft survival rate has improved from 65% in group A to 75% in group B (p < 0.0001) and to 79% in group C (B versus C, p < 0.0001). Graft half-life was 31 years, overall; it was 41 years for children who survived the first year after transplant. The late annual graft loss rate in teenagers is higher than that in children aged <12 years and similar to that of young adults. No evidence for accelerated graft loss after age 18 years was found. Conclusions: Pediatric liver transplantation has reached a high efficacy as a cure or treatment for severe liver disease in infants and children. Grafts that survived the first year had a half-life similar to standard human half-life. Transplantation before or after puberty may be the pivot-point for lower long-term outcome in children. Further studies are necessary to revisit some old concepts regarding transplant benefit (survival time) for small children, the role of recipient pathophysiology versus graft aging, and risk at transition to adult age.

There are limited clinical data regarding prolonged-release tacrolimus (PR-T) use in pediatric transplant recipients. This Phase 2 study assessed the efficacy and safety of PR-T in stable pediatric kidney, liver, and heart transplant recipients (aged ≥5 to ≤16 years) over 1 year following conversion from immediate-release tacrolimus (IR-T), on a 1:1 mg total-daily-dose basis. Endpoints included the incidence of acute rejection (AR), a composite endpoint of efficacy failure (death, graft loss, biopsy-confirmed AR, and unknown outcome), and safety. Tacrolimus dose and whole-blood trough levels (target 3.5–15 ng/ml) were also evaluated. Overall, 79 patients (kidney, n = 48; liver, n = 29; heart, n = 2) were assessed. Following conversion, tacrolimus dose and trough levels remained stable; however, 7.6–17.7% of patients across follow-up visits had trough levels below the target range. Two (2.5%) patients had AR, and 3 (3.8%) had efficacy failure. No graft loss or deaths were reported. No new safety signals were identified. Drug-related treatment-emergent adverse events occurred in 28 patients (35.4%); most were mild, and all resolved. This study suggests that IR-T to PR-T conversion is effective and well tolerated over 1 year in pediatric transplant recipients and highlights the importance of therapeutic drug monitoring to maintain target tacrolimus trough levels.

Hepatocellular carcinoma (HCC) in childhood differs from adult HCC because it is often associated with inherited liver disease. It is, however, unclear whether liver transplantation (LT) for HCC in childhood with or without associated inherited disease has a comparable outcome to adult HCC. On the basis of data from the European Liver Transplant Registry (ELTR), we aimed to investigate if there are differences in patient and graft survival after LT for HCC between children and adults and between patients with underlying inherited versus noninherited liver disease, respectively. We included all 175 children who underwent LT for HCC and were enrolled in ELTR between 1985 and 2012. Of these, 38 had an associated inherited liver disease. Adult HCC patients with (n=79) and without (n=316, matched by age, sex, and LT date) inherited liver disease served as an adult comparison population. We used multivariable piecewise Cox regression models with shared frailty terms (for LT center) to compare patient and graft survival between the different HCC groups. Survival analyses demonstrated a superior longterm survival of children with inherited liver disease when compared with children with HCC without inherited liver disease (hazard ratio [HR], 0.29; 95% CI, 0.10-0.90; P=0.03) and adults with HCC with inherited liver disease (HR, 0.27; 95% CI, 0.06-1.25; P=0.09). There was no survival difference between adults with and without inherited disease (HR, 1.05; 95% CI, 0.66-1.66; P=0.84). In conclusion, the potential survival advantage of children with an HCC based on inherited disease should be acknowledged when considering transplantation and prioritization for these patients. Further prospective studies accounting for tumor size and extension at LT are necessary to fully interpret our findings. Liver Transplantation 24 246-255 2018 AASLD.

As pediatric liver transplantation comes of age, experts gathered to discuss current paradigms and define gaps in knowledge warranting research to further improve patient and graft outcomes. Identified areas ripe for collaborative research include understanding the molecular and cellular mechanisms of tolerance and the role of donor-specific antibodies, considering ways to expand donor pool, minimizing long-term side effects of immunosuppression, and fine-tuning surgical techniques to minimize biliary and vascular complications. Copyright © 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.