Current approaches for risk assessment of intestinal transplant patients: A view from the histocompatibility laboratory.

Despite its recent decline in volumes, intestinal transplantation remains an important option for patients with irreversible intestinal failures. The long-term outcome of an intestinal transplant has stagnated. The major cause of graft loss is rejection, resulting from mismatches in human leukocyte antigens (HLA) and the presence of antibodies to mismatched donor-specific HLA antigens (DSA). Literature has reported that DSAs, either preformed before transplantation or developed de novo after transplantation, are harmful to intestinal grafts, especially for those without combined liver grafts. A comprehensive assessment of DSA by the histocompatibility laboratory is critical for successful intestinal transplantation and its long-term survival. This paper briefly reviews the history and current status of different methods for detecting DSA and their clinical applications in intestinal transplantation. The focus is on applying different antibody assays to manage immunologically challenging intestinal transplant patients before and after transplantation. A clinical case is presented to illustrate the complexity of HLA tests and the necessity of multiple assays. The review of risk assessment by the histocompatibility laboratory also highlights the need for close interaction between the laboratory and the intestinal transplant program.

Pediatric intestine transplant cost: Analysis of the Pediatric Health Information System database.

BACKGROUND: We aimed to evaluate costs from transplant to discharge in children who had undergone intestine transplant. METHODS: We performed a cross-sectional observational study of pediatric intestine transplant recipients from 2004 through 2020, utilizing the Pediatric Health Information System database. Standardized costs were applied to all charges and converted to 2021 US dollars. We analyzed the association of cost from transplant to discharge with age, sex, race and ethnicity, length of stay, insurance type, transplant year, short bowel syndrome diagnosis, liver-containing graft, hospitalization status, and immunosuppressive regimen. Predictors with a P value <0.20 in univariable analysis were included in a multivariable model, which was reduced using backwards selection with a P value of 0.05. RESULTS: We identified 376 intestinal transplant recipients across nine centers (median age, 2 years; 44% female). Most patients had short bowel syndrome (294; 78%). The liver was included in 218 transplants (58%). Median posttransplant cost was $263,724 (interquartile range [IQR], $179,564-$384,147), and length of stay was 51.5 days (IQR, 34-77). In the final model, increased cost from transplant to hospital discharge was associated with liver-containing graft (+$31,805; P = 0.028), T-cell-depleting antibody use (+$77,004; P < 0.001), and mycophenolate mofetil use (+$50,514; P = 0.012) while controlling for insurance type and length of stay. A 60-day posttransplant hospital stay would cost an estimated $272,533. CONCLUSIONS: Intestine transplant has high immediate cost and long length of stay that varies by center, graft type, and immunosuppression regimen. Future work will examine the cost-effectiveness of various management strategies before and after transplant.

Cost-Effectiveness of Primary Liver Transplantation Versus Hepatoportoenterostomy in the Management of Biliary Atresia in the United States.

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.

Impact of Acuity Circles on Outcomes for Pediatric Liver Transplant Candidates.

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.

Factors Associated With Neurobehavioral Complications in Pediatric Abdominal Organ Transplant Recipients Identified Using Computable Composite Definitions.

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.

Disease burden of Crigler-Najjar syndrome: Systematic review and future perspectives.

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.

Barriers to ideal outcomes after pediatric liver transplantation.

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.

Ethical Analysis and Policy Recommendations Regarding Domino Liver Transplantation.

Due to the widening gap between supply and demand, patients who need a liver transplant due to metabolic disease may be asked to serve as domino liver donors-to have their native liver transplanted into another candidate. We here analyze the ethical problems surrounding informed consent for the implant and explant procedures in transplant candidates who will serve as domino donors, using the case of a child with maple syrup urine disease. We discuss the need for 2 distinct consent processes separated in time to ensure that potential domino donors (or their surrogates) give a truly voluntary consent. We propose a Domino Donor Advocate-based on the concept of the independent living donor advocate to help the patient and/or his or her surrogates consider the risks, benefits and alternatives. Finally, we evaluate the Organ Procurement and Transplantation Network policy regarding "therapeutic organ donation" and propose several modifications to ensure that the decision by the potential domino donor (and/or his or her surrogate) is voluntary and informed.

Trajectory of adherence behavior in pediatric and adolescent liver transplant recipients: The medication adherence in children who had a liver transplant cohort.

Knowledge of the longterm trajectory of nonadherence to immunosuppressants can inform decisions regarding organ allocation, adherence monitoring, and intervention efforts. The Medication Adherence in Children Who Had a Liver Transplant (MALT) prospective multisite study followed 400 pediatric and adolescent liver transplant recipients for 2 years, using the Medication Level Variability Index to monitor adherence. We hypothesized that adherence is an unstable (fluctuating) phenomenon: that patients who are adherent in year 1 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 the 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 1 of the years, and 34.9% of those who were nonadherent in both years (P < 0.001), establishing a "dose-dependent" effect of adherence on transplant outcomes. Single-parent households were associated with worsening adherence. Our results suggest that good baseline adherence does not guarantee adherence later on, that nonadherence is likely to persist in the absence of interventions, and that monitoring of adherence and interventions to improve it should be expected to last for years if transplant outcomes are to be improved. Liver Transplantation 24 80-88 2018 AASLD.

Global lessons in graft type and pediatric liver allocation: A path toward improving outcomes and eliminating wait-list mortality.

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.

Pancreaticobiliary complications after composite visceral transplantation: incidence, risk, and management strategies.

BACKGROUND: Combined liver/small-bowel (L/SB) and multivisceral (MV) transplantation has been increasingly used with significant improvement in outcome. OBJECTIVE: To report our experience with pancreaticobiliary (PB) complications in this unique population. DESIGN AND SETTING: Single-center cohort study using a prospectively completed database. PATIENTS AND INTERVENTIONS: From May 1990 to November 2008, records of 271 consecutive patients who received 289 composite visceral grafts were retrospectively reviewed; 151 of the allografts were L/SB (52%) and the remaining 138 were MV. MAIN OUTCOME MEASUREMENTS: Type, incidence, risk factors, clinical features, and management of PB complications. RESULTS: PB complications were diagnosed in 44 patients with an incidence of 16%. Biliary complications developed in 20 patients (ampullary stenosis in 9, bile duct casts/stones in 6, and bile duct leaks in 5), pancreatic complications occurred in 19 patients (necrotizing pancreatitis in 7, edematous pancreatitis in 6, and pancreatic duct fistulae in 6), and combined biliary and pancreatic complications occurred in 5 patients. The risk of PB complications was significantly higher in MV graft recipients compared with L/SB recipients with a rate of 25% compared with 9%, respectively. ERCP was instrumental in the diagnosis and/or treatment of ampullary stenosis, bile duct casts and stones, bile duct leaks, and recurrent acute pancreatitis. Combined endoscopic and surgical intervention was required in most cases of pancreatic duct fistulae. Surgical intervention was performed in patients with pancreatic allograft necrosis and complex anastomotic biliary leaks. LIMITATIONS: Single-center study. CONCLUSIONS: PB complications are common after composite visceral transplantation. Awareness of these complications is important to the transplantation team to ensure early diagnosis and appropriate intervention in an attempt to minimize morbidity and mortality.

Pediatric intestinal transplantation: historical notes, principles and controversies.

The development in technique and immunosuppressive management of the last 12 yr have made intestinal transplantation an effective treatment for children with intestinal failure. The information provided in this review support such a conclusion, but was more clearly validated by the March 2001 Medicare Report which provided a national coverage decision of the Social Security Act for intestinal transplantation. As of May 2001, there were 55 centers world-wide which have performed 696 intestinal transplants in 656 patients. (Intestinal Transplant Registry, http://www.lhsc.on.ca/itr) the majority of recipients have been children, and there has been a greater need for liver replacement in conjunction with the allograft intestine because of a higher incidence of TPN-induced cholestatic liver disease in children. Though overall long-term survival is approximately 50%, similar advances in surgical, clinical and immunosuppressive management since 1995 have improved patient survival to more than 70% in most experienced programs. Over 80% of survivors are enjoying nutrition-supporting intestinal function. The major causes of graft loss and patient demise continues to be rejection and infection. Tacrolimus remains the mainstay of immunosuppressive therapy. Further experience other induction protocols utilizing rapamycin and daclizumab, as well graft pretreatment protocols may further enhance results in the future.