Banff 2022 Liver Group Meeting report: Monitoring long-term allograft health.

The Banff Working Group on Liver Allograft Pathology met in September 2022. Participants included hepatologists, surgeons, pathologists, immunologists, and histocompatibility specialists. Presentations and discussions focused on the evaluation of long-term allograft health, including noninvasive and tissue monitoring, immunosuppression optimization, and long-term structural changes. Potential revision of the rejection classification scheme to better accommodate and communicate late T cell-mediated rejection patterns and related structural changes, such as nodular regenerative hyperplasia, were discussed. Improved stratification of long-term maintenance immunosuppression to match the heterogeneity of patient settings will be central to improving long-term patient survival. Such personalized therapeutics are in turn contingent on a better understanding and monitoring of allograft status within a rational decision-making approach, likely to be facilitated in implementation with emerging decision-support tools. Proposed revisions to rejection classification emerging from the meeting include the incorporation of interface hepatitis and fibrosis staging. These will be opened to online testing, modified accordingly, and subject to consensus discussion leading up to the next Banff conference.

Caregivers' and providers' perspectives of social and medical care after pediatric liver transplant: Results from the multicenter SOCIAL-Tx study.

Disparities exist in pediatric liver transplant (LT). We characterized barriers and facilitators to providing transplant and social care within pediatric LT clinics. This was a multicenter qualitative study. We oversampled caregivers reporting household financial strain, material economic hardship, or demonstrating poor health literacy. We also enrolled transplant team members. We conducted semistructured interviews with participants. Caregiver interviews focused on challenges addressing transplant and household needs. Transplant provider interviews focused on barriers and facilitators to providing social care within transplant teams. Interviews were recorded, transcribed, and coded according to the Capability, Opportunity, Motivation-Behavior model. We interviewed 27 caregivers and 27 transplant team members. Fifty-two percent of caregivers reported a household income <$60,000, and 62% reported financial resource strain. Caregivers reported experiencing (1) high financial burdens after LT, (2) added caregiving labor that compounds the financial burden, (3) dependency on their social network's generosity for financial and logistical support, and (4) additional support being limited to the perioperative period. Transplant providers reported (1) relying on the pretransplant psychosocial assessment for identifying social risks, (2) discomfort initiating social risk discussions in the post-transplant period, (3) reliance on social workers to address new social risks, and (4) social workers feeling overburdened by quantity and quality of the social work referrals. We identified barriers to providing effective social care in pediatric LT, primarily a lack of comfort in assessing and addressing new social risks in the post-transplant period. Addressing these barriers should enhance social care delivery and improve outcomes for these children.

Ambient air pollution is associated with graft failure/death in pediatric liver transplant recipients.

Children exposed to disproportionately higher levels of air pollution experience worse health outcomes. In this population-based, observational registry study, we examine the association between air pollution and graft failure/death in children following liver transplantation (LT) in the US. We modeled the associations between air pollution (PM2.5) levels localized to the patient's ZIP code at the time of transplant and graft failure or death using Cox proportional-hazards models in pediatric LT recipients aged <19 years in the US from 2005-2015. In univariable analysis, high neighborhood PM2.5 was associated with a 56% increased hazard of graft failure/death (HR: 1.56; 95% CI: 1.32, 1.83; P < .001). In multivariable analysis, high neighborhood PM2.5 was associated with a 54% increased risk of graft failure/death (HR: 1.54; 95% CI: 1.29, 1.83; P < .001) after adjusting for race as a proxy for racism, insurance status, rurality, and neighborhood socioeconomic deprivation. Children living in high air pollution neighborhoods have an increased risk of graft failure and death posttransplant, even after controlling for sociodemographic variables. Our findings add further evidence that air pollution contributes to adverse health outcomes for children posttransplant and lay the groundwork for future studies to evaluate underlying mechanisms linking PM2.5 to adverse LT outcomes.

Association of state Medicaid expansion policies with pediatric liver transplant outcomes.

Children from minoritized/socioeconomically deprived backgrounds suffer disproportionately high rates of uninsurance and graft failure/death after liver transplant. Medicaid expansion was developed to expand access to public insurance. Our objective was to characterize the impact of Medicaid expansion policies on long-term graft/patient survival after pediatric liver transplantation. All pediatric patients (<19 years) who received a liver transplant between January 1, 2005, and December 31, 2020 in the US were identified in the Scientific Registry of Transplant Recipients (N = 8489). Medicaid expansion was modeled as a time-varying exposure based on transplant and expansion dates. We used Cox proportional hazards models to evaluate the impact of Medicaid expansion on a composite outcome of graft failure/death over 10 years. As a sensitivity analysis, we conducted an intention-to-treat analysis from time of waitlisting to death (N = 1 1901). In multivariable analysis, Medicaid expansion was associated with a 30% decreased hazard of graft failure/death (hazard ratio, 0.70; 95% confidence interval, 0.62, 0.79; P < .001) after adjusting for Black race, public insurance, neighborhood deprivation, and living in a primary care shortage area. In intention-to-treat analyses, Medicaid expansion was associated with a 72% decreased hazard of patient death (hazard ratio, 0.28; 95% confidence interval, 0.23-0.35; P < .001). Policies that enable broader health insurance access may help improve outcomes and reduce disparities for children undergoing liver transplantation.

Caregiver Perceptions of Social Risk Screening in Pediatric Liver Transplantation: From the Multicenter SOCIAL-Tx Study.

BACKGROUND: The social determinants of health contribute to adverse post-liver transplant outcomes. Identifying unmet social risks may enable transplant teams to improve long-term outcomes for at-risk children. However, providers may feel uncomfortable asking about household-level social risks in the posttransplant period because they might make their patients/families uncomfortable. METHODS: We conducted a mixed-methods analysis of caregiver participants (ie, parents/guardians of pediatric liver transplant recipients) in the Social and Contextual Impact on Children Undergoing Liver Transplantation study to assess their perceptions of provider-based social risk screening. Participants (N = 109) completed a 20-min social determinants of health questionnaire that included questions on the acceptability of being asked intimate social risk questions. A subset of participants (N = 37) engaged in an in-depth qualitative interview to share their perceptions of social risk screening. RESULTS: Of 109 participants across 9 US transplant centers, 60% reported financial strain and 30% reported at least 1 material economic hardship (eg, food insecurity, housing instability). Overall, 65% of respondents reported it very or somewhat appropriate and 25% reported being neutral to being screened for social risks in a liver transplant setting. In qualitative analyses, participants reported trust in the providers and a clear understanding of the intention of the screening as prerequisites for liver transplant teams to perform social risk screening. CONCLUSIONS: Only a small minority of caregivers found social risk screening unacceptable. Pediatric liver transplant programs should implement routine social risk screening and prioritize the patient and family voices when establishing a screening program to ensure successful implementation.

A review of racial, socioeconomic, and geographic disparities in pediatric liver transplantation.

Equity is a core principle in both pediatrics and solid organ transplantation. Health inequities, specifically across race, socioeconomic position, or geography, reflect a moral failure. Ethical principles of prudential life span, maximin principle, and fair innings argue for allocation priority to children related to the number of life years gained, equal access to transplant, and equal opportunity for ideal posttransplant outcomes. Iterative policy changes have aimed to narrow these disparities to achieve pediatric transplant equity. These policy changes have focused on modifying pediatric priority for organ allocation to eliminate mortality on the pediatric transplant waiting list. Yet disparities remain in pediatric liver transplantation at all time points: from access to referral for transplantation, likelihood of living donor transplantation, use of exception narratives, waitlist mortality, and inequitable posttransplant outcomes. Black children are less likely to be petitioned for exception scores, have higher waitlist mortality, are less likely to be the recipient of a living donor transplant, and have worse posttransplant outcomes compared with White children. Children living in the most socioeconomically deprived neighborhoods have worse posttransplant outcomes. Children living farther from a transplant center have higher waitlist mortality. Herein we review the current knowledge of these racial and ethnic, socioeconomic, and geographic disparities for these children. To achieve equity, stakeholder engagement is required at all levels from providers and health delivery systems, learning networks, institutions, and society. Future initiatives must be swift, bold, and effective with the tripartite mission to inform policy changes, improve health care delivery, and optimize resource allocation to provide equitable transplant access, waitlist survival, and posttransplant outcomes for all children.

Racial/ethnic disparities in wait-list outcomes are only partly explained by socioeconomic deprivation among children awaiting liver transplantation.

BACKGROUND AND AIMS: Racial/ethnic minority children have worse liver transplant (LT) outcomes. We evaluated whether neighborhood socioeconomic deprivation affected associations between race/ethnicity and wait-list mortality. APPROACH AND RESULTS: We included children (age <18) listed 2005-2015 in the Scientific Registry of Transplant Recipients. We categorized patients as non-Hispanic White, Black, Hispanic, and other. We matched patient ZIP codes to a neighborhood socioeconomic deprivation index (range, 0-1; higher values indicate worse deprivation). Primary outcomes were wait-list mortality, defined as death/delisting for too sick, and receipt of living donor liver transplant (LDLT). Competing risk analyses modeled the association between race/ethnicity and wait-list mortality, with deceased donor liver transplant (DDLT) and LDLT as competing risks, and race/ethnicity and LDLT, with wait-list mortality and DDLT as competing risks. Of 7716 children, 17% and 24% identified as Black and Hispanic, respectively. Compared to White children, Black and Hispanic children had increased unadjusted hazard of wait-list mortality (subhazard ratio [sHR], 1.44; 95% CI, 1.18, 1.75 and sHR, 1.48; 95% CI, 1.25, 1.76, respectively). After adjusting for neighborhood deprivation, insurance, and listing laboratory Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease, Black and Hispanic children did not have increased hazard of wait-list mortality (sHR, 1.12; 95% CI, 0.91, 1.39 and sHR, 1.21; 95% CI, 1.00, 1.47, respectively). Similarly, Black and Hispanic children had a decreased likelihood of LDLT (sHR, 0.58; 95% CI, 0.45, 0.75 and sHR, 0.61; 95% CI, 0.49, 0.75, respectively). Adjustment attenuated the effect of Black and Hispanic race/ethnicity on likelihood of LDLT (sHR, 0.79; 95% CI, 0.60, 1.02 and sHR, 0.89; 95% CI, 0.70, 1.11, respectively). CONCLUSIONS: Household and neighborhood socioeconomic factors and disease severity at wait-list entry help explain racial/ethnic disparities for children awaiting transplant. A nuanced understanding of how social adversity contributes to wait-list outcomes may inform strategies to improve outcomes.

Addressing Social Adversity to Improve Outcomes for Children After Liver Transplant.

The social determinants of health, defined as the conditions in which we live, learn, work, and play, undoubtedly impact health outcomes. Social adversity in childhood perpetuates over the life course and has consequences extending into adulthood. This link between social adversity and adverse outcomes extends to children undergoing liver transplant, with children from socioeconomically deprived neighborhoods experiencing a greater burden of morbidity and mortality after transplant. Yet, we lack an in-depth understanding of how to address social adversity for these children. Herein, we lay out a strategy to develop and test interventions to address social adversity for children undergoing liver transplant. To do so, we believe that more granular data on how specific social risk factors (e.g., food insecurity) impact outcomes for children after liver transplant are needed. This will provide the liver transplant community with knowledge on the most pressing problems. Then, using the National Academies of Sciences, Engineering, and Medicine's framework for integrating social needs into medical care, the health system can start to develop and test health system interventions. We believe that attending to our patients' social adversity will realize improved outcomes for children undergoing liver transplant.

Neighborhood socioeconomic deprivation, racial segregation, and organ donation across 5 states.

One in 10 people die awaiting transplantation from donor shortage. Only half of Americans register as organ donors. In this cross-sectional study, we evaluated population-level associations of neighborhood socioeconomic deprivation and racial segregation on organ donor registration rates. We analyzed state identification card demographic and organ donor registration data from 5 states to estimate the association between a neighborhood socioeconomic deprivation index (range [0, 1]; higher values indicate more deprivation) and a racial index of concentration at the extreme (ICE) (range [-1, 1]; lower values indicate predominantly black neighborhoods, higher values indicate predominantly white neighborhoods) on organ donor registration rates within a specified geography (census tract or ZIP code tabulation area [ZCTA]). Among 26 720 738 registrants, 32% of the sample were registered organ donors. At the census tract level, with each 0.1 decrease in the deprivation index, the organ donor registration rate increased by 6.8% (95% confidence interval [CI]: 6.6%, 7.0%). With each 0.1 increase in the racial ICE, the rate increased by 1.5% (95% CI: 1.5%, 1.6%). These associations held true at the ZCTA level. Areas with less socioeconomic deprivation and a higher concentration of white residents have higher organ donor registration rates. Public health initiatives should consider neighborhood context and novel data sources in designing optimal intervention strategies.

Association Between Neighborhood-level Socioeconomic Deprivation and the Medication Level Variability Index for Children Following Liver Transplantation.

BACKGROUND: Neighborhood socioeconomic deprivation is associated with adverse health outcomes. We sought to determine if neighborhood socioeconomic deprivation was associated with adherence to immunosuppressive medications after liver transplantation. METHODS: We conducted a secondary analysis of a multicenter, prospective cohort of children enrolled in the medication adherence in children who had a liver transplant study (enrollment 2010-2013). Participants (N = 271) received a liver transplant ≥1 year before enrollment and were subsequently treated with tacrolimus. The primary exposure, connected to geocoded participant home addresses, was a neighborhood socioeconomic deprivation index (range 0-1, higher indicates more deprivation). The primary outcome was the medication level variability index (MLVI), a surrogate measure of adherence to immunosuppression in pediatric liver transplant recipients. Higher MLVI indicates worse adherence behavior; values ≥2.5 are predictive of late allograft rejection. RESULTS: There was a 5% increase in MLVI for each 0.1 increase in deprivation index (95% confidence interval, -1% to 11%; P = 0.08). Roughly 24% of participants from the most deprived quartile had an MLVI ≥2.5 compared with 12% in the remaining 3 quartiles (P = 0.018). Black children were more likely to have high MLVI even after adjusting for deprivation (adjusted odds ratio 4.0 95% confidence interval, 1.7-10.6). CONCLUSIONS: This is the first study to evaluate associations between neighborhood socioeconomic deprivation and an objective surrogate measure of medication adherence in children posttransplant. These findings suggest that neighborhood context may be an important consideration when assessing adherence. Differential rates of medication adherence may partly explain links between neighborhood factors and adverse health outcomes following pediatric liver transplantation.

Neighborhood socioeconomic deprivation is associated with worse patient and graft survival following pediatric liver transplantation.

Long-term outcomes remain suboptimal following pediatric liver transplantation; only one third of children have normal biochemical liver function without immunosuppressant comorbidities 10 years posttransplant. We examined the association between an index of neighborhood socioeconomic deprivation with graft and patient survival using the Scientific Registry of Transplant Recipients. We included children <19 years who underwent liver transplantation between January 1, 2008 to December 31, 2013 (n = 2868). Primary exposure was a neighborhood socioeconomic deprivation index-linked via patient home ZIP code-with a range of 0-1 (values nearing 1 indicate neighborhoods with greater socioeconomic deprivation). Primary outcome measures were graft failure and death, censored at 10 years posttransplant. We modeled survival using Cox proportional hazards. In univariable analysis, each 0.1 increase in the deprivation index was associated with a 14.3% (95% confidence interval [CI]): 3.8%-25.8%) increased hazard of graft failure and a 12.5% (95% CI: 2.5%-23.6%) increased hazard of death. In multivariable analysis adjusted for race, each 0.1 increase in the deprivation index was associated with a 11.5% (95% CI: 1.6%-23.9%) increased hazard of graft failure and a 9.6% (95% CI: -0.04% to 20.7%) increased hazard of death. Children from high deprivation neighborhoods have diminished graft and patient survival following liver transplantation. Greater attention to neighborhood context may result in improved outcomes for children following liver transplantation.

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.

Similarities and Differences in Allocation Policies for Pediatric Liver Transplantation Across the World.

OBJECTIVES: We aimed to investigate national allocation policies for pediatric liver transplantation (LT). METHOD: A survey was prepared by the European Society for Paediatric Gastroenterology Hepatology and Nutrition Hepatology Committee in collaboration with the North American Studies of Pediatric Liver Transplantation consortium. The survey was sent to pediatric hepatologists and transplant surgeons worldwide. National data were obtained from centrally based registries. RESULTS: Replies were obtained from 15 countries from 5 of the world continents. Overall donation rate varied between 9 and 35 per million inhabitants. The number of pediatric LTs was 4 to 9 per million inhabitants younger than 18 years for 13 of the 15 respondents. In children younger than 2 years mortality on the waiting list (WL) varied between 0 and 20%. In the same age group, there were large differences in the ratio of living donor LT to deceased donor LT and in the ratio of split liver segments to whole liver. These differences were associated with possible discrepancies in WL mortality. CONCLUSIONS: Similarities but also differences between countries were detected. The described data may be of importance when trying to reduce WL mortality in the youngest children.

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.

Analysis of Liver Offers to Pediatric Candidates on the Transplant Wait List.

BACKGROUND & AIMS: Approximately 10% of children on the liver transplant wait-list in the United States die every year. We examined deceased donor liver offer acceptance patterns and their contribution to pediatric wait-list mortality. METHODS: We performed a retrospective cohort study of children on the US liver transplant wait-list from 2007 through 2014 using national transplant registry databases. We determined the frequency, patterns of acceptance, and donor and recipient characteristics associated with deceased donor liver organ offers for children who died or were delisted compared with those who underwent transplantation. Children who died or were delisted were classified by the number of donor liver offers (0 vs 1 or more), limiting analyses to offers of livers that were ultimately transplanted into pediatric recipients. The primary outcome was death or delisting on the wait-list. RESULTS: Among 3852 pediatric liver transplant candidates, children who died or were delisted received a median 1 pediatric liver offer (inter-quartile range, 0-2) and waited a median 33 days before removal from the wait-list. Of 11,328 donor livers offered to children, 2533 (12%) were transplanted into children; 1179 of these (47%) were immediately accepted and 1354 (53%) were initially refused and eventually accepted for another child. Of 27,831 adults, 1667 (6.0%; median, 55 years) received livers from donors younger than 18 years (median, 15 years), most (97%) allocated locally or regionally. Of children who died or were delisted, 173 (55%) received an offer of 1 or more liver that was subsequently transplanted into another pediatric recipient, and 143 (45%) died or were delisted with no offers. CONCLUSIONS: Among pediatric liver transplant candidates in the US, children who died or were delisted received a median 1 pediatric liver offer and waited a median of 33 days. Of livers transplanted into children, 47% were immediately accepted and 53% were initially refused and eventually accepted for another child. Of children who died or were delisted, 55% received an offer of 1 or more liver that was subsequently transplanted into another pediatric recipient, and 45% died or were delisted with no offers. Pediatric prioritization in the allocation and development of improved risk stratification systems is required to reduce wait-list mortality among children.

Obtaining consensus regarding international transplantation continues to be difficult for pediatric centers in the United States.

Organ transplant is life-saving and any given organ may be valuable to a multitude of potential recipients. An allocation system must be used to reconcile the difference between supply and demand, and this system must take into account the impact that accepting international patients may have on the local system. The principles for allocation must be clear, equitable, provide utility and must be monitored so as to maintain public trust. The impact of the system on metrics deemed to be critical must be measured. Finally, strategies must take into account the local culture, size of the region to be supported, the number and experience of transplant centers, and the resources of the healthcare delivery system. Our focus is on the United States, recognizing that strategies and challenges may vary across countries.

Outcomes after liver transplantation: keep the end in mind.

Since the advent of transplantation as a life-saving procedure for patients with end-stage liver disease, more than 15,000 children and adolescents have received liver transplants. With the improvements in long-term posttransplant survival offered by advances in medical and surgical therapy, the concept of transplantation outcome has expanded beyond simple patient and graft survival rates. The quality of the life years restored, the long-term complications of transplant immunosuppression, and the overall cost of care have been increasingly recognized as important components of liver transplantation outcome. This review focuses on the efforts of a single pediatric transplant center to examine the incidence of, and risk factors for, common posttransplantation complications, to characterize posttransplantation health-related quality of life, to describe the cost of posttransplant care, and to implement novel programs to improve health care delivery. Together, these projects set the future course for research and care improvement initiatives in this population and encourage us to "keep the end in mind" when considering pediatric liver transplantation.

Outcome after pediatric liver transplantation impact of living donor transplantation on cost.

OBJECTIVE: To compare the direct health care cost of living donor liver transplantation (LDLT) with that of cadaver donor liver transplantation (CDLT) in children and identify predictors of cost. STUDY DESIGN: All 16 children who underwent LDLT from January 1997 through January 2002 at Cincinnati Children's Hospital Medical Center comprised the study population. They were matched for age, diagnosis, and nutritional status with 31 children who received CDLT during the same era. A historic cohort analysis was performed. RESULTS: There was no difference in the 1-year mortality rates between both groups. Costs associated with graft retrieval contributed 15.3% and 31% of the initial transplant cost for LDLT and CDLT, respectively. Mean cost of care in the first year was 60.3% higher for LDLT than CDLT (P=.01). Multivariate analysis identified biliary complications and insurance status as predictors of cost for initial transplantation (R(2)=0.57), whereas biliary complications and pediatric end stage liver disease scores were identified as predictors of cost of care in the first year after transplantation (R(2)=0.77). CONCLUSIONS: The comprehensive cost of LDLT in the first year after transplantation is higher than cadaveric transplantation. This must be balanced against the time spent and care needs of patients on the waiting list.