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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 (

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.

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.

Domino liver transplantation (DLT) involves transplanting liver from a patient with metabolic disease into a patient with end‐stage liver disease with the expectation that the recipient will not develop the metabolic syndrome or the recurrent syndrome will have minimal affect. The domino donor gets a deceased donor or a segment of live‐donor liver through the deceased donor organ allocation system. Waitlist mortality for the domino recipient exceeds morbidity associated with getting the donor disease. Between 2015 and 2017, four patients with three metabolic disorders at UPMC Children's Hospital of Pittsburgh underwent DLT with domino allografts from maple syrup urine disease (MSUD) patients. These included patients with propionic acidemia (PA) (n = 1), Crigler‐Najjar (CN) syndrome type‐1 (n = 2), and carbamoyl phosphate synthetase deficiency (CPSD) (n = 1). Mean follow‐up was 1.6 years (range 1.1‐2.1 years). Total bilirubin levels normalized postoperatively in both CN patients and they maintain normal allograft function. The PA patient had normal to minimal elevations of isoleucine and leucine, and no other abnormalities on low protein diet supplemented with a low methionine and valine free formula. No metabolic crises have occurred. The patient with CPSD takes normal baby food. No elevation in ammonia levels have been observed in any of the patients. DLT for a select group of metabolic diseases alleviated the recipients of their metabolic defect with minimal evidence of transferrable‐branched chain amino acid elevations or clinical MSUD despite increased protein intake. DLT using allografts with MSUD expands the live donor liver pool and should be considered for select metabolic diseases that may have a different enzymatic deficiency.

OBJECTIVES Define clinical spectrum and long-term outcomes of gut malrotation. With new insights, an innovative procedure was introduced and predictive models were established. METHODS Over 30-years, 500 patients were managed at 2 institutions. Of these, 274 (55%) were children at time of diagnosis. At referral, 204 (41%) patients suffered midgut-loss and the remaining 296 (59%) had intact gut with a wide range of digestive symptoms. With midgut-loss, 189 (93%) patients underwent surgery with gut transplantation in 174 (92%) including 16 of 31 (16%) who had autologous gut reconstruction. Ladd's procedure was documented in 192 (38%) patients with recurrent or de novo volvulus in 41 (21%). For 80 patients with disabling gastrointestinal symptoms, gut malrotation correction (GMC) surgery "Kareem's procedure" was offered with completion of the 270° embryonic counterclockwise-rotation, reversal of vascular-inversion, and fixation of mesenteric-attachments. Concomitant colonic dysmotility was observed in 25 (31%) patients. RESULTS The cumulative risk of midgut-loss increased with volvulus, prematurity, gastroschisis, and intestinal atresia whereas reduced with Ladd's and increasing age. Transplant cumulative survival was 63% at 10-years and 54% at 20-years with best outcome among infants and liver-containing allografts. Autologous gut reconstruction achieved 78% and GMC had 100% 10-year survival. Ladd's was associated with 21% recurrent/de novo volvulus and worsening (P > 0.05) of the preoperative National Institute of Health patient-reported outcomes measurement information system gastrointestinal symptom scales. GMC significantly (P ≤ 0.001) improved all of the symptomatology domains with no technical complications or development of volvulus. GMC improved quality of life with restored nutritional autonomy (P < 0.0001) and daily activities (P < 0.0001). CONCLUSIONS Gut malrotation is a clinicopathologic syndrome affecting all ages. The introduced herein definitive correction procedure is safe, effective, and easy to perform. Accordingly, the current standard of care practice should be redefined in this orphan population.

Assessment of T-cell immunity to the COVID-19 coronavirus requires reliable assays and is of great interest, given the uncertain longevity of the antibody response. Some recent reports have used immunodominant spike (S) antigenic peptides and anti-CD28 co-stimulation in varying combinations to assess T-cell immunity to SARS-CoV-2. These assays may cause T-cell hyperstimulation and could overestimate antiviral immunity in chronically immunosuppressed transplant recipients, who are predisposed to infections and vaccination failures. Here, we evaluate CD154-expressing T-cells induced by unselected S antigenic peptides in 204 subjects-103 COVID-19 patients and 101 healthy unexposed subjects. Subjects included 72 transplanted and 130 non-transplanted subjects. S-reactive CD154+T-cells co-express and can thus substitute for IFNγ (n=3). Assay reproducibility in a variety of conditions was acceptable with coefficient of variation of 2-10.6%. S-reactive CD154+T-cell frequencies were a) higher in 42 healthy unexposed transplant recipients who were sampled pre-pandemic, compared with 59 healthy non-transplanted subjects (p=0.02), b) lower in Tr COVID-19 patients compared with healthy transplant patients (p

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.

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.

Introduction: On January 30, 2020 the World Health Organization (WHO) declared the 2019-CoV outbreak in China as a global public health emergency and subsequently, a pandemic on March 11th. It was considered that intestinal failure and intestinal transplant patients might have a higher risk of severe complications from the COVID-19 disease, multidisciplinary intestinal failure teams had to adapt their clinical approaches in order to keep this vulnerable group of patients as safe as possible during the pandemic;but data was lacking. Therefore, in order to improve our knowledge, we designed a voluntary, international survey aiming to address the impact of the COVID-19 disease in intestinal failure and transplant patients worldwide. Patient and Methods: A retrospective, observational, multicenter survey was sent to all centers registered at the Intestinal Rehabilitation and Transplant Association (IRTA). The survey contained three modules: the 1st one consisted of 14 questions about the hospital's activity during the COVID-19 pandemic. The 2nd one, contained 43 questions, was about intestinal failure patient management and outcome and the 3rd one (52 questions) focused on intestinal transplant patients. We used the Google Form platform. We aim to present the preliminary results of the first module. Statistical analysis was performed with the IBM SPSS Statistic version 25.0® program. Results: 13/42 (41%) centers responded;including centers from France, Netherlands, Italy, United States, UK, Sweden, Germany and Argentina. Only 2 centers reported moratorium on intestinal (IT) or multivisceral transplant (MVT), with a mean of 3 months (±4) [Table 1]. Since the pandemic started, 2 institutions reported 4 patients with intestinal rehabilitation or on TPN diagnosed with COVID-19 while 7 centers hospitals claimed to have had 9 patients post-IT/MTV affected by the disease. While 7 centers had their routine follow up and 'protocol biopsies' in the post-IT/MTV affected, none reported higher rates of rejection or complications. At the same time, 8 centers (77%) were affected by a mean of 15% decrease in referrals for new evaluations of intestinal failure or transplantation (compared to 2019) [Figure 1]. All centers adapted to utilizing telemedicine to follow up on IT/MVT patients Conclusions: Many aspects of healthcare have been impacted by the COVID-19 pandemic. The survey showed that the number of affected patients has been lower than expected, the reduced number of centers required transient moratorium of their activity, but a secondary observation was that despite the availability of telemedicine, and probably related to the lockdown, there has been a significant reduction in the referrals for evaluation of intestinal failure and transplant patients, that may have the deleterious effect of the delay of treatment in health care system.

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.

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.

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.

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.

Learning Health Networks (LHN) improve the well-being of populations by aligning clinical care specialists, technology experts, patients and patient advocates, and other thought leaders for continuous improvement and seamless care delivery. A novel LHN focused on pediatric transplantation, the Starzl Network for Excellence in Pediatric Transplantation (SNEPT), convened its inaugural meeting in September 2018. Clinical care team representatives, patients, and patient families/advocates partnered to take part in educational sessions, pain point exercises, and project identification workshops. Participants discussed the global impact of transplant from both a population and individual perspective, identifying challenges and opportunities where the Starzl Network could work to improve outcomes at scale across a variety of transplant-related conditions.

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

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.

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.

Approaches to the management of portal hypertension and variceal hemorrhage in pediatrics remain controversial, in large part because they are not well informed by rigorous clinical studies. Fundamental biological and clinical differences preclude automatic application of approaches used for adults to children. On April 11-12, 2015, experts in the field convened at the first Baveno Pediatric Satellite Meeting to discuss and explore current available evidence regarding indications for MesoRex bypass (MRB) in extrahepatic portal vein obstruction and the role of primary prophylaxis of variceal hemorrhage in children. Consensus was reached regarding MRB. The vast majority of children with extrahepatic portal vein obstruction will experience complications that can be prevented by successful MRB surgery. Therefore, children with extrahepatic portal vein obstruction should be offered MRB for primary and secondary prophylaxis of variceal bleeding and other complications, if appropriate surgical expertise is available, if preoperative and intraoperative evaluation demonstrates favorable anatomy, and if appropriate multidisciplinary care is available for postoperative evaluation and management of shunt thrombosis or stenosis. In contrast, consensus was not achieved regarding primary prophylaxis of varices. Although variceal hemorrhage is a concerning complication of portal hypertension in children, the first bleed appears to be only rarely fatal and the associated morbidity has not been well characterized. Conclusion: There are few pediatric data to indicate the efficacy and safety of pharmacologic or endoscopic therapies as primary prophylaxis or that prevention of a sentinel variceal bleed will ultimately improve survival; therefore, no recommendation for primary prophylaxis with endoscopic variceal ligation, sclerotherapy, or nonspecific beta-blockade in children was proposed. (Hepatology 2016;63:1368–1380)

BACKGROUND Alloreactive T-cell apoptosis may explain reduced immunosuppression requirements with proapoptotic immunosuppression and among rejection-free recipients. This possibility remains unproven. METHODS Apoptotic (caspase-3+, cathepsin B+) and inflammatory (CD154+) T-cell subsets were evaluated before and after adding rabbit antithymocyte globulin (rATG) to mixed lymphocyte co-cultures between human leukocyte antigen-mismatched peripheral blood lymphocytes from healthy adults. In random samples from children with liver (LTx-20) and intestine (ITx-13) transplantation, apoptotic T cells were evaluated for association with rejection-free outcomes using the caspase-3 substrate, phiphilux. RESULTS In mixed lymphocyte co-cultures between normal human peripheral blood lymphocytes, (1) frequencies of memory (M) and naive (N) Th and Tc, which expressed activated caspase-3, were enhanced most by the combination of allostimulation and rATG, than either stimulus alone. These findings were confirmed with antibody to activated caspase-3, phiphilux, and terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) assay; (2) frequencies of Th subsets, which expressed activated cathepsin B, were similarly increased with combined stimulation. Tc seemed resistant to cathepsin B activation; (3) with increasing rATG concentrations, proportionately more allospecific CD154+T-cytotoxic memory cells (TcM) survived than TcM, resulting in relative enrichment of allospecific CD154+TcM. In random blood samples, phiphilux+T-cell subset frequencies were higher among 14 rejection-free LTx and ITx recipients and demonstrated a greater increase with ex vivo rATG pretreatment than 19 rejectors. In logistic regression analysis, phiphilux+TcM associated best with rejection-free outcomes with a sensitivity of 57% and a specificity of 89%. CONCLUSION Rabbit antithymocyte globulin facilitates apoptosis of alloreactive T cells by means of caspase-3 activation, which may explain its steroid-sparing effect in pediatric liver and intestine recipients. Apoptotic susceptibility of T-cytotoxic memory cells, which resist cathepsin B activation, may distinguish rejection-free and rejection-prone liver recipients.

Background Crigler-Najjar syndrome type I (CNI) arises from biallelic variants of UGT1A1 that abrogate uridine diphosphate glucuronosyltransferase (UGT1A1) activity resulting in unconjugated hyperbilirubinemia. Historically, liver parenchyma in CNI was considered structurally and histologically normal. Recent review of CNI liver explants revealed fibrosis. Our aim was to investigate the association between hepatic histology and disease phenotype in CNI. Methods We extracted data from the medical record at the time of liver transplant from 22 patients with CNI at the Children's Hospital of Pittsburgh, and reviewed explant histology. Continuous data were normally distributed, are presented as mean (±1 SD), and analyzed using two-tailed Student t-test. Categorical data were analyzed using the Chi-square test. Results Both alanine transaminase (ALT; mean 87.4 IU/L) and aspartate transaminase (AST; mean 54.6 IU/L) were elevated. Nine (41%) of 22 explants had significant fibrosis. Pericentral (n = 5), periportal (n = 2), and mixed (n = 2) patterns of fibrosis occurred. A significant difference in mean age of subjects with fibrotic versus non-fibrotic livers (16.1 years vs 10.5 years; P = 0.02) was seen. There were no indices of synthetic liver dysfunction or portal hypertension. Neither a history of gallstone disease nor excess weight appeared to contribute to the development of fibrosis. Conclusions For the first time, we report a 41% prevalence of clinically silent, yet histologically significant fibrosis among subjects with Crigler-Najjar type 1. Risk for fibrosis appears to accrue with time, indicating that earlier intervention may be prudent whenever considering alternative treatments such as hepatocyte transplant, auxiliary liver transplant, or viral gene therapy.

Knowledge of the long term trajectory of nonadherence to immunosupressants can inform decisions regarding organ allocation, adherence monitoring, and intervention efforts. The MALT (Medication Adherence in children who had a Liver Transplant) prospective multi-site study followed 400 pediatric and adolescent liver transplant recipients for 2 years, using the Medication Level Variability Index (MLVI) to monitor adherence. We hypothesized that adherence is an unstable (fluctuating) phenomenon: that patients who are adherent in year one may become nonadherent in year 2, and vice-versa. However, we also hypothesized that a majority (more than 50%) of nonadherent patients remain nonadherent over time. We further hypothesized that the longer nonadherence lasts, the higher the likelihood of adverse events (rejection). Finally, we explored the effect of socioeconomic factors on the evolution of adherence over time. Most (59.7%) of MALT patients who were nonadherent in year 1 remained so in year 2; 18.5% of patients who were adherent in year 1 became nonadherent in year 2. Only 4.4% of patients who were adherent in both year 1 and year 2 had a rejection, compared with 22.9% of patients who were nonadherent during one of the years, and 34.9% of those who were nonadherent in both years (p

Nonadherence to immunosuppressant medications is a leading cause of poor long-term outcomes in transplant recipients. The Medication Level Variability Index (MLVI) provides a vehicle for transplant outcome risk-stratification through continuous assessment of adherence. The MALT (Medication Adherence in children who had a Liver Transplant) prospective multi-site study evaluated whether MLVI predicts late acute rejection (LAR). Four hundred pediatric (1-17-year-old) liver transplant recipients were enrolled and followed for 2 years. The a-priori hypothesis was that a higher MLVI predicts LAR. Predefined secondary analyses evaluated other outcomes such as liver enzyme levels, and sensitivity analyses compared adolescents to pre-adolescents. In the primary analysis sample of 379 participants, a higher prerejection MLVI predicted LAR (mean prerejection MLVI with LAR: 2.4 [3.6 standard deviation] versus without LAR, 1.6 [1.1]; p = 0.026). Fifty-three percent of the adolescents with MLVI>2 in year 1 had LAR by the end of year 2, as compared with 6% of those with year 1 MLVI≤2. A higher MLVI was significantly associated with all secondary outcomes. MLVI, a marker of medication adherence that uses clinically derived information, predicts LAR in pediatric liver transplant recipients.

Vaccination of the donor might have prevented infection in the recipient and subsequent transmission to healthcare workers., Although transmission of hepatitis A virus (HAV) through blood transfusion has been documented, transmission through organ transplantation has not been reported. In August 2015, state health officials in Texas, USA, were notified of 2 home health nurses with HAV infection whose only common exposure was a child who had undergone multi–visceral organ transplantation 9 months earlier. Specimens from the nurses, organ donor, and all organ recipients were tested and medical records reviewed to determine a possible infection source. Identical HAV RNA sequences were detected from the serum of both nurses and the organ donor, as well as from the multi–visceral organ recipient’s serum and feces; this recipient’s posttransplant liver and intestine biopsy specimens also had detectable virus. The other organ recipients tested negative for HAV RNA. Vaccination of the donor might have prevented infection in the recipient and subsequent transmission to the healthcare workers.

We conducted a prospective pilot study to evaluate the potential role of combined systemic antifungal and liposomal amphotericin B lock therapy in children with intestinal insufficiency with fungal catheter-related bloodstream infections whose central venous catheters had not been removed. Our results provide supportive evidence for the conduct of larger clinical trials to confirm the efficacy and safety of this approach.

There is little detailed clinical information on recurrent primary sclerosing cholangitis (rPSC) after liver transplantation in children. Our purpose was to describe the characteristics of children who had experienced rPSC after liver transplantation so that we could identify potential risk factors for recurrence. Clinical information for pediatric patients undergoing transplantation for primary sclerosing cholangitis (PSC) was retrospectively reviewed, and variables related to the pretransplant diagnosis of PSC and posttransplant variables were abstracted. The studied variables included the following: cytomegalovirus/Epstein-Barr virus status, early/late rejection, induction regimen, immunosuppression in the first year, steroid-resistant rejection, diagnosis of inflammatory bowel disease, and human leukocyte antigen markers commonly associated with PSC. A diagnosis of rPSC was made on the basis of radiographic features, histology, or both. Twelve patients underwent liver transplantation for PSC between 1993 and 2012. Patients received tacrolimus for maintenance immunosuppression after induction with steroids (n = 6) or thymoglobulin (n = 6). Three patients were diagnosed with rPSC 44, 60, and 62 months after transplantation. A fourth patient underwent retransplantation for graft failure with features of both hepatic artery stenosis and rPSC. This patient had distinct histological features of rPSC in the second graft. Three of the 4 patients were 7 years old or younger at the diagnosis of PSC. The patient and graft survival rates were similar for the steroid and thymoglobulin groups. All 4 children with rPSC received steroid-free thymoglobulin induction. In conclusion, our observation of an association between thymoglobulin, and age less than 10 years at the diagnosis of PSC, and rPSC adds to the existing suggestion of a link between the immune environment and the pathogenesis of rPSC. Defining the natural history of rPSC and searching for the etiology and risk factors of rPSC are important for the long-term outcomes of pediatric patients.