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With advances in surgical techniques, medical management, and more equitable allocation systems, children who receive a liver transplantation (LT) today can expect remarkable outcomes early after LT. However, beyond 1 year after transplant, attrition rates have not improved. We reviewed two separate eras (Era 1: January 1995-June 2004 vs. Era 2: July 2004-March 2018) of the Society of Pediatric Liver Transplantation registry to explore the evolution and associated factors contributing to late graft loss (LGL) and late mortality (LM). The fraction of long-term pediatric LT recipients surviving after 1 year with their first graft significantly improved (81.5% in Era 1 vs. 85.7% in Era 2; p 0.0001). This improvement occurred despite significant changes in patient selection toward higher risk populations (p 0.001) and without notable improvement in perioperative complications such as hepatic artery thrombosis (p = 0.24) and early posttransplant reoperation (p = 0.94) that have historically contributed to poor late-allograft outcomes. Improved outcomes were associated with changes in patient characteristics and perioperative practices, which subsequently impacted both early post-LT complications as well as other sequalae known to contribute to adverse events in long-term pediatric LT recipients. In conclusion, despite significant changes in patient selection toward higher risk populations, and without notable improvement in several perioperative complications known to contribute to poor late-allograft outcomes, significant improvements in LGL and a trend toward improvement in LM was seen in a more contemporary cohort of children receiving an LT.

Management of unresectable pediatric hepatoblastoma (HB) and hepatocellular carcinoma (HCC) remains challenging. The Society of Pediatric Liver Transplantation (SPLIT) database was used to study survival predictors in pediatric liver transplantation (LT) for HB and HCC. Event-free survival (EFS), associated risk factors, and postoperative complications were studied in children requiring LT for HB/HCC at 16 SPLIT centers. Three-year EFS was 81% for HB (n = 157) and 62% for HCC (n = 18) transplants. Of HB transplants, 6.9% were PRETEXT II and 15.3% were POST-TEXT I/II. Tumor extent did not impact survival (p = NS). Salvage (n = 13) and primary HB transplants had similar 3-year EFS (62% versus 78%, p = NS). Among HCC transplants, 3-year EFS was poorer in older patients (38% in ≥8-year-olds vs 86%8-year-olds) and those with larger tumors (48% for those beyond versus 83% within Milan criteria, p = NS). Risk of infection (HR 1.5, 95% CI 1.1-2.2, p = .02) and renal injury (HR 2.4, 95% CI 1.7-3.3, p .001) were higher in malignant versus nonmalignant LT. Survival is favorable for pediatric HB and HCC LT, including outcomes after salvage transplant. Unexpected numbers of LTs occurred in PRE/POST-TEXT I/II tumors. Judicious patient selection is critical to distinguish tumors that are potentially resectable; simultaneously, we must advocate for patients with unresectable malignancies to receive organs.

Liver allocation was updated on February 4, 2020, replacing a Donor Service Area (DSA) with acuity circles (AC). The impact on waitlist outcomes for patients listed for combined liver-intestine transplantation (multivisceral transplantation [MVT]) remains unknown. The Organ Procurement and Transplantation Network/United Network for Organ Sharing database was used to identify all candidates listed for both liver and intestine between January 1, 2018 and March 5, 2021. Two eras were defined: pre-AC (2018–2020) and post-AC (2020–2021). Outcomes included 90-day waitlist mortality and transplant probability. A total of 127 adult and 104 pediatric MVT listings were identified. In adults, the 90-day waitlist mortality was not statistically significantly different, but transplant probability was lower post-AC. After risk-adjustment, post-AC was associated with a higher albeit not statistically significantly different mortality hazard (sub-distribution hazard ratio[sHR]: 8.45, 95% CI: 0.96–74.05; p = .054), but a significantly lower transplant probability (sHR: 0.33, 95% CI: 0.15–0.75; p = .008). For pediatric patients, waitlist mortality and transplant probability were similar between eras. The proportion of patients who underwent transplant with exception points was lower post-AC both in adult (44% to 9%; p = .04) and pediatric recipients (65% to 15%; p = .002). A lower transplant probability observed in adults listed for MVT may ultimately result in increased waitlist mortality. Efforts should be taken to ensure equitable organ allocation in this vulnerable patient population.

The SRTR maintains the liver-simulated allocation model (LSAM), a tool for estimating the impact of changes to liver allocation policy. Integral to LSAM is a model that predicts the decision to accept or decline a liver for transplant. LSAM implicitly assumes these decisions are made identically for adult and pediatric liver transplant (LT) candidates, which has not been previously validated. We applied LSAM's decision-making models to SRTR offer data from 2013 to 2016 to determine its efficacy for adult (≥18) and pediatric (

Background and aims Tolerance is transplantation's holy grail, as it denotes allograft health without immunosuppression and its toxicities. Our aim was to determine, among stable long-term pediatric liver transplant recipients, the efficacy and safety of immunosuppression withdrawal to identify operational tolerance. Approach and results We conducted a multicenter, single-arm trial of immunosuppression withdrawal over 36-48 weeks. Liver tests were monitored biweekly (year 1), monthly (year 2), and bimonthly (years 3-4). For-cause biopsies were done at investigators' discretion but mandated when alanine aminotransferase or gamma glutamyltransferase exceeded 100 U/L. All subjects underwent final liver biopsy at trial end. The primary efficacy endpoint was operational tolerance, defined by strict biochemical and histological criteria 1 year after stopping immunosuppression. Among 88 subjects (median age 11 years; 39 boys; 57 deceased donor grafts), 33 (37.5%; 95% confidence interval [CI] 27.4%, 48.5%) were operationally tolerant, 16 were nontolerant by histology (met biochemical but failed histological criteria), and 39 were nontolerant by rejection. Rejection, predicted by subtle liver inflammation in trial entry biopsies, typically (n = 32) occurred at ≤32% of the trial-entry immunosuppression dose and was treated with corticosteroids (n = 32) and/or tacrolimus (n = 38) with resolution (liver tests within 1.5 times the baseline) for all but 1 subject. No death, graft loss, or chronic, severe, or refractory rejection occurred. Neither fibrosis stage nor the expression level of a rejection gene set increased over 4 years for either tolerant or nontolerant subjects. Conclusions Immunosuppression withdrawal showed that 37.5% of selected pediatric liver-transplant recipients were operationally tolerant. Allograft histology did not deteriorate for either tolerant or nontolerant subjects. The timing and reversibility of failed withdrawal justifies future trials exploring the efficacy, safety, and potential benefits of immunosuppression minimization.

Biliary atresia (BA) is the leading indication to perform a pediatric liver transplantation (LT). Timely hepatoportoenterostomy (HPE) attempts to interrupt the natural history and allow for enteric bile flow; however, most patients who are treated with HPE require LT by the age of 10 years. We determined the cost-effectiveness of foregoing HPE to perform primary LT (pLT) in children with BA compared with standard-of-care HPE management. A Markov model was developed to simulate BA treatment over 10 years. Costs were measured in 2018 US dollars and effectiveness in life-years (LYs). The primary outcome was incremental cost-effectiveness ratio (ICER) between treatments. Model parameters were derived from the literature. In the base model, we assumed similar LT outcomes after HPE and pLT. Sensitivity analyses on all model parameters were performed, including a scenario in which pLT led to 100% patient and graft survival after LT. Children undergoing HPE accumulated $316,692 in costs and 8.17 LYs per patient. Children undergoing pLT accumulated $458,059 in costs and 8.24 LYs per patient, costing $1,869,164 per LY gained compared with HPE. With parameter variation over plausible ranges, only post-HPE and post-LT costs reduced the ICER below a typical threshold of $100,000 per LY gained. On probabilistic sensitivity analysis, 93% of iterations favored HPE at that threshold. With 100% patient and graft survival after pLT, pLT cost $283,478 per LY gained. HPE is more economically favorable than pLT for BA. pLT is unfavorable even with no graft or patient loss. The ability to predict those patients who may experience high costs after HPE or low costs after LT may help identify those patients for whom pLT could be considered.

Metabolic liver diseases (MLDs) are a heterogeneous group of inherited conditions for which liver transplantation can provide definitive treatment. The limited availability of deceased donor organs means some who could benefit from transplant do not have this option. Living related liver transplant (LrLT) using relatives as donors has emerged as one solution to this problem. This technique is established worldwide, especially in Asian countries, with shorter waiting times and patient and graft survival rates equivalent to deceased donor liver transplantation. However, living donors are underutilized for MLDs in many western countries, possibly due to the fear of limited efficacy using heterozygous donors. We have reviewed the published literature and shown that the use of heterozygous donors for liver transplantation is safe for the majority of MLDs with excellent metabolic correction. The use of LrLT should be encouraged to complement deceased donor liver transplantation (DDLT) for treatment of MLDs.

Over the past three decades, we studied 184 individuals with 174 different molecular variants of branched-chain α-ketoacid dehydrogenase activity, and here delineate essential clinical and biochemical aspects of the maple syrup urine disease (MSUD) phenotype. We collected data about treatment, survival, hospitalization, metabolic control, and liver transplantation from patients with classic (i.e., severe; n = 176), intermediate (n = 6) and intermittent (n = 2) forms of MSUD. A total of 13,589 amino acid profiles were used to analyze leucine tolerance, amino acid homeostasis, estimated cerebral amino acid uptake, quantitative responses to anabolic therapy, and metabolic control after liver transplantation. Standard instruments were used to measure neuropsychiatric outcomes. Despite advances in clinical care, classic MSUD remains a morbid and potentially fatal disorder. Stringent dietary therapy maintains metabolic variables within acceptable limits but is challenging to implement, fails to restore appropriate concentration relationships among circulating amino acids, and does not fully prevent cognitive and psychiatric disabilities. Liver transplantation eliminates the need for a prescription diet and safeguards patients from life-threatening metabolic crises, but is associated with predictable morbidities and does not reverse pre-existing neurological sequelae. There is a critical unmet need for safe and effective disease-modifying therapies for MSUD which can be implemented early in life. The biochemistry and physiology of MSUD and its response to liver transplantation afford key insights into the design of new therapies based on gene replacement or editing.

Most surgeons from high-income countries who work in global surgery will do so through partnerships between their institutions and institutions in low- and middle-income countries (LMICs). In this article, the American Surgical Association Working Group for Global Surgery lays out recommendations for criteria that contribute to equitable, sustainable, and effective partnerships. These include ethically engaging with the LMIC partner institution by putting its interests first and by proactively seeking to be aware of cultural issues. Formally structuring the partnership with a memorandum of understanding and clearly designating leaders at both institutions are important criteria for assuring long-term sustainability. Needs assessments can be done using existing methods, such as those established for development of national surgical, obstetric, and anesthesia plans. Such assessments help to identify opportunities for partnerships to be most effective in addressing the biggest surgical needs in the LMIC. Examples of successful high-income countries-LMIC partnerships are provided.

The aim of the study was to analyze the long-term outcomes of transplants utilizing ITx donors1 year and to compare these results with older donors.Between January 2007 and December 2019, the primary ITx donors in the Children's Hospital of Pittsburgh of UPMC were retrospectively reviewed. Short- and long-term outcomes of recipients receiving a deceased donor organ from donors1 year were compared with those found in all other recipients.During the study period, there were 89 primary ITx donors, using 30 donors (33.7%) aged1 year. The mean age of their recipients was 1.6 ± 0.7 (0.7-3.2) years. The 30 graft types were isolated intestine (n = 3, 10.0%), liver bowel (n = 20, 66.7%), and multivisceral (n = 7, 23.3%). Technical complications occurred in 12 (40.0%) recipients. Candidates transplanted with intestine allografts from donors1 year of age had shorter wait times (p .001), more liver-inclusive grafts (p .001), and less donor-specific antibodies (DSA) (p = .014). During follow-up, the recipients had less graft loss (p = .018), and more remained alive with graft in place (p = .011). Among children transplanted with such donors, 3-year and graft survival rates were 86.7% and 82.9% compared to 62.8% and 49.9% in the cohort of donors1 year (p = .032 and .011).Donor age1 year was associated with improved graft survival. Optimal utilization of this population for toddler candidates would increase intestine availability, reduce time to transplantation, and potentially improve long-term outcome.

Sarcopenia has been associated with poor surgical outcomes but has not been studied in pediatric intestinal transplantation. We aimed to determine sarcopenia prevalence in intestinal transplant recipients and the association of sarcopenia with outcomes.We performed a cross-sectional retrospective chart review of intestinal transplant recipients from 2000-present. We estimated total psoas muscle area (tPMA) at L3-L4 and L4-L5 from computed tomography scans prior to or in the immediate peri-operative period. Sarcopenia was defined by tPMA below the 5Of the 56 intestinal transplant recipients included, 36 (64%) were sarcopenic. Graft survival was 79% at one year and 59% at five years. Overall patient survival was 86% at one year and 76% at five years. Peri-transplant sarcopenia was associated with improved graft survival (Hazard ratio 0.42, 95% confidence interval: 0.20-0.88) but not overall survival (Hazard ratio 0.47, 95% confidence interval: 0.19-1.20).In this first report of sarcopenia in pediatric intestinal transplant, we found a high sarcopenia prevalence without an association with worse outcomes. The potential improved graft survival in sarcopenic patients along with underlying mechanisms warrant further exploration.

Background: Neuroendocrine tumors (NET) have an increasing incidence and are characterized by an invasive and metastatic presentation, rendering a curative resection not always feasible. For some patients the only lifesaving option would be a multivisceral transplantation (MvTx). This systematic review aims to summarize the reported experience on combined liver-intestinal and MvTx for NET according PRISMA-guidelines.Methods: PubMed, EMBASE and Cochrane Controlled Trial Reports were searched until April 7, 2020. Structured data abstraction was performed, and methodological quality assessed.Results: Fourteen single-center and three multicenter retrospective studies reported on 1 combined liver intestinal and 38 MvTx for NET. Nine previously unreported MvTx were added to the analysis. This review found that: i) overall patient survival of 51.2% is attainable; ii) recurrence of 35% is similar to recurrence after liver transplantation for NET; and iii) NET with diffuse abdominal presentation, normally considered a contraindication, could actually benefit from radical resection and MvTx. Data on tailoring of immunosuppression and (neo-)adjuvant treatment are limited, and further studies are needed to optimize post-transplant management. Conclusions: Although results are encouraging, the reported MvTx experience for NET is limited and requires more detailed prospective multicenter studies and appropriate follow-up and reporting.

Background Split liver transplantation (SLT) is a strategy to address organ shortage, but is a technically more demanding procedure than whole graft liver transplantation (LT). We aimed to determine the outcomes following SLT in adult recipients as well as to highlight the impact that having a pediatric LT program has on SLT implementation. Methods All SLTs conducted at a single-center from 2010 to 2019 were identified. Patient data was obtained through retrospective review of the electronic medical record. Kaplan-Meier analysis assessed primary outcomes of 1-,3-, and 5-year graft and patient survival. Results We identified 37 SLTs performed at our institution from 2010 to 2019. Twenty-four donated livers resulted in 21 extended right lobes and 16 left lateral segments for adults and pediatrics recipients, respectively. Eighty-one percent (30/37) of the SLTs were performed after introduction of the combined pediatric program in 2016. 13/24 donor livers were split with both grafts allocated and used at our institution and 92% occurred after introduction of the pediatric program. Graft survival rates at 1-, 3-, and 5-years were 94% in adult recipients and 100% for all time periods in pediatric recipients. Actuarial post-transplant patient survival was 100% at 1-, 3-, and 5-years in both. Conclusions The introduction of a pediatric liver transplantation program resulted in more than a fourfold increase in the number of SLTs performed at our center. Increase in allocation and use of both grafts at our institution was also seen.

BACKGROUND: Domino liver transplantation aims to address the need to increase the liver donor supply. In a domino liver transplant, the domino recipient receives the explanted liver from the recipient of a traditional liver transplant. The domino donor typically requires liver transplant to correct a metabolic disorder; the explanted liver thus has a single gene defect but otherwise normal structure and function. METHODS: In this review, we detail the history of domino liver transplantation, appropriate domino donor indications, the technical advances to the surgical approach, current outcomes, and future opportunities. RESULTS: Development of de novo disease in the domino recipient has relegated adult domino liver transplant to be considered a source of marginal donor livers. However, pediatric domino liver transplant has leveraged certain metabolic disorders, especially maple syrup urine disease, in which the liver enzyme deficiency can be compensated by the systemic presence of sufficient enzyme. Advances in the surgical aspects of assuring adequate length of vasculature have improved the safety of the procedure in both domino donors and recipients. CONCLUSIONS: Pediatric domino liver transplant utilizing domino donors with specific metabolic liver diseases should be considered a viable live donor option for children awaiting liver transplant.

Background Progressive familial intrahepatic cholestasis type 1 (PFIC1) arises from biallelic variants in the ATP8B1 gene that annul FIC1 activity, resulting in progressive liver disease. Liver transplant (LT) is indicated in refractory disease; however, post-LT complications including worsening diarrhea and steatohepatitis progressing to fibrosis with graft loss have been reported. We aim to describe long-term outcomes of PFIC1 LT recipients at our center, focusing on the histological changes of the allografts. Methods We assessed 7 PFIC1 patients post-LT at the Children's Hospital of Pittsburgh (CHP). All pre-transplant, explant, and sequential post-transplant pathology samples were reviewed. Continuous data are presented as the mean ± SD. We compared the pre- and post-transplant height and weight z-scores using Wilcoxon signed-rank test. Results Seven (29% male) patients with PFIC1 received a LT (n = 6) or had post-LT care (n = 1) at CHP. Six had confirmed or suspected identical genetic. At a mean follow-up of 10.9 years, both patient survival and graft survival were 100%. Diarrhea persisted (n = 3) or newly developed (n = 4) in all patients after LT contributing to ongoing growth failure, with mean z-scores -2.63 (weight) and -2.98 (height) at follow-up. Histologically, allograft steatosis was common but was not accompanied by significant inflammation, ballooning, or fibrosis. Conclusion We show that extrahepatic disease persists and near-universal allograft steatosis occurs. However, at a mean follow-up period of over 10 years, no patients developed steatohepatitis or significant fibrosis, and both patient survival and graft survival are excellent.

The goal of this work was to examine the change in health-related quality of life (HRQOL) and cognitive functioning from early childhood to adolescence in pediatric liver transplantation (LT) recipients. Patients were recruited from 8 North American centers through the Studies of Pediatric Liver Transplantation consortium. A total of 79 participants, ages 11-18 years, previously tested at age 5-6 years in the Functional Outcomes Group study were identified as surviving most recent LT by 2 years and in stable medical follow-up. The Pediatric Quality of Life 4.0 Generic Core Scale, Pediatric Quality of Life Cognitive Function Scale, and PROMIS Pediatric Cognitive Function tool were distributed to families electronically. Data were analyzed using repeated measures and paired t tests. Predictive variables were analyzed using univariate regression analysis. Of the 69 families contacted, 65 (94.2%) parents and 61 (88.4%) children completed surveys. Median age of participants was 16.1 years (range, 12.9-18.0 years), 55.4% were female, 33.8% were nonwhite, and 84.0% of primary caregivers had received at least some college education. Median age at LT was 1.1 years (range, 0.1-4.8 years). The majority of participants (86.2%) were not hospitalized in the last year. According to parents, adolescents had worse HRQOL and cognitive functioning compared with healthy children in all domains. Adolescents reported HRQOL similar to healthy children in all domains except psychosocial, school, and cognitive functioning (P = 0.02; P 0.001; P = 0.04). Participants showed no improvement in HRQOL or cognitive functioning over time. For cognitive and school functioning, 60.0% and 50.8% of parents reported "poor" functioning, respectively (1 standard deviation below the healthy mean). Deficits in HRQOL seem to persist in adolescence. Over half of adolescent LT recipients appear to be at risk for poor school and cognitive functioning, likely reflecting attention and executive function deficits.

Purpose of review Pediatric transplantation faces unique challenges in implementing dynamic quality improvement measures because of proportionally smaller volumes compared to adults, logistics of being integrated successfully within larger or complex hospital systems, lack of adult-affiliated transplant centers, varying focus in prioritization of relevant outcome metrics, and potential lack of sufficient resources. Recent findings To address these challenges, multiinstitutional collaborations have developed which have proven increasingly effective in driving awareness and quality improvement measures to supplement regulatory efforts in the pediatric population. Relevant work from the Pediatric Heart Transplant Society and Studies in Pediatric Liver Transplantation will be highlighted. The introduction of learning networks such as the Improving Renal Outcomes Collaborative and the Starzl Network for Excellence in Pediatric Transplantation have further focused on continuous learning initiatives in renal and liver transplantation using collaboration and patient informed measures. Summary Optimal transplant performance improvement is fully integrated into health delivery at all points of the patient pathway. Progress in performance improvement will require ongoing integration of big data solutions, improved patient engagement and technology solutions. VIDEO ABSTRACT:.

Objective Learning health systems (LHS) integrate research, improvement, management, and patient care, such that every child receives "the right care at the right time...every time," that is, evidence-based, personalized medicine. Here, we report our efforts to establish a sustainable, productive, multicenter LHS focused on pediatric liver transplantation. Methods The Starzl Network for Excellence in Pediatric Transplantation (SNEPT) is the first multicenter effort by pediatric liver transplant families and providers to develop shared priorities and a shared agenda for innovation in clinical care. This report outlines SNEPT's structure, accomplishments, and challenges as an LHS. Results We prioritized 4 initial projects: immunosuppression, perioperative anticoagulation, quality of life, and transition of care. We shared center protocols/management to identify areas of practice variability between centers. We prioritized actionable items that address barriers to providing "the right care at the right time" to every pediatric liver transplant recipient: facilitating transparency of practice variation and the connection of practices to patient outcomes, harnessing existing datasets to reduce the burden of tracking outcomes, incorporating patient-reported outcomes into outcome metrics, and accelerating the implementation of knowledge into clinical practice. This has allowed us to strengthen collaborative relationships, design quality improvement projects, and collect pilot data for each of our priority projects. Conclusions The field of pediatric liver transplantation can be advanced through application of LHS principles. Going forward, SNEPT will continue to unite patient advocacy, big data, technology, and transplant thought leaders to deliver the best care, while developing new, scalable solutions to pediatric transplantation's most challenging problems.

A central pathology or site reading of biopsy slides is used in liver transplant clinical trials to determine rejection. We evaluated interrater reliability of readings of "rejection or not" using digitized slides from the Medication Adherence in Children who had a Liver Transplant (MALT) study. Four masked experienced pathologists read the digitized slides and then reread them after a study-specific histologic endpoint development program. Agreement was expressed throughout as a Kappa or Fleiss Kappa statistic (ҡ). A ҡ>0.6 was predefined as desirable. Readings were correlated with immunosuppressant adherence (the Medication Level Variability Index, [MLVI]), and maximal liver enzyme levels during the study period. Interrater agreement between site and central review in MALT, and between 4 pathologists later on, was low (ҡ=0.44, Fleiss ҡ=0.41, respectively). Following the endpoint development program, agreement improved and became acceptable (ҡ=0.71). The final reading was better-aligned with maximal gamma-glutamyl transferase levels and MLVI as compared with the original central reading. We found substantial disagreement between experienced pathologists reading the same slides. A unique study-specific procedure improved interrater reliability to the point it was acceptable. Such a procedure may be indicated to increase reliability of histopathologic determinations in future research, and perhaps also clinically.

Liver transplantation is a successful option for inherited metabolic disease yet little is published on the outcome among siblings. We report outcomes of siblings who have undergone liver transplantation for metabolic disease in a single program. Seventy-one siblings (35 males) from 33 individual families underwent liver transplantation since 1982. Outcomes were compared over three consecutive eras. Twenty-eight families had two siblings, four had three siblings, and one had four siblings. In half of families where dates of listing were known, siblings were listed simultaneously. Mean (SD) age at listing for the oldest and second sibling was 13.2 (7.1) and 9.8 (5.7) years, respectively (p < .01). In 18/33 families, the oldest sibling underwent transplantation first. Mean (SD) age at transplant fell from the oldest to second sibling from 12.9 (7.2) to 9.5 (6.3) years, respectively (p < .001). Ten-year patient survival was 83.5% which improved over the eras: era 1 (1982-1994) 65.0%, era 2 (1995-2007) 87.5%, and era 3 (2008-2019) 93.8%: p < .03. Sex, age at transplant, order of transplant, and presence of structural liver disease did not significantly impact survival. When siblings undergo liver transplant for inherited metabolic disease, later siblings are listed and transplanted at a significantly younger age.

BACKGROUND In December 2018, United Network for Organ Sharing approved an allocation scheme based on recipients' geographic distance from a deceased donor (acuity circles [ACs]). Previous analyses suggested that ACs would reduce waitlist mortality overall, but their impact on pediatric subgroups was not considered. METHODS We applied Scientific Registry of Transplant Recipients data from 2011 to 2016 toward the Liver Simulated Allocation Model to compare outcomes by age and illness severity for the United Network for Organ Sharing-approved AC and the existing donor service area-/region-based allocation schemes. Means from each allocation scheme were compared using matched-pairs t tests. RESULTS During a 3-year period, AC allocation is projected to decrease waitlist deaths in infants (39 versus 55; P < 0.001), children (32 versus 50; P < 0.001), and teenagers (15 versus 25; P < 0.001). AC allocation would increase the number of transplants in infants (707 versus 560; P < 0.001), children (677 versus 547; P < 0.001), and teenagers (404 versus 248; P < 0.001). AC allocation led to decreased median pediatric end-stage liver disease/model for end-stage liver disease at transplant for infants (29 versus 30; P = 0.01), children (26 versus 29; P < 0.001), and teenagers (26 versus 31; P < 0.001). Additionally, AC allocation would lead to fewer transplants in status 1B in children (97 versus 103; P = 0.006) but not infants or teenagers. With AC allocation, 77% of pediatric donor organs would be allocated to pediatric candidates, compared to only 46% in donor service area-/region-based allocation (P < 0.001). CONCLUSIONS AC allocation will likely address disparities for pediatric liver transplant candidates and recipients by increasing transplants and decreasing waitlist mortality. It is more consistent with federally mandated requirements for organ allocation.

OBJECTIVES Neurologic complications occur in up to 40% of adult abdominal solid organ transplant recipients and are associated with increased mortality. Comparable pediatric data are sparse. This study describes the occurrence of neurologic and behavioral complications (neurobehavioral complications) in pediatric abdominal solid organ transplant recipients. We examine the association of these complications with length of stay, mortality, and tacrolimus levels. DESIGN The electronic health record was interrogated for inpatient readmissions of pediatric abdominal solid organ transplant recipients from 2009 to 2017. A computable composite definition of neurobehavioral complication, defined using structured electronic data for neurologic and/or behavioral phenotypes, was created. SETTING Quaternary children's hospital with an active transplant program. PATIENTS Pediatric abdominal solid organ transplant recipients. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Computable phenotypes demonstrated a specificity 98.7% and sensitivity of 63.0% for identifying neurobehavioral complications. There were 1,542 readmissions among 318 patients, with 65 (20.4%) having at least one admission with a neurobehavioral complication (total 109 admissions). Median time from transplant to admission with neurobehavioral complication was 1.2 years (interquartile range, 0.52-2.28 yr). Compared to encounters without an identified neurobehavioral complication, encounters with a neurobehavioral complication were more likely to experience ICU admission (odds ratio, 3.9; 2.41-6.64; p < 0.001), have longer ICU length of stay (median 10.3 vs 2.2 d; p < 0.001) and hospital length of stay (8.9 vs 4.3 d; p < 0.001), and demonstrate higher maximum tacrolimus level (12.3 vs 9.8 ng/mL; p = 0.001). Patients with a neurobehavioral complication admission were more likely to die (odds ratio, 5.04; 1.49-17.09; p = 0.009). In a multivariable analysis, type of transplant, ICU admission, and tacrolimus levels were independently associated with the presence of a neurobehavioral complication. CONCLUSIONS Common electronic health record variables can be used to accurately identify neurobehavioral complications in the pediatric abdominal solid organ transplant population. Late neurobehavioral complications are associated with increased hospital resource utilization, mortality, and tacrolimus exposure. Additional studies are required to delineate the relationship between maximum tacrolimus level and neurobehavioral complications to guide therapeutic drug monitoring and dosing.

There is an unacceptably high burden of death and disability from conditions that are treatable by surgery, worldwide and especially in low- and middle-income countries (LMICs). The major actions to improve this situation need to be taken by the surgical communities, institutions, and governments of the LMICs. The US surgical community, including the US academic surgical community, has, however, important roles to play in addressing this problem. The American Surgical Association convened a Working Group to address how US academic surgery can most effectively decrease the burden from surgically treatable conditions in LMICs. The Working Group believes that the task will be most successful (1) if the epidemiologic pattern in a given country is taken into account by focusing on those surgically treatable conditions with the highest burdens; (2) if emphasis is placed on those surgical services that are most cost-effective and most feasible to scale up; and (3) if efforts are harmonized with local priorities and with existing global initiatives, such as the World Health Assembly with its 2015 resolution on essential surgery. This consensus statement gives recommendations on how to achieve those goals through the tools of academic surgery: clinical care, training and capacity building, research, and advocacy. Through all of these, the ethical principles of maximally and transparently engaging with and deferring to the interests and needs of local surgeons and their patients are of paramount importance. Notable benefits accrue to US surgeons, trainees, and institutions that engage in global surgical activities.

Propionic acidemia (PA) and methylmalonic acidemia (MMA) comprise the most common organic acidemias and account for profound morbidity in affected individuals. Although liver transplantation (LT) has emerged as a bulk enzyme-replacement strategy to stabilize metabolically fragile patients, it is not a metabolic cure because patients remain at risk for disease-related complications. We retrospectively studied LT and/or liver-kidney transplant in 9 patients with PA or MMA with additional focus on the optimization of metabolic control and management in the perioperative period. Metabolic crises were common before transplant. By implementing a strategy of carbohydrate minimization with gradual but early lipid and protein introduction, lactate levels significantly improved over the perioperative period (P < 0.001). Posttransplant metabolic improvement is demonstrated by improvements in serum glycine levels (for PA; P < 0.001 × 10-14 ), methylmalonic acid levels (for MMA; P < 0.001), and ammonia levels (for PA and MMA; P < 0.001). Dietary restriction remained after transplant. However, no further metabolic crises have occurred. Other disease-specific comorbidities such as renal dysfunction and cardiomyopathy stabilized and improved. In conclusion, transplant can provide a strategy for altering the natural history of PA and MMA providing stability to a rare but metabolically brittle population. Nutritional management is critical to optimize patient outcomes.

Transplantation of the intestine in children has presented significant challenges even as it has become a standard to treat nutritional failure due to short gut syndrome. These challenges have been addressed in part by significant improvements in short and long-term care. Noteworthy enhancements include reduced need for intestine transplantation, drug-sparing immunosuppressive regimens, immune monitoring, and improved surveillance and management of PTLD and non-adherence.

PURPOSE OF REVIEW The field of intestinal transplantation has shown significant growth and has become the gold standard therapy for patients that suffer from the complications of total parenteral nutrition due to irreversible intestinal failure. In the early years of intestinal transplant, retransplantation was associated with extremely high morbidity and mortality. The purpose of this review is to summarize recent encouraging reports, showing significant improvement in outcomes after intestinal retransplantation. RECENT FINDINGS Recent studies at large volume centers have reported significant progress in patient and graft survival after intestinal retransplantation. Recent literature described the most common indications for retransplantation, surgical techniques, timing of graft enterectomy, immunologic monitoring, and complications. Improvement in outcomes due to advances in immunosuppression management and the importance of liver-containing grafts are also described. SUMMARY Improving early to midterm patient and graft survival has made consideration for intestinal retransplantation even more necessary. Current clinical evidence supports the benefit of intestinal retransplantation in well selected recipients. Initial immunosuppression protocols, technical modifications, proper timing of enterectomy, and improved infectious disease monitoring have contributed to improved outcomes.

OBJECTIVES: To assess outcomes following liver transplantation for maple syrup urine disease by determining attainment and sustainability of metabolic control and apply an “ideal” outcome composite in long-term survivors. STUDY DESIGN: A single center, retrospective review collected clinical data including branched-chain amino acid (leucine, isoleucine, and valine) levels following liver transplant and determined achievement of an ideal long-term outcome profile of a first allograft stable on immunosuppression monotherapy, normal growth, and absence of common transplant-related sequelae. RESULTS: Of 77 patients meeting inclusion criteria identified, 23 were long-term (≥10-year) survivors and were additionally assessed for ideal outcome attainment. Patient and graft survival were 100% and 99%, respectively, and all patients were on an unrestricted protein intake diet. Although significant variation was noted in mean isoleucine (P < .01) and leucine (P < .05) levels postliver transplantation, no difference was seen in valine (P = .29) and overall clinical impact was likely negligible as metabolic stability was achieved and sustained beyond 3 years postliver transplantation and no metabolic crises were identified. Of 23 long-term survivors with available data, 9 (39%) achieved all composite metrics determined to define “ideal” outcomes in pediatric postliver transplantation populations. CONCLUSIONS: Liver transplant enables long-term metabolic stability for patients with maple syrup urine disease. A combination of experience and improvement in both pre- and postliver transplantation care has enabled excellent survival and minimal comorbidities following transplant.

A tenth of all pediatric liver transplantations (LTs) are performed for unresectable liver malignancies, especially the more common hepatoblastoma (HBL). Less understood are outcomes after LT for the rare hepatocellular carcinoma, nonhepatoblastoma embryonal tumors (EMBs), and slow growing metastatic neuroendocrine tumors of childhood. Pediatric LT is increasingly performed for rare unresectable liver malignancies other than HBL. We performed a retrospective review of outcomes after LT for malignancy in the multicenter US Scientific Registry of Transplant Recipients (SRTR; n = 677; 1987-2015). We then reviewed the Children's Hospital of Pittsburgh (CHP; n = 74; 1981-2014) experience focusing on LT for unresectable hepatocellular cancer (HCC), EMBs, and metastatic liver tumors (METS). HBL was included to provide reference statistics. In the SRTR database, LT for HCC and HBL increased over time (P

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.

The field of intestinal transplantation has experienced dramatic growth since the first reported cases 3 decades ago. Improvements in operative technique, donor assessment and immunosuppressive protocols have afforded children who suffer from life-threatening complications of intestinal failure a chance at long-term survival. As experience has grown, newer diseases, with more systemic manifestations have arisen as potential indications for transplant. After discussing the historical developments of intestinal transplant as a backdrop, this review focuses on the specific pre-operative indications for transplant as well as the great success that intestinal rehabilitation has witnessed over the past decade. A detailed discussion of evolution of immunosuppressive strategies is followed a general review of the common infectious complications experienced by children after intestinal transplant as well as the current long- and short-term results, including a section on new research on the quality of life in this challenging population of patients.

Background & Aims Hepatocyte transplantation partially corrects genetic disorders and has been associated anecdotally with reversal of acute liver failure. Monitoring for graft function and rejection has been difficult, and has contributed to limited graft survival. Here we aimed to use preparative liver-directed radiation therapy, and continuous monitoring for possible rejection in an attempt to overcome these limitations. Methods Preparative hepatic irradiation was examined in non-human primates as a strategy to improve engraftment of donor hepatocytes, and was then applied in human subjects. T cell immune monitoring was also examined in human subjects to assess adequacy of immunosuppression. Results Porcine hepatocyte transplants engrafted and expanded to comprise up to 15% of irradiated segments in immunosuppressed monkeys preconditioned with 10Gy liver-directed irradiation. Two patients with urea cycle deficiencies had early graft loss following hepatocyte transplantation; retrospective immune monitoring suggested the need for additional immunosuppression. Preparative radiation, anti-lymphocyte induction, and frequent immune monitoring were instituted for hepatocyte transplantation in a 27year old female with classical phenylketonuria. Post-transplant liver biopsies demonstrated multiple small clusters of transplanted cells, multiple mitoses, and Ki67 + hepatocytes. Mean peripheral blood phenylalanine (PHE) level fell from pre-transplant levels of 1343±48μM (normal 30–119μM) to 854±25μM (treatment goal ≤360μM) after transplant (36% decrease; p Conclusions Radiation preconditioning and serial rejection risk assessment may produce better engraftment and long-term survival of transplanted hepatocytes. Hepatocyte xenografts engraft for a period of months in non-human primates and may provide effective therapy for patients with acute liver failure. Lay summary Hepatocyte transplantation can potentially be used to treat genetic liver disorders but its application in clinical practice has been impeded by inefficient hepatocyte engraftment and the inability to monitor rejection of transplanted liver cells. In this study, we first show in non-human primates that pretreatment of the host liver with radiation improves the engraftment of transplanted liver cells. We then used this knowledge in a series of clinical hepatocyte transplants in patients with genetic liver disorders to show that radiation pretreatment and rejection risk monitoring are safe and, if optimized, could improve engraftment and long-term survival of transplanted hepatocytes in patients.

Familial intrahepatic cholestasis 1 (FIC1) deficiency is caused by a mutation in the ATP8B1 gene. Partial external biliary diversion (PEBD) is pursued to improve pruritus and arrest disease progression. Our aim is to describe clinical variability after PEBD in FIC1 disease.We performed a single-center, retrospective review of genetically confirmed FIC1 deficient patients who received PEBD. Clinical outcomes after PEBD were cholestasis, pruritus, fat-soluble vitamin supplementation, growth, and markers of disease progression that included splenomegaly and aspartate aminotransferase-to-platelet ratio index.Eight patients with FIC1 disease and PEBD were included. Mean follow-up was 32 months (range 15-65 months). After PEBD, total bilirubin was2 mg/dL in all patients at 8 months after surgery, but 7 of 8 subsequently experienced a total of 15 recurrent cholestatic events. Subjective assessments of pruritus demonstrated improvement, but itching exacerbation occurred during cholestatic episodes. High-dose fat-soluble vitamin supplementation persisted, with increases needed during cholestatic episodes. Weight z scores improved (-3.4 to -1.65, P 0.01). Splenomegaly did not worsen or develop and 1 patient developed an aminotransferase-to-platelet ratio index score of0.7 suggesting development of fibrosis 24 months after PEBD.Clinical variability is evident among genetically defined FIC1 deficient patients after PEBD, even among those with identical mutations. Recurrent, self-limited episodes of cholestasis and pruritus are reminiscent of the benign recurrent intrahepatic cholestasis phenotype. Despite diversion of bile from the intestinal lumen, weight gain improved while fat-soluble vitamin requirements persisted. Significant progression of liver disease was not evident during follow-up.

Background AKI after pediatric liver transplantation is associated with increased morbidity and mortality. The role of urinary biomarkers for the prediction of AKI in pediatric patients after liver transplantation has not been previously reported. The primary objective of this prospective pilot study was to determine the predictive capabilities of urinary KIM-1, NGAL, TIMP-2, and IGFBP7 for diagnosing AKI. Methods Sixteen children undergoing liver transplantation were enrolled in the study over a 19-month time period. The Kidney Disease Improving Outcomes criteria for urine output and serum creatinine were used to define AKI. Predictive ability was evaluated using the area under the curve obtained by ROC analysis. Results AKI occurred in 6 (37.5%) of the patients between 2 and 4 days after transplant. There were no differences in any of the biomarkers prior to transplant. When obtained within 6 hours after transplant, the area under the ROC curve for predicting AKI was 0.758 (95% CI: 0.458-1.00) for KIM-1, 0.900 (95% CI: 0.724-1.00) for NGAL, and 0.933 (95% CI: 0.812-1.00) for the product of TIMP-2 and IGFBP7 ([TIMP-2]·[IGFBP7]). Conclusions Our results show that both NGAL and [TIMP-2]·[IGFBP7] provide significant discrimination for AKI risk following liver transplant in children. Larger studies are needed to determine the optimal time point for measuring these biomarkers and to validate our findings.

Aim/background Domino liver transplantation (DLT) using liver allografts from patients with metabolic disorders enhances organ utilization. Short- and long-term course and outcome of these patients can impact the decision to offer this procedure to patients, especially those with diseases that can potentially be cured with liver transplant. We reviewed the outcomes of DLT from maple syrup urine disease (MSUD) patients in our large academic pediatric and adult transplant program. Methods All patients receiving DLT were analyzed retrospectively with a minimum of one-year follow-up period for patient and donor characteristics, early and late postoperative complications and patient and graft survival with their MSUD donors in terms of age, weight, MELD/PELD scores, cold ischemia time, postoperative leucine levels, and peak ALT (alanine aminotransferase) levels during the first 48 postoperative hours. Results Between 2006 and May 2019, 21 patients underwent domino liver transplantation with live donor allografts from MSUD patients. Four patients transplanted for different metabolic diseases are focus of a separate report. Seventeen patients with minimum one-year follow-up period are reported herein. The indications were primary sclerosing cholangitis (PSC, n = 4), congenital hepatic fibrosis (CHF, n = 2), alpha-1 antitrypsin deficiency (A-1 ATD, n = 2), progressive familial intrahepatic cholestasis (PFIC, n = 2), cystic fibrosis (n = 1), primary biliary cirrhosis (PBC, n = 1), neonatal hepatitis (n = 1), embryonal sarcoma (n = 1), Caroli disease (n = 1), hepatocellular carcinoma (HCC, n = 1), and chronic rejection after liver transplantations for PSC (n = 1). All patients and grafts survived at median follow-up of 6.4 years (range 1.2-12.9 years). Median domino recipient age was 16.2 years (range 0.6-64.6 years) and median MSUD recipient age was 17.6 years (range 4.8-32.1 years). There were no vascular complications during the early postoperative period, one patient had portal vein thrombosis 3 years after DLT and a meso-Rex bypass was successfully performed. Small for size syndrome (SFSS) occurred in reduced left lobe DLT recipient and was managed successfully with conservative management. Biliary stricture developed in 2 patients and was resolved by stenting. Comparison between DLT and MSUD recipients' peak postoperative ALT results and PELD/MELD scores showed lower levels in DLT group (P-value Conclusions Patient and graft survival in DLT from MSUD donors was excellent at short- and long-term follow-up. Metabolic functions have been normal in all recipients on a normal unrestricted protein diet. Ischemia preservation injury based on peak ALT was significantly decreased in DLT recipients. Domino transplantation from pediatric and adult recipients with selected metabolic diseases should be increasingly considered as an excellent option and alternative to deceased donor transplantation, thereby expanding the living donor pool. This, to date, is the largest world experience in DLT utilizing livers from patients with MSUD.

PTSS as well as symptoms of depression have been reported in children who experience a serious medical adversity as well as their caretakers. The adverse effects of PTSS, when experienced by the patients, on medical outcomes have been clearly documented. However, the impact of those symptoms, if any, when experienced by the caretakers on child outcomes has not been investigated prospectively. We evaluated whether caregiver PTSS and depression symptoms predict adherence to medications and medical outcomes in a prospective multisite study. Four hundred children participated in MALT. Caretaker PTSS were assessed by the IES and depressive symptoms by CES-D. During 2 years of follow-up, the MLVI was used to determine adherence. Centrally read, biopsy-confirmed organ rejection was the primary medical outcome. IES scores were not associated with either adherence or rejection outcomes. In contrast, there were significant correlations between CES-D (depression) scores and lower adherence, r = .13, P < .001, and a trend toward higher scores on the CES-D among those whose children had experienced rejection, 12.4 (SD = 10.9) versus 9.1 (SD = 8.6), P = .077. Caregivers' PTSS were not a risk factor for poor child outcomes in this cohort, whereas depression symptoms were associated with non-adherence and possibly increased rates of rejection. Further study can validate if caregivers' depression as opposed to PTSS confers greater risk and should be a focus during the clinical care of medically ill children.

Long-term survival for children who undergo LT is now the rule rather than the exception. However, a focus on the outcome of patient or graft survival rates alone provides an incomplete and limited view of life for patients who undergo LT as an infant, child, or teen. The paradigm has now appropriately shifted to opportunities focused on our overarching goals of "surviving and thriving" with long-term allograft health, freedom of complications from long-term immunosuppression, self-reported well-being, and global functional health. Experts within the liver transplant community highlight clinical gaps and potential barriers at each of the pretransplant, intra-operative, early-, medium-, and long-term post-transplant stages toward these broader mandates. Strategies including clinical research, innovation, and quality improvement targeting both traditional as well as PRO are outlined and, if successfully leveraged and conducted, would improve outcomes for recipients of pediatric LT.

Objective To define long-term outcome, predictors of survival, and risk of disease recurrence after gut transplantation (GT) in patients with chronic intestinal pseudo-obstruction (CIPO). Background GT has been increasingly used to rescue patients with CIPO with end-stage disease and home parenteral nutrition (HPN)-associated complications. However, long-term outcome including quality of life and risk of disease recurrence has yet to be fully defined. Methods Fifty-five patients with CIPO, 23 (42%) children and 32 (58%) adults, underwent GT and were prospectively studied. All patients suffered gut failure, received HPN, and experienced life-threatening complications. The 55 patients received 62 allografts; 43 (67%) liver-free and 19 (33%) liver-contained with 7 (13%) retransplants. Hindgut reconstruction was adopted in 1993 and preservation of native spleen was introduced in 1999. Immunosuppression was tacrolimus-based with antilymphocyte recipient pretreatment in 41 (75%). Results Patient survival was 89% at 1 year and 69% at 5 years with respective graft survival of 87% and 56%. Retransplantation was successful in 86%. Adults experienced better patient (P = 0.23) and graft (P = 0.08) survival with lower incidence of post-transplant lymphoproliferative disorder (P = 0.09) and graft versus host disease (P = 0.002). Antilymphocyte pretreatment improved overall patient (P = 0.005) and graft (P = 0.069) survival. The initially restored nutritional autonomy was sustainable in 23 (70%) of 33 long-term survivors with improved quality of life. The remaining 10 recipients required reinstitution of HPN due to allograft enterectomy (n = 3) or gut dysfunction (n = 7). Disease recurrence was highly suspected in 4 (7%) recipients. Conclusions GT is life-saving for patients with end-stage CIPO and HPN-associated complications. Long-term survival is achievable with better quality of life and low risk of disease recurrence.

BACKGROUND SPLIT was founded in 1995 in order to collect comprehensive prospective data on pediatric liver transplantation, including waiting list data, transplant, and early and late outcomes. Since 2011, data collection of the current registry has been refined to focus on prospective data and outcomes only after transplant to serve as a foundation for the future development of targeted clinical studies. OBJECTIVE To report the outcomes of the SPLIT registry from 2011 to 2018. METHODS This is a multicenter, cross-sectional analysis characterizing patients transplanted and enrolled in the SPLIT registry between 2011 and 2018. All patients

Cell-mediated immunity to CMV, if known, could improve antiviral drug therapy in at-risk children and young adults with LT and IT. Host immunity has been measured with CMV-specific T cells, which express IFNγ, but not those which express CD154, a possible substitute for IFNγ. CMV-specific CD154+ T cells and their subsets were measured with flow cytometry after stimulating PBL from recipient blood samples with an overlapping peptide mix of CMV-pp65 antigen for up to 6 hours. CMV-specific CD154+ T cells co-expressed IFNγ in PBL from three healthy adults and averaged 3.8% (95% CI 3.2%-4.4%) in 40 healthy adults. CMV-specific T cells were significantly lower in 19 CMV DNAemic LT or IT recipients, compared with 126 non-DNAemic recipients, 1.3% (95% CI 0.8-1.7) vs 4.1 (95% CI 3.6-4.6, P < .001). All T-cell subsets demonstrated similar between-group differences. In logistic regression analysis of 46 training set samples, 12 with DNAemia, all obtained between days 0 and 60 from transplant, CMV-specific T-cell frequencies ≥1.7% predicted freedom from DNAemia with NPV of 93%. Sensitivity, specificity, and PPV were 83%, 74%, and 53%, respectively. Test performance was replicated in 99 validation samples. In 32 of 46 training set samples, all from seronegative recipients, one of 19 recipients with CMV-specific T-cell frequencies ≥1.7% experienced DNAemia, compared with 8 of 13 recipients with frequencies

Pediatric recipients of intestinal transplants have a high incidence of PTLD, but the impact of specific induction immunosuppression agents is unclear. In this single-center retrospective review from 2000 to 2017, we describe the incidence, characteristics, and outcomes of PTLD after primary intestinal transplantation in 173 children with or without liver, after induction with rATG, alemtuzumab, or anti-IL-2R agents. Thirty cases of PTLD occurred among 28 children, 28 EBV+ and 2 EBV-. Although not statistically significant, the PTLD incidence was higher after isolated intestinal transplant compared with liver-inclusive allograft (19.3% vs 13.3%, P = .393) and after induction with anti-IL-2R antibody and alemtuzumab compared with rATG (28.6% and 27.3% vs 13.3%, P = .076). The 30 PTLD cases included 13 monomorphic PTLD, 13 polymorphic PTLD, one spindle cell, one Burkitt lymphoma, and two cases too necrotic to classify. After reduction of immunosuppression, management was based on disease histology and extent. Resection with or without rituximab was used for polymorphic tumors and limited disease extent, whereas chemotherapy was used for diffuse disease. Of the 28 patients, 11 recovered with functioning allografts (39.3%), 10 recovered after enterectomy (35.7%), and seven patients died (25%), three due to PTLD and four due to other causes. All who died of progressive PTLD had received chemotherapy, highlighting the mortality of PTLD, toxicity of treatment and need for novel agents. Alemtuzumab is no longer used for induction at our center.

OBJECTIVE The aim of the study was to investigate the impact of prioritizing infants, children, adolescents, and the sickest adults (Status 1) for deceased donor livers. We compared outcomes under two "SharePeds" allocation schema, which prioritize children and Status 1 adults for national sharing and enhanced access to pediatric donors or all donors younger than 35 years, to outcomes under the allocation plan approved by the Organ Procurement and Transplant Network in December 2017 (Organ Procurement and Transplantation Network [OPTN] 12-2017). METHODS The 2017 Liver Simulated Allocation Model and Scientific Registry of Transplant Recipients data on all US liver transplant candidates and liver offers 7/2013 to 6/2016 were used to predict waitlist deaths, transplants, and post-transplant deaths under the OPTN 12-2017 and SharePeds schema. RESULTS Prioritizing national sharing of pediatric donor livers with children (SharePeds 1) would decrease waitlist deaths for infants (

Background Allospecific CD154+T-cytotoxic memory cells (CD154+TcM) predict acute cellular rejection after liver transplantation (LTx) or intestine transplantation (ITx) in small cohorts of children and can enhance immunosuppression management, but await validation and clinical implementation. Methods To establish safety and probable benefit, CD154+TcM were measured in cryopreserved samples from 214 children younger than 21 years (National Clinical Trial 1163578). Training set samples (n = 158) were tested with research-grade reagents and 122 independent validation set samples were tested with current good manufacturing practices-manufactured reagents after assay standardization and reproducibility testing. Recipient CD154+TcM induced by stimulation with donor cells were expressed as a fraction of those induced by HLA nonidentical cells in parallel cultures. The resulting immunoreactivity index (IR) if greater than 1 implies increased rejection-risk. Results Training and validation set subjects were demographically similar. Mean coefficient of test variation was less than 10% under several conditions. Logistic regression incorporating several confounding variables identified separate pretransplant and posttransplant IR thresholds for prediction of rejection in the respective training set samples. An IR of 1.1 or greater in posttransplant training samples and IR of 1.23 or greater in pretransplant training samples predicted LTx or ITx rejection in corresponding validation set samples in the 60-day postsampling period with sensitivity, specificity, positive, and negative predictive values of 84%, 80%, 64%, and 92%, respectively (area under the receiver operator characteristic curve, 0.792), and 57%, 89%, 78%, and 74%, respectively (area under the receiver operator characteristic curve, 0.848). No adverse events were encountered due to phlebotomy. Conclusions Allospecific CD154+T-cytotoxic memory cells predict acute cellular rejection after LTx or ITx in children. Adjunctive use can enhance clinical outcomes.

Current literature and policy in pediatric liver allocation and organ procurement are reviewed here in narrative fashion, highlighting historical context, ethical framework, technical/procurement considerations, and support for a logical way forward to an equitable pediatric liver allocation system that will improve pediatric wait-list and posttransplant outcomes without adversely affecting adults. Where available, varying examples of successful international pediatric liver allocation and split-liver policy will be compared to current US policy to highlight potential strategies that can be considered globally. Liver Transplantation 23:86-95 2017 AASLD.

Liver transplantation (LT) in children now has a 20-year survival of >80%, but the longterm outcome of these grafts remains uncertain. Serial protocol liver biopsies after transplantation from several pediatric centres have demonstrated the gradual development of unexplained graft inflammation ("idiopathic" posttransplant hepatitis; IPTH) and graft fibrosis in biopsies obtained >12 months post-LT in children with good graft function and (near) normal liver biochemistry. Although the clinical significance of these findings is uncertain, there is evidence to suggest that IPTH may be a form of rejection or chronic antibody-mediated rejection as it is associated with the presence of auto/alloantibodies; de novo Class II donor-specific HLA antibodies (DSA); previous episodes of rejection, and may improve or be prevented with increased immunosuppression. Currently, the only method of diagnosing either hepatitis or fibrosis has been by serial protocol biopsies as neither serum markers of fibrosis nor noninvasive methods to detect fibrosis such as transient elastography (TE) are sufficiently validated in children. This review will focus on the diagnosis and management of idiopathic posttransplant hepatitis and graft fibrosis, discuss current methods for detecting graft injury, and potential mechanisms for their development. Liver Transplantation 22 1593-1602 2016 AASLD.

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

Applying principles of user-centered design, we iteratively developed and tested the prototype of TPP, an mHealth application to promote medication adherence and enhance communication about medication management between adolescents and primary caregivers. A purposive sample of seven adolescent solid organ transplant recipients who were ≥ one yr post-transplant and their primary caregivers participated. Participants completed up to three face-to-face laboratory usability sessions, a 6-week field test, and a debriefing session. Primary caregivers participated in an additional usability telephone session. Participants completed usability and satisfaction measures. Sample included liver (n = 4), heart (n = 2), and lung (n = 1) recipients aged 11-18 yr (57% were female, 86% were Caucasian), and nine primary caregivers aged 42-61 yr (88.9% were parents, 88% were female, 88% were Caucasian). Ninety percent of the adolescents endorsed the graphs or logs of missed/late medication dosing as useful and 100% endorsed the remaining features (e.g., medication list, dose time reminders/warnings) as useful. All adolescents expressed interest in using TPP for monitoring medications and satisfaction with the automatic messaging between adolescent and caregiver versions of the application. Adolescents unanimously found TPP easy to use. TPP shows promise as an mHealth adherence tool.

Background and aim Crigler-Najjar syndrome (CNS) results from biallelic mutations of UGT1A1 causing partial or total loss of uridine 5'-diphosphate glucuronyltransferase activity leading to unconjugated hyperbilirubinemia and its attendant risk for irreversible neurological injury (kernicterus). CNS is exceedingly rare and has been only partially characterized through relatively small studies, each comprising between two and 57 patients. Methods A systematic literature review was conducted to consolidate data on the patient, caregiver, and societal burden of CNS. Results Twenty-eight articles on clinical aspects of CNS were identified, but no published data on its humanistic or economic burden were found. In patients with complete UGT1A1 deficiency (type 1 CNS [CNS-I]), unconjugated bilirubin levels increase 3-6 mg/dL/day during the newborn period and reach neurologically dangerous levels between 5 and 14 days of age. Phototherapy is the mainstay of treatment but poses significant challenges to patients and their families. Despite consistent phototherapy, patients with CNS-I have worsening hyperbilirubinemia with advancing age. Liver transplantation is the only definitive therapy for CNS-I and is increasingly associated with excellent long-term survival but also incurs high costs, medical and surgical morbidities, and risks of immunosuppression. Conclusions Crigler-Najjar syndrome is associated with a substantial burden, even with existing standards of care. The development of novel disease-modifying therapies has the potential to reduce disease burden and improve the lives of CNS patients and their families.

Liver transplantation in children is often associated with coagulopathy and significant blood loss. Available data are limited. In this observational retrospective study, we assessed transfusion practices in pediatric patients undergoing liver transplantation at a single institution over the course of 9 years.Data were retrospectively collected from patient medical records at the Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center. All patients who underwent liver transplantation from January 2008 to June 2017 were included. Primary and secondary outcomes were volume of red blood cells (RBCs) transfused and mortality, respectively.From January 2008 to June 2017, there were 278 liver transplants in 271 patients. The number of primary transplants were 259, second retransplants 15, and third retransplants 4. Average age at transplantation was 6.9 years. Biliary atresia, maple syrup urine disease, urea cycle defect, and liver tumor were the leading indications accounting for 66 (23.7%), 45 (16.2%), 24 (8.6%), and 23 (8.3%) of transplants, respectively. Seventy-six cases (27.3%) did not require RBC transfusions. Among those transfused, 181 (89.6%) of the cases required1 blood volume (BV). The median BV transfused among all cases was 0.21 (range, 0-9; Q1, 0; Q3, 0.45). There is a trend toward higher volume transfusions among infants (median, 0.46 BV) compared to children12 months of age (0.12 BV). By diagnosis, the group requiring the highest median volume transfusion was patients with total parenteral nutrition-related liver failure (3.41 BV) followed by patients undergoing repeat transplants (0.6 BV). Comparison of primary versus repeat transplants shows a trend toward higher volume transfusions in third transplants (median, 2.71 BV), compared to second transplants (0.43 BV) and primary transplants (0.18 BV). Four of 271 patients (1.5%) died during admission involving liver transplantation. Nine of 271 patients (3.3%) died subsequently. Total mortality was 4.8%.In contrast to historically reported trends, evaluation of current transfusion practices reveals that most patients undergoing liver transplantation receive1 BV of packed RBCs. More than 1 in 4 transplantations require no transfusion at all. Risk factors for greater transfusion need include younger age, total parenteral nutrition-related liver failure, and repeat transplantation.

Indications for liver transplantation (LT) in metabolic disease are evolving. We reviewed the US experience with primary LT for metabolic disease in the Scientific Registry for Transplant Recipients (October 1987 to June 2017) to determine the following: temporal changes in indications, longterm outcomes, and factors predicting survival. Patients were grouped by the presence of structural liver disease (SLD) and whether the defect was confined to the liver. There were 5996 patients who underwent LT for metabolic disease, 2354 (39.3%) being children. LT for metabolic disease increased in children but not in adults. Children experienced a 6-fold increase in LT for metabolic disease without SLD. Indications for LT remained stable in adults. Living donor liver transplantation increased between era 1 and era 3 from 5.6% to 7.6% in children and 0% to 4.5% in adults. Patient and graft survival improved with time. The latest 5-year patient survival rates were 94.5% and 81.5% in children and adults, respectively. Outcomes were worse in adults and in those with extrahepatic disease (P