Faculty Bibliography

INTRODUCTION/BACKGROUND:Biological parental donations provide the best option for many pediatric recipients, yielding unique immunological benefits that may enable minimization of immunosuppression in transplanted children. However, living related maternal donation in the postpartum period may introduce an increased risk of donor complications due to the physiological changes of pregnancy and childbirth, and the optimal timing of postpartum living donation is unknown. METHODS:Using US national registry data, we characterized donor and recipient outcomes for pediatric living donor liver transplants performed between 2004 and 2022 where a biological mother donated to a child ≤ 24 months old. RESULTS:Our study population included 256 donor-recipient pairs, with biliary atresia representing the most common indication for transplantation (68.0%). Donors had a median [IQR] age of 30 [25, 34] years, and the median [IQR] time from birth to donation was 9.0 [6.8, 13.0] months. 6.3% of donors experienced a biliary or other complication. When stratifying by donors who donated ≤ 6 vs. > 6 months postpartum, we found no significant differences in donor complications or readmission. Stratified analyses were also comparable for recipient mortality, graft survival, and rejection-free survival. Donors ≤ 6 months postpartum (n = 64) were more likely to experience reoperation than mothers who donated > 6 months postpartum (n = 192) (6.2% vs. 1.0%, p = 0.04). CONCLUSIONS:While maternal living donor liver transplantation is safe for most donors, there is a higher risk of reoperation when donation is performed ≤ 6 months postpartum. Surgeons should be aware that these donors are a higher risk population, requiring discussion upon consent and warranting close post-operative monitoring.

Extracorporeal liver cross-circulation (ELC) using gene-edited porcine liver xenografts offers a potential bridge therapy for liver failure. We previously performed five ELC procedures in four brain-dead human decedents, during which the recipients developed severe thrombocytopenia. The porcine liver xenografts maintained their parenchymal structure, with immune cell infiltration and detectable IgM deposition on endothelial cells. Here, to investigate the underlying host-xenograft interactions, we performed longitudinal proteomic, lipidomic and metabolomic profiling of 64 blood samples, alongside spatial transcriptomics and histology of 25 porcine liver xenograft and 3 native human liver biopsies. Spatial transcriptomic analysis revealed progressive infiltration of human immune cells (predominantly inflammatory macrophages and neutrophils) in the xenografts, concurrent with the loss of porcine Kupffer-like macrophages and T cells. Distinct human and porcine complement dynamics were observed, with suppressed human but elevated porcine complement levels, accompanied by increased levels of porcine acute-phase proteins and coagulation factors. Moreover, multiomics analyses identified candidate cellular and molecular factors associated with thrombocytopenia. Human platelets colocalized with activated porcine endothelial cells, which showed increasing porcine vWF expression over time, as well as with immune cells (primarily macrophages and neutrophils) and hepatocytes in the xenografts. Integrative analyses indicated that ELC procedures provided hepatic support for apolipoprotein synthesis, bilirubin clearance, energy metabolism and detoxification, although circulating lipid levels remained low under anhepatic conditions. Collectively, these findings yield insights into the complex interplay between human and xenograft systems during ELC and inform strategies to improve liver xenograft biocompatibility for clinical translation.

BACKGROUND AND AIMS/OBJECTIVE:Liver transplantation is a lifesaving, standard of care intervention for infants, children, and adolescents with liver tumors, inborn errors of metabolism, and irreversible liver disease caused by a wide spectrum of liver conditions. The American Association for the Study of Liver Diseases (AASLD) last published guidelines for the evaluation and selection of pediatric liver transplant candidates in 2014. This 2026 update aims to provide evidence-based recommendations that reflect current best practices and evolving clinical knowledge. METHODS:A multidisciplinary writing group of pediatric liver transplant experts and a medical librarian was convened by AASLD, with guidance by its Practice Guidelines Development Policy, and in collaboration with the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) and the American Society of Transplantation (AST). We conducted a systematic global literature review, formulated key clinical questions, and developed recommendations. Each recommendation was graded using the Oxford Centre for Evidence-Based Medicine framework and categorized by strength through a consensus voting process. CONCLUSION/CONCLUSIONS:This document provides clear, evidence-based guidelines on the transplant evaluation process and journey in infants, children, and adolescents. It outlines indications, contraindications, and barriers to transplantation based on robust, relevant published data. It offers best practices for pre-transplant assessment, organ allocation, and strategies to optimize survival, while allowing flexibility for individual clinical scenarios.

BACKGROUND:Access to liver transplantation (LT) for pediatric registrants is complex and impacted by many factors. Assessing the state of pediatric LT requires understanding the balance between policy, the availability of livers, and the quantity of pediatric patients requiring LT. METHODS:Using Scientific Registry of Transplant Recipients data with Cox regression (to compare rates) and competing risk regression (to compare cumulative incidence), we evaluated pediatric patient characteristics, number of registrants transplanted, and waitlist mortality from (January 1, 2017-February 4, 2020) to (May 1, 2020-June 4, 2023) using the implementation of acuity circles to divide the eras. RESULTS:In 4314 pediatric LT registrants, transplantation rate increased in the post-policy era, compared with the pre-policy era (adjusted hazard ratio [HR], 1.05 1.12 1.20 ; P  < 0.001). When accounting for competing risks, the increase was attenuated and not statistically significant (adjusted subdistribution HR, 0.99 1.06 1.14 ; P  = 0.08); recipients were no more likely to die on the waitlist (adjusted subdistribution HR, 0.78 1.01 1.30 ; P  = 0.99). Importantly, the prevalent pediatric waitlist dropped from 396 (2017) to 225 (2023), the rate of deceased donor LT from pediatric donors increased (weighted HR, 1.20 1.31 1.42 ; P  < 0.001), and access to living donor LT increased, compared with the pre-policy era (weighted HR, 1.11 1.33 1.59 ; P  = 0.002). The transplant rate for pediatric patients did not decrease during the study period despite the introduction of acuity circles. During the study period, the prevalent waitlist shrank, access to LT from pediatric donors increased, and access to living donor LT increased. CONCLUSIONS:Comprehensive assessment following the policy change is necessary to ensure that pediatric candidates maintain priority. Changes in pediatric transplantation are modest and likely related to changes in the pool, rather than to the policy of acuity circles.

Xenotransplantation of genetically-modified pig kidneys offers a solution to the scarcity of organs for end-stage renal disease patients.¹ We performed a 61-day alpha-Gal knock-out pig kidney and thymic autograft transplant into a nephrectomized brain-dead human using clinically approved immunosuppression, without CD40 blockade or additional genetic modification. Hemodynamic and electrolyte stability and dialysis independence were achieved. Post-operative day (POD) 10 biopsies revealed glomerular IgM and IgA deposition, activation of early complement components and mesangiolysis with stable renal function without proteinuria, a phenotype not seen in allotransplantation. On POD 33, an abrupt increase in serum creatinine was associated with antibody-mediated rejection and increased donor-specific IgG. Plasma exchange, C3/C3b inhibition and rabbit anti-thymocyte globulin (rATG), completely reversed xenograft rejection. Pre-existing donor-reactive T cell clones expanded progressively in the circulation post-transplant, acquired an effector transcriptional profile and were detected in the POD 33 rejecting xenograft prior to rATG treatment. This study provides the first long-term physiologic, immunologic, and infectious disease monitoring of a pig-to-human kidney xenotransplant and indicates that pre-existing xenoreactive T cells and induced antibodies to unknown epitope(s) present a major challenge, despite significant immunosuppression. It also demonstrates that a minimally gene-edited pig kidney can support long-term life-sustaining physiologic functions in a human.

Organ shortage remains a major challenge in transplantation, and gene-edited pig organs offer a promising solution^1-3. Despite gene-editing, the immune reactions following xenotransplantation can still cause transplant failure⁴. To understand the immunological response of a pig-to-human kidney xenotransplantation, we conducted large-scale multi-omics profiling of the xenograft and the host's blood over a 61-day procedure in a brain-dead human (decedent) recipient. Blood plasmablasts, natural killer (NK) cells, and dendritic cells increased between postoperative day (POD)10 and 28, concordant with expansion of IgG/IgA B-cell clonotypes, and subsequent biopsy-confirmed antibody-mediated rejection (AbMR) at POD33. Human T-cell frequencies increased from POD21 and peaked between POD33-49 in the blood and xenograft, coinciding with T-cell receptor diversification, expansion of a restricted TRBV2/J1 clonotype and histological evidence of a combined AbMR and cell-mediated rejection at POD49. At POD33, the most abundant human immune population in the graft was CXCL9+ macrophages, aligning with IFN-γ-driven inflammation and a Type I immune response. In addition, we see evidence of interactions between activated pig-resident macrophages and infiltrating human immune cells. Xenograft tissue showed pro-fibrotic tubular and interstitial injury, marked by S100A6⁵, SPP1⁶ (Osteopontin), and COLEC11⁷, at POD21-POD33. Proteomics profiling revealed human and pig complement activation, with decreased human component after AbMR therapy with complement inhibition. Collectively, these data delineate the molecular orchestration of human immune responses to a porcine kidney, revealing potential immunomodulatory targets for improving xenograft survival.

With U.S. Food and Drug Administration (FDA) clearance of clinical trials of kidney xenotransplantation (XTx) in living humans, understanding the recipient experience is critical. Semi-structured interviews with the three living XTx recipients identified core domains of the recipient experience, including quality of life (QoL), fears about XTx, and healthcare team communication and support. Transcribed interviews were analyzed by two qualitative researchers using an inductive thematic approach and were mapped onto the Warwick Patient Experience Model, a validated framework to assess key aspects of patient satisfaction with the healthcare experience. All three recipients (53-year-old female; 66-year-old male; 54-year old male) described a restoration of hope, contrasted with their poor quality of life on dialysis. They emphasized that access to XTx and graft survival requires mutual confidence and commitment between recipients and healthcare teams. XTx recipients use dialysis as a point of reference when describing changes in their post-transplant QoL and seemed well-situated to handle the possibility of graft failure. These insights may aid in the creation of decision aids and educational materials tailored to the specific needs of XTx recipients.