Finding Value in Pediatric Liver Transplantation: When Does Volume Matter?

Editorial introductions

The Starzl Network for Excellence in Pediatric Transplantation identified optimizing immunosuppression (IS) as a priority practice improvement area for patients, families, and providers. We aimed to evaluate associations between clinical characteristics, early IS, and outcomes. We analyzed pediatric liver transplant (LT) data from 2013 to 2018 in the United Network for Organ Sharing (UNOS) and the Society of Pediatric Liver Transplantation (SPLIT) registries. We included 2542 LT recipients in UNOS and 1590 in SPLIT. IS choice varied between centers with steroid induction and mycophenolate mofetil (MMF) use each ranging from 0% to 100% across centers. Clinical characteristics associated with early IS choice were inconsistent between the two data sets. T-cell depleting antibody use was associated with improved 1-year graft (hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.34-0.76) and patient (HR 0.40, 95% CI 0.20-0.79) survival in UNOS but decreased 1-year patient survival (HR 4.12, 95% CI 1.31-12.93) and increased acute rejection (HR 1.58, 95% CI 1.07-2.34) in SPLIT. Non-T-cell depleting antibody use was not associated with differential risk of survival nor rejection. MMF use was associated with improved 1-year graft survival (HR 0.73, 95% CI 0.54-0.99) in UNOS only. Variation exists in center choice of early IS regimen. UNOS and SPLIT data provide conflicting associations between IS and outcomes in multivariable analysis. These results highlight the need for future multicenter collaborative work to identify evidence-based IS best practices.

Objective To summarize the experiences of diagnosing and treating portal vein stenosis (PVS) after pediatric liver transplantation from China donation after citizen’s death (CDCD) grafts. Methods Retrospective analysis was performed for 30 cases of pediatric CDCD liver transplantation recipients with PVS. The screening, diagnosis, treatment and prognosis of PVS were analyzed. Results Among 218 pediatric liver transplantation recipients with CDCD grafts, PVS was diagnosed in 30 cases with an incidence rate of 13.8% (30/218). The initial diagnosis of PVS ranged from 5 days to 27 months post-operation with a median age of 2.9 months. Ultrasonography indicated that stenotic rate of anastomotic site diameter was (41.28±12.93)% and blood flow velocity ratio (358.77±117.82)%. Intervention examination showed average pressure gradient was (9.06±5.34) mmHg between both sides of stenosis. All cases underwent percutaneous intrahepatic balloon dilatation. The recipients were followed up for a median follow-up time of 23(3-63) months. For three cases of restenosis, percutaneous intrahepatic balloon dilatation was repeated. Two cases underwent stent implantation due to ineffective balloon dilation. After treatment, the stenotic rate of anastomotic site diameter was (34.69±8.82) and blood flow velocity ratio (61.18±63.11)% on ultrasound while the average pressure gradient was (1.03±0.85) mmHg. Conclusions PVS is a common vascular complication after pediatric CDCD liver transplantation. Portal vein balloon dilation is both safe and efficacious. However, some cases require repeated balloon dilation and stent implantation serves as the last option for intractable PVS. Color ultrasound is both convenient and effective for making a primary diagnosis and evaluating outcomes. Key words: pediatric liver transplantation; portal vein stenosis; balloon dilation

Impact of segmental grafts on pediatric liver transplantation—A review of the United Network for Organ Sharing Scientific registry data (1990–1996)

Racial and socioeconomic disparities exist in liver transplantation (LT) outcomes among adults, but little research exists for pediatric LT populations. We examined racial differences in graft survival and mortality within a retrospective cohort of pediatric and young adult LT recipients at a large children's transplant center in the Southeast between 1998 and 2011. The association between race/ethnicity and rates of graft failure and mortality was examined with Cox proportional hazards models that were adjusted for demographic and clinical factors as well as individual-level and census tract-level socioeconomic status (SES). Among the 208 LT recipients, 51.0% were white, 34.6% were black, and 14.4% were other race/ethnicity. Graft survival and patient survival were higher for whites versus minorities 1, 3, 5, and 10 years after transplantation. The 10-year graft survival rates were 84% [95% confidence interval (CI) = 76%-91%] for white patients, 60% (95% CI = 46%-74%) for black patients, and 49% (95% CI = 23%-77%) for other race/ethnicity patients. The 10-year patient survival rates were 92% (95% CI = 84%-96%), 65% (95% CI = 52%-79%), and 76% (95% CI = 54%-97%) for the white, black, and other race/ethnicity groups, respectively. In analyses adjusted for demographic, clinical, and socioeconomic characteristics, the rates of graft failure [black: hazard ratio (HR) = 2.59, 95% CI = 1.29-5.45; other: HR = 3.01, 95% CI = 1.23-7.35] and mortality (black: HR = 4.24, 95% CI = 1.54-11.69; other: HR = 3.09, 95% CI = 0.78-12.19) were higher for minority groups versus whites. In conclusion, at a large pediatric transplant center in the Southeastern United States, racial/ethnic disparities exist in pediatric and young adult LT outcomes that are not fully explained by measured SES and clinical factors.

Pediatric Transplantation Using Hearts Refused on the Basis of Donor Quality

Multisystem inflammatory syndrome in children associated with SARS-CoV-2 in a solid organ transplant recipient.

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. 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. 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. 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.

Pediatric liver transplant is a life-saving procedure, but risks remain for children in the pre-, peri-, and post-transplant period-impacting survival, graft, and child health, and quality of life. Learning health networks offer a structure that multi-disciplinary teams across many centers can use to collaborate on improving outcomes for children with rare diseases-with a mantra of "sharing seamlessly" to coordinate across centers and "stealing shamelessly" from best practices within or outside of the network. We describe the development of the Starzl Network for Excellence in Pediatric Transplantation (SNEPT) as a learning health network dedicated to improving health and quality of life for children with liver transplants and their families. SNEPT was founded in 2017 as a collaborative effort between pediatric liver transplant centers and the families that they serve, initially at 10 and then 16 centers across the US and Canada. Stakeholders identified four priority projects: Peri-Operative and Surgical Practices, Optimizing Immunosuppression, Quality of Life, and Transition of Care. Over the last 8 years, we built SNEPT infrastructure to efficiently support work on each project. Our four working groups each developed methods to improve practice by sharing protocols, data, and experience between centers and adapting best-practice strategies from other centers for efficient improvement. Coordination as a learning health network has improved transparency and enhanced collaboration between SNEPT centers, creating opportunities for best-practices development and better outcomes in pediatric liver transplant.

Liver transplantation for alcoholic hepatitis in the United States: Excellent outcomes with profound temporal and geographic variation in frequency.

Lymphoproliferative disorders after liver transplantation

Living donor liver transplantation

Tacrolimus is beneficial in liver transplantation for reversing steroid-resistant acute rejection, and for controlling the process of chronic rejection in allograft recipients receiving Cyclosporine- (CyA) based regimens. Very little is known about the long-term efficacy of tacrolimus in pediatric transplantation after conversion from CyA. Our study examines the long-term outcome after conversion to tacrolimus for acute or chronic rejection in pediatric liver transplant (LTx) recipients. Seventy-three children (age < 18 years) receiving their primary LTx under CyA between August 1989 and April 1996 were converted to tacrolimus for ongoing acute rejection (n=22, group I) or chronic rejection (n=51, group II). Mean age at the time of conversion was 10.2+/-5.5 years with a mean interval from LTx to conversion of 3.5+/-2.9 (range 0.5-10.1 years). There were 33 boys and 40 girls. All patients were followed until June 1999. Mean follow-up was 97.3+/-17.4 months (range 62.4-118.9 months). Overall 5-year actual patient survival was 78.1% and 8-year actuarial survival was 74.6%. Patients converted to tacrolimus therapy to resolve acute rejection (group I) experience significantly better patient and graft survival at 5 and 8 years than those converted to resolve chronic rejection (group II). Eight-year patient survival and graft survival was 95.5 and 90.9% for group I compared to 74.6 and 53.5% for group II, respectively (long rank P=0.035 and 0.01, respectively). Nearly 75% of children were weaned off steroids after conversion. There was a marked improvement in hypertension, gum hyperplasia, hirsutism, and cushingoid appearance. One child in group I (4.5%) and four children in group II (7.8%) developed posttransplant lymphoproliferative disorder after conversion. There was an improvement in growth in children who were less than the age of 12 years at the time of conversion and who were weaned off steroids; more significantly girls responded more favorably than boys. The benefit of transplantation is maintained long-term after conversion to tacrolimus for acute or chronic rejection. The response rate was significantly better in group I as compared with group 11. Marked improvement in growth, hypertension, and reversal of the brutalizing effects of CyA was noted after conversion to tacrolimus. The results suggest that early conversion of pediatric liver transplant patients is warranted for the treatment of acute and chronic rejection, and for improvements in quality of life.

Current American Association for the Study of Liver Diseases (AASLD) liver transplant evaluation guidelines include both adult and pediatric patients. While pediatric liver transplants account for 7.8% of all liver transplants in the United States, sufficient differences between pediatric and adult patients seeking liver transplantation (LT) now require independent, yet complementary documents. This document will focus on pediatric issues at each level of the evaluation process. Disease categories suitable for referral to a pediatric LT program are similar to adults: acute liver failure, autoimmune, cholestasis, metabolic or genetic, oncologic, vascular, and infectious. However, specific etiologies and outcomes differ widely from adult patients, justifying independent pediatric guidelines. Data supporting our recommendations are based on a Medline search of the English language literature from 1997 to the present. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the available evidence supporting the recommendations, the AASLD Practice Guidelines Committee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup with minor modifications (Table 1). The classifications and recommendations are based on three categories: the source of evidence in levels I through III; the Abbreviations: ALF, acute liver failure; GRADE, Grading of Recommendation Assessment, Development, and Evaluation; HB, hepatoblastoma; HCC, hepatocellular carcinoma; HPE, hepatoportoenterostomy; LT, liver transplantation; OTPN, Organ Procurement and Transplantation Network; PFIC, progressive familial intrahepatic cholestasis; TIPS, transjugular intrahepatic portosystemic shunt. From the Department of Pediatrics, University of Pittsburgh School of Medicine; Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA; Department of Pediatrics, University of Toronto; Division of Pediatric Gastroenterology, Hepatology and Nutrition, SickKids Transplant and Regenerative Medicine Center, Hospital for Sick Children, Toronto, Canada; Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Emory University School of Medicine; Children’s Healthcare of Atlanta, Atlanta, GA; Department of Pediatrics, Division of Pediatric Gastroenterology and Hepatology, Yale School of Medicine, New Haven, CT; Department of Paediatrics, University of Melbourne; Department of Gastroenterology, Royal Children’s Hospital, Melbourne, Australia; Department of Surgery, Section of Transplantation and Immunology, Yale School of Medicine, New Haven, CT; Department of Surgery, University of Pittsburgh School of Medicine; Division of Pediatric Transplantation, Hillman Center for Pediatric Transplantation, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA. Financial support to develop this practice guideline was provided by the American Association for the Study of Liver Diseases. All AASLD Practice Guidelines are updated annually. If you are viewing a Practice Guideline that is more than 12 months old, please visit www.aasld.org for an update in the material. Received April 22, 2014; accepted April 22, 2014. Address reprint requests to: Robert H. Squires, M.D., Professor of Pediatrics, University of Pittsburgh, Children’s Hospital of Pittsburgh of UPMC, 4401 Penn Ave., Pittsburgh, PA 15224. E-mail: squiresr@upmc.edu Copyright VC 2014 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27191 Potential conflict of interest: Dr. Romero received grants from Bristol-Myers Squibb.

Not everything that counts can be counted: Tracking long-term outcomes in pediatric liver transplant recipients