BACKGROUND: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. METHODS: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. RESULTS: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. CONCLUSIONS: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.

Acute T-cell-mediated transplant rejection, the earliest contributor to immunological graft failure responds variably to T-cell suppression. Early rejection can co-exist with donor-specific antibodies which also shorten graft survival, without affecting graft histology visibly. Here, during early liver transplant rejection, blood leukocytes manifest primed T-cells with heat shock protein (HSP) signaling and transcriptional programs for memory cell expansion. Corresponding biopsies demonstrate upregulated immune synapse and proteasomal genes in T-cell-infiltrated portal and central regions of the liver lobule. With donor-specific antibodies, the intervening intralobular region demonstrates a germinal-center-like allograft response with upregulated CD40, chemokine, T-follicular and complement signaling, which intensifies along the direction of sinusoidal blood flow from portal to central regions. Proteasomal and HSP90 inhibitors suppress donor-specific alloresponses of T- and B-cells in blood samples from patients with early rejection. The molecular injury spectrum of early rejection is complex, spatially differentiated and reveals novel early immunosuppressive strategies to extend graft survival. ### Competing Interest Statement The authors have declared no competing interest.

Guidelines for managing hepatic artery thrombosis (HAT) and stenosis (HAS) after pediatric liver transplantation (pLT) are lacking, with heterogeneous local practices. This study aims to evaluate management practices for HAT and HAS after pLT. An online and paper-based survey was sent to 36 international pLT centers. The survey included 36 questions covering center experience, screening protocols, diagnostic criteria, preventive management, post-procedural care, and follow-up. Treatment strategies were explored through hypothetical case scenarios categorized by early (≤14 d after pLT) and late onset complications (>14 d after pLT). Responses from 36 centers showed that 60% applied interrupted sutures and 76% used a surgical loupe during transplantation. In addition, 89% followed a specific anticoagulation protocol after uncomplicated pLT. All centers initiated Doppler ultrasound (DUS) within 24 hours after pLT, with 60% conducting it daily during the first week. Immediate re-transplantation was preferred for early HAT with pediatric acute liver failure (PALF) (61% vs. 11% for non-PALF, p <0.001), and surgical revascularization was more frequently chosen for non-PALF cases (51% vs. 24% for PALF, p <0.001). Endovascular therapy was selected in 35% of cases for both late HAT and HAS, with conservative management chosen in 51% for late HAT and 61% for late HAS (all p <0.001, compared to early cases). Internationally, there is agreement on the importance of early DUS screening in current management practices. Immediate re-transplantation was preferred for early HAT with PALF, while surgical revascularization was favored for non-PALF cases. Conservative management and endovascular therapy emerged as potential strategies for late-onset cases. This worldwide survey on real-world practice provides a basis for developing and implementing guidelines.

BACKGROUND Liver transplantation (LT) is the only curative, life-saving option for children and adults with end-stage liver disease. Due to the well-known shortage and heterogeneity of grafts, split LT (SLT) is an attractive strategy to expand the donor pool and reduce waitlist times. Given increased risk of cold ischemia time with SLT, machine perfusion represents a promising option to reduce it and optimize transplant logistics and outcomes. The present communication describes various possible combinations of procurement steps to perform SLT facilitated by placing one or both grafts on a normothermic machine perfusion (NMP) closed circuit device. CASE SUMMARY A 19-month-old female with biliary atresia after failed Kasai portoenterostomy and a 42-year-old woman with unresectable intrahepatic cholangiocarcinoma were selected as recipients for a SLT from a 17-year-old male donor. The SLT generated a left lateral segment and a right trisectional graft of appropriate volume for both recipients. After a mixed in-situ and ex-situ split, in order to improve logistics, the right trisectional graft was placed on a closed circuit NMP device, following an appropriate vascular reconstruction. Both grafts were implanted with excellent short-term outcomes. CONCLUSION Use of NMP with SLT for preservation prior to implantation allows not only for graft optimization but also for significant improvement of transplant logistics. We propose various models and standardization of logistic options for combining SLT with NMP to optimize graft availability and outcomes.

Introduction Hepatic artery complications (HACs), such as a thrombosis or stenosis, are serious causes of morbidity and mortality after paediatric liver transplantation (LT). This study will investigate the incidence, current management practices and outcomes in paediatric patients with HAC after LT, including early and late complications.Methods and analysis The HEPatic Artery stenosis and Thrombosis after liver transplantation In Children (HEPATIC) Registry is an international, retrospective, multicentre, observational study. Any paediatric patient diagnosed with HAC and treated for HAC (at age <18 years) after paediatric LT within a 20-year time period will be included. The primary outcomes are graft and patient survivals. The secondary outcomes are technical success of the intervention, primary and secondary patency after HAC intervention, intraprocedural and postprocedural complications, description of current management practices, and incidence of HAC.Ethics and dissemination All participating sites will obtain local ethical approval and (waiver of) informed consent following the regulations on the conduct of observational clinical studies. The results will be disseminated through scientific presentations at conferences and through publication in peer-reviewed journals.Trial registration number The HEPATIC registry is registered at the ClinicalTrials.gov website; Registry Identifier: NCT05818644.

Background. Enhanced B-cell presentation of donor alloantigen relative to presentation of HLA-mismatched reference alloantigen is associated with acute cellular rejection (ACR), when expressed as a ratio called the antigen presenting index (API) in an exploratory cohort of liver and intestine transplant (LT and IT) recipients. Methods. To test clinical performance, we measured the API using the previously described 6-h assay in 84 LT and 54 IT recipients with median age 3.3 y (0.05–23.96). Recipients experiencing ACR within 60 d after testing were termed rejectors. Results. We first confirmed that B-cell uptake and presentation of alloantigen induced and thus reflected the alloresponse of T-helper cells, which were incubated without and with cytochalasin and primaquine to inhibit antigen uptake and presentation, respectively. Transplant recipients included 76 males and 62 females. Rejectors were tested at median 3.6 d before diagnosis. The API was higher among rejectors compared with nonrejectors (2.2 ± 0.2 versus 0.6 ± 0.04, P value = 1.7E-09). In logistic regression and receiver-operating-characteristic analysis, API ≥1.1 achieved sensitivity, specificity, and positive and negative predictive values for predicting ACR in 99 training set samples. Corresponding metrics ranged from 80% to 88% in 32 independent posttransplant samples, and 73% to 100% in 20 independent pretransplant samples. In time-to-event analysis, API ≥1.1 predicted higher incidence of late donor-specific anti-HLA antibodies after API measurements in LT recipients (P = 0.011) and graft loss in IT recipients (P = 0.008), compared with recipients with API <1.1, respectively. Conclusions. Enhanced donor antigen presentation by circulating B cells predicts rejection after liver or intestine transplantation as well as higher incidence of DSA and graft loss late after transplantation

Pediatric liver transplant is a lifesaving intervention for children with disparate pathology ranging from single-gene defects to global liver dysfunction and complications from progressive cirrhosis and portal hypertension. The Starzl Network for Excellence in Pediatric Transplantation (SNEPT), a novel learning health system dedicated to pediatric liver transplant, has previously identified practice variability, waitlist mortality, perioperative complications, and inadequate quality initiative implementation as critical barriers that deserve prioritization in the field. This project was a novel partnership between SNEPT and the United Network for Organ Sharing to co-design a pediatric transplant-specific data mart and web portal to systematically map an approach to understanding these barriers and deliver strategies to combat them. We combined transplant-specific data from center Standard Transplant Analysis and Research files with project specific metrics identified by SNEPT to develop a web-based application to display progress and disseminate results. Customized, dynamic visualizations were built to display project data for center-level review and network-wide benchmarking, quality assurance, and performance improvement. Our DataMart platform represents a successful, scalable, systems-level approach to data management that can be adopted by other transplant communities to ensure transplant-specific learning health system development, growth, and expansion.

BACKGROUND:There is limited data in the literature about pediatric kidney transplant (KT) following gut transplant (GT). The purpose of this study is to highlight the technical challenges and outcomes of KT in pediatric gut recipients who developed kidney failure (KF). METHODS:A retrospective single-center study of pediatric GT recipients from January 2000 to December 2019 was performed. In total, 14 (7%) out of 206 pediatric GT recipients developed KF and were listed for KT. Ten patients underwent kidney after gut transplant (KAGT), three patients underwent simultaneous kidney and re-do gut transplant (SKAGT), and one patient died on the KT waitlist. RESULTS:1-, 5-, and 10-year kidney graft survival was 100%, 91%, and 78%, respectively. 1-, 5-, and 10-year GT graft survival was 100%, 77%, and 77%, respectively. 1-, 5-, and 10-year patient survival was 100%, 91%, and 91%, respectively. CONCLUSION:Despite the technical complexity, KAGT and SKAGT for pediatric GT recipients that develop KF can be performed with favorable outcomes.

Multivisceral transplant (MVT) is a complex procedure with high potential for systemic and graft-related vascular events. We aim to describe vascular complications post-MVT and their impact on graft and patient outcomes. All post-MVT patients treated at our institution (2000-2022) were retrospectively reviewed for arterial (aneurysm, aortoenteric fistula, visceral artery stenosis, thrombosis, bleeding) and venous (deep vein thrombosis, visceral vein thrombosis, pulmonary embolism) complications. Two groups were created: with (VC) and without (NVC) vascular complications. Requiring a second transplant or death from graft rejection denoted graft-failure. Median time to VC was reported and compared using one-way analysis of variance. Kaplan-Meier estimates with log-rank testing and multivariate Cox models were generated for graft and mortality outcomes. Forty of 90 (44%) patients had 50 vascular complications. Baseline demographics (mean age, 36.6 years; range, 1-71 years) were similar between VC vs NVC groups. Venous thrombosis was the most common complication (54%), while one celiac stenosis occurred (Table). Nine aneurysms developed: five donor aorta, two celiac artery, one external iliac artery, and one femoral artery. Rates and time to development of VC were nonsignificantly different, with arterial stenosis observed the earliest and aortoenteric fistula the latest. Medical therapy was most common for venous thrombosis (82.3%), while endovascular/surgical management were frequent with arterial complications. Two reinterventions occurred for thrombosis of a repaired aneurysm and for recurrent mesenteric artery bleeding postembolization. While survival rates were similar between NVC and VC at 1 (59.6% vs 69.5%; P = .49), 3 (59.6% vs 48.9%; P = .79), and 5 years (51.1% vs 31.3%; P = .46), a notable decline is seen after 1 year in VC group. Graft survival was similar between both groups at 1, 3, and 5 years. Aneurysm formation was the only mortality predictor among the VC group at 1 year (aHR, 4.88; P = .003), 3 years (aHR, 3.08; P = .02), and 5 years (aHR, 2.8; P = .02). Aneurysm formation was also a predictor of graft failure at 1 year (aHR, 5.15; P = .004), 3 years (aHR, 4.2; P = .001), and 5 years (aHR, 4.27; P = .001). MVT carries a high risk of vascular complications (44.4%) at variable timepoints; the most common being venous thromboembolism. Vascular complications, particularly aneurysm formation, increases long-term mortality risk and graft failure which may be mitigated by preventive and surveillance strategies post-MVT.TableTime to development and treatment of complications in years by type of complicationType of complicationMedian, yearsIQRFrequency (n = 50)Medical treatment (n = 17)Endovascular treatment (n = 11)Surgical treatment (n = 8)P valueAneurysm5.552.23-7.219 (18)04 (36.5)2 (25).62Aortoenteric fistula6.830.22-13.452 (4)01 (9.0)1 (12.5)Mesenteric stenosis0.35-1 (2)01 (9.0)0Bleeding2.620.07-5.058 (16)1 (5.9)4 (36.5)3 (37.5)Arterial thrombosis4.643.94-7.373 (6)2 (11.8)00Venous thrombosis1.910.59-7.9827 (54)14 (82.3)1 (9.0)2 (25)Values are number (%) unless otherwise noted. Open table in a new tab

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

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<0.0001), c) lower in Tr patients with severe COVID-19 (p<0.0001), or COVID-19 requiring hospitalization (p<0.05), compared with healthy Tr recipients. S-reactive T-cells were not significantly different between the various COVID-19 disease categories in NT recipients. Among transplant recipients with COVID-19, cytomegalovirus co-infection occurred in 34%; further, CMV-specific T-cells (p<0.001) and incidence of anti-receptor-binding-domain IgG (p=0.011) were lower compared with non-transplanted COVID-19 patients. Healthy unexposed transplant recipients exhibit pre-existing T-cell immunity to SARS-CoV-2. COVID-19 infection leads to impaired T-cell and antibody responses to SARS-CoV-2 and increased risk of CMV co-infection in transplant recipients.

BackgroundOperational tolerance after retransplantation of the intestine has never been reported. PurposeTo two recently described intestine transplant recipients with operational tolerance, we now add a third. MethodsReview of case record and immunological testing to confirm donor-specific hyporesponsiveness in multiple immune cell compartments. ResultsRe-transplanted with a multivisceral liver- and kidney-inclusive intestine allograft at age 12 years, this recipient self-discontinued immunosuppression 14 years after the retransplant and has been rejection free for 2 years thereafter. As in the two previous reports, immunological testing demonstrated decreased donor-specific inflammatory response of T-cytotoxic memory cells and B-cells, decreased presentation of donor antigen by B-cells and monocytes, absence of donor-specific anti-HLA antibodies, circulating FOXP3 + T-helper cells, and intact cellular and humoral immunity to cytomegalovirus and Epstein-Barr virus. Additionally, our recipient demonstrated enhanced donor-activation-induced apoptosis of alloreactive T-cytotoxic memory cells. ConclusionsDespite variable paths to tolerance which include graft versus host disease in two previous cases, and rejection-related loss of the primary isolated intestinal allograft in our recipient, the three cases with operational tolerance are bound by common themes: a relatively large donor antigenic load transmitted during intestine transplantation, and donor-specific hyporesponsiveness. Cell-based assays suggest enhanced donor-induced apoptosis of recipient T-cells and circulating T-regulatory cells as mechanistic links between antigenic load and donor-specific hyporesponsiveness.

In this issue, Esmati et al.1 present a fascinating analysis of the impact on waitlist outcomes of a 2014 Eurotransplant (ET) policy that prioritizes patients younger than the age of 2 years with biliary atresia for deceased donor liver transplantation (DDLT) offers. In comparing 882 children listed in the preimplementation phase with 173 children in the postimplementation phase, the authors found that waitlist mortality decreased from 6.7% before to 2.3% after implementation of the new policy. Unexpectedly, this was not associated with an increase in DDLTs. In addition, wait times for DDLT for these youngest children actually increased in the postpolicy versus prepolicy time period. During the same time period, the proportion of young patients with BA who underwent living donor liver transplantation (LDLT) increased from 55% to 74%. The authors thus argue that the significant decline in waitlist mortality was attributed to the increase in LDLT. Although the postpolicy cohort is smaller and bigger sample sizes will be needed to confirm this trend, these findings are striking. The impact of LDLT both in terms of waitlist outcomes and longer term benefit is clear in the current data from Europe, the United States, and other countries.2 LDLT needs to be implemented more widely. Why this increase in LDLT occurred in the ET experience will take further study. This study highlights four important lessons in the liver transplantation community's approach to serving one of our most at‐risk populations who have continued to have the highest risk of death while on the waiting list in the United States and Europe: children aged younger than 2 years. ET focused on children specifically with biliary atresia, but these lessons apply to all children who require liver transplantation in very early childhood—and who deserve prioritization with the babies who have biliary atresia. First, Europe and other regions have set an example for the global community by intentional efforts to prioritize children for live‐saving liver grafts for DDLTs.3,4 Their data‐driven policy is clearly further supported by the ethical justification for prioritizing children for this scarce resource.5 Their experience highlights that prioritizing children for DDLT does not de facto trigger decreased use of LDLT, which has been noted by some as an argument against increasing pediatric priority for adult deceased donors. The second lesson is that there are clearly many potential ways to achieve our desired goal of zero waitlist mortality; multiple strategies can successfully be pursued in parallel. The authors hypothesize that raising awareness of children's waitlist mortality also spurred action to increase LDLT use. Reports from other countries outline complementary strategies that can also improve outcomes for children without disadvantaging adult candidates. For example, the United Kingdom's intent‐to‐split policy resulted in an even more dramatic reduction of waitlist mortality and was accomplished with DDLT technical variant split grafts.6 The UK policy addressed the goal of increasing pediatric access specifically by mandating that livers fitting specific criteria were allocated to two recipients as split‐liver transplants. Policy change focusing only on pediatric allocation may not have the desired effect—especially because young children depend on technical variant grafts, both in DDLT and LLDT, to have the best chance of a timely transplant. Despite the lack of impact on DDLT in the current study, the authors did not report on whether the proportion of split DDLT grafts increased after implementation of the modified score. Of note, the splitting of suitable livers in ET is not mandatory. Third, we strongly concur with the authors' call to systematically evaluate the effects of policy after adjustment of allocation rules, although we note that this is done more routinely in some transplant systems than others. The US transplant community does regularly assess the impact of policy change, although these reassessments may take too much time and often do not distinguish between pediatric and adult outcomes, limiting their ability to drive efficient cycles of continuous improvement. Critically, projected outcomes based on even the best modeling practices7,8 may not be found true in actual practice both because of an inability to predict behavior change (i.e., splitting more livers or implementing a living donor program) and because modeling for rare disease conditions such as in the smaller volume of our pediatric candidates remains challenging. Fourth, the elephant in the room in many of these policy discussions is that without adaptions to the pediatric Model for End‐Stage Liver Disease (MELD) or Pediatric End‐Stage Liver Disease scores, children can never fairly “compete” for deceased donor livers because of the tremendous volume and demand from the adult candidate list. In the ET policy described here, the pediatric MELD score of 32 given to these children was thought to be a meaningful prioritization. However, unless coupled with other policy initiatives to incentivize or mandate splitting, it may not drive practice change. In summary, pediatric liver transplantation waitlist mortality is a solvable problem, with the solution likely reachable by multiple paths that should be used in parallel toward the goal. Children cannot wait any longer. Alerting the transplant community to the fact that children still die on the liver transplantation waiting list is not new; that waitlist deaths continue to occur among children is especially tragic.9 Today, we are reminded that focused allocation policy to prioritize children is rational, ethical, and urgent. Multiple techniques—especially LDLT and splitting deceased donor livers—can be combined with policy change to eliminate preventable deaths; we just need to finally get it done.

To assess the impact of technical variant grafts (TVGs) [including living donor (LD) and deceased donor split/partial grafts] on waitlist (WL) and transplant outcomes for pediatric liver transplant (LT) candidates, we performed a retrospective analysis of Organ Procurement and Transplantation Network (OPTN) data on first-time LT or liver-kidney pediatric candidates listed at centers that performed >10 LTs during the study period, 2004–2020. Center variance was plotted for LT volume, TVG usage, and survival. A composite center metric of TVG usage and WL mortality was developed to demonstrate the existing variation and potential for improvement. Sixty-four centers performed 7842 LTs; 657 children died on the WL. Proportions of WL mortality by center ranged from 0% to 31% and those of TVG usage from 0% to 76%. Higher TVG usage, from deceased donor or LD, independently or in combination, significantly correlated with lower WL mortality. In multivariable analyses, death from listing was significantly lower with increased center TVG usage (HR = 0.611, CI: 0.40–0.92) and LT volume (HR = 0.995, CI: 0.99–1.0). Recipients of LD transplants (HR = 0.637, CI: 0.51–0.79) had significantly increased survival from transplant compared with other graft types, and recipients of deceased donor TVGs (HR = 1.066, CI: 0.93–1.22) had statistically similar outcomes compared with whole graft recipients. Increased TVG utilization may decrease WL mortality in the US. Hence, policy and training to increase TVG usage, availability, and expertise are critical.

Background: Liver transplant is a life-saving therapy that can restore quality life for several pediatric liver diseases. However, it is not available to all children who need one. Expertise in medical and surgical management is heterogeneous, and allocation policies are not optimally serving children. Technical variant grafts from both living and deceased donors are underutilized. Methods: Several national efforts in pediatric liver transplant to improve access to and outcomes from liver transplant for children have been instituted and include adjustments to allocation policies, UNOS-sponsored collaborative improvement projects, and the emergence of national learning networks to study ongoing challenges in the field the Surgical Working group of the Starzl Network for Excellence in Pediatric Transplantation (SNEPT) discusses key issues and proposes potential solutions to eliminate the persistent wait list mortality that pediatric patients face. Results: A discussion of the factors impacting pediatric patients' access to liver transplant is undertaken, along with a proposal of several measures to ensure equitable access to life-saving liver transplant. Conclusions Pediatric liver transplant wait list mortality can and should be eliminated. Several measures, including collaborative efforts among centers, could be leveraged to acheive this goal.