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Introduction: Surgical site infections (SSI) are a significant cause of morbidity in liver transplant recipients, and the current data in the pediatric population are limited. The goal of this study was to identify the incidence, classification, risk factors, and outcomes of SSIs among children undergoing liver transplantation (LT)., Methods: A single-center, retrospective descriptive analysis was performed of patients age ≤18 years undergoing LT between September 2007 and April 2017. SSI identified within the first 30 days were analyzed. Primary endpoints included incidence, classification, risk factors, and outcomes associated with SSIs., Results: We included 86 patients, eight patients (9.3%) developed SSIs. Among segmental grafts (SG) recipients, 7/61 (11.4%) developed SSI. Among whole grafts recipients, 1/25 (4%) developed SSI. SSIs were associated with the presence of biliary complications (35% vs. 3%, p < .01; odds ratios 24, 95% CI: 3.41-487.37, p<.01). There were no differences in long term graft or patient survival associated with SSI. Patients who developed SSI were more likely to undergo reoperation (50% vs. 16.7%, p = .045) and had an increased total number of hospital days in the first 60 days post-transplant (30.5 vs. 12.5 days, p = .001)., Conclusions: SSIs after pediatric LT was less frequent than what has been previously reported in literature. SSIs were associated with the presence of biliary complications without an increase in mortality. SG had an increased rate of biliary complications without an association to SSIs but, considering its positive impact on organ shortage barriers, should not be a deterrent to the utilization of SGs., (© 2022 Wiley Periodicals LLC.)

Background: Our knowledge of de novo anti-HLA donor-specific antibodies (dnDSA) in liver transplantation continues to be defined. We hypothesized that differences of HLA-DR/DQ mismatches can improve precision in alloimmune risk categorization and be applied to tailor immunosuppression., Methods: A retrospective chart review of 244 pediatric patients consecutively transplanted at our center between 2003 and 2019 was performed to identify patients tested for dnDSA. Records were queried for: demographics, pre-transplant diagnosis, biopsy-proven T-cell-mediated rejection (TCMR), radiology proven biliary complications, tacrolimus trough levels, dnDSA characteristics, and HLA typing. The eplet mismatch analyses were performed using HLAMatchmaker ™ 3.1. All statistical analyses were conducted using R software version 3.40., Results: There were 99 dnDSA-negative patients and 73 dnDSA-positive patients (n = 70 against class II and n = 3 against class I and II). ROC analysis identified optimal cutoff of eplet mismatch load for dnDSA and defined risk groups for an alloimmune outcome. Kaplan-Meier curves and log-rank tests showed high eplet mismatch load was associated with shorter dnDSA-free survival (log-rank p = .001). Multivariable Cox regression models showed that tacrolimus coefficient of variation and tacrolimus mean levels were significantly associated with dnDSA-free survival (p < .001 and p = .036). Fisher's exact test showed that dnDSA was associated with an increased likelihood of TCMR (OR 14.94; 95% CI 3.65 - 61.19; p < .001). Patients without TCMR were more likely to have dnDSA to HLA-DQ7 and less likely to have dnDSA to HLA-DQ2 (p = .03, p = .080)., Conclusions: Mismatched epitope load predicts dnDSA-free survival in pediatric liver transplant, while dnDSA specificity may determine alloimmune outcome., (© 2022 Wiley Periodicals LLC.)

To understand factors contributing to liver graft loss and patient death, we queried a national database designed to follow pediatric patients transplanted between 1987 and 1995 till adulthood. A comparison was made to a cohort transplanted between 2000 and 2014. The 5-, 10-, 15-, 20-, and 25-year patient survival and graft survival were 95.5%, 93.7%, 89.1%, 80.8%, and 73.1%, and 92.5%, 86.7%, 77.6%, 68.7%, and 62.2%, respectively. The twenty-year patient/graft survival was significantly worse in those transplanted between 5 and 17 years of age compared to those transplanted at <5 years of age (P < 0.001). For the modern era cohort, the 3-year patient survival was significantly lower in children transplanted at 16-17 years of age compared to those transplanted at <5 and 11-15 years of age (P ≤ 0.02). The 3-year graft survival was similarly lower in children transplanted at 16-17 years of age compared to those transplanted at <5, 5-10, and 11-15 years of age (P ≤ 0.001). Infection as a cause of death occurred either early or >15 years post-transplant. Chronic rejection remained the leading cause of graft loss in both cohorts and the commonest indication for retransplantation 20-25 years following primary transplant. Further research is required to identify modifiable factors contributing to development of chronic rejection., (© 2019 Wiley Periodicals, Inc.)

The long-term course and outcome of DAIH is unknown. A retrospective multicenter study assessing associations and long-term consequences of DAIH developing in a transplanted allograft is presented. Children with DAIH were followed from diagnosis until death, re-LT, or transfer of care and for a minimum of 1 year. A total of 31 patients of 1833 (1.7%) LT were identified; 29 followed for a median of 7.1 years (range, 1.6-15); 52% had no rejection preceding diagnosis of DAIH. Transaminases fell following treatment with steroids and antimetabolites (ALT 108 vs 39 U/L (P=.002); AST 112 vs 52 U/L (P=.003); GGT 72 vs 36 U/L (P=.03), but this was not universally sustained. Transaminases >2X ULN observed in 38% of patients at last follow-up; commonly GGT, attributed to bile duct injury and ductopenia. Portal hypertension (PHT) was seen in four patients and associated with severe fibrosis and cirrhosis. Re-LT occurred in two patients for chronic rejection (CR) and uncontrolled PHT with gastrointestinal bleeding, respectively. No deaths from DAIH were reported. DAIH is an uncommon complication following pediatric LT requiring prolonged and augmented immunosuppression. It is associated with continued allograft dysfunction and may lead to bile duct injury, CR, and PHT necessitating re-LT., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We describe longitudinal results in a cohort of pediatric liver transplant patients successfully minimized to once daily CNI monotherapy for longer than five yr and assess changes in liver biochemistries and liver histology. A retrospective chart review of all pediatric liver transplant patients at a single center was performed. Biopsies and serum biochemistries (AST, ALT, total bilirubin, direct bilirubin, INR, creatinine) are reported at time points: PM, five-yr, seven-yr, and nine-yr post-minimization. Biopsies were assessed for inflammation and fibrosis using Ishak and Batts grading systems. Successful minimization to daily CNI monotherapy was defined as normal liver enzymes with no episodes of rejection. Thirty-three patients have successfully remained on once daily CNI for >5 yr, and 19/33 of these patients have serial liver biopsies available for review. We report on the clinical and histological findings of these 19 patients. All 19 patients continue to have normal liver biochemistries. On post-minimization biopsies, fibrosis progressed by ≥2 stages in one patient (5.3%) despite normal liver biochemistries. Carefully selected patients can tolerate minimization to once daily CNI monotherapy as few have progression of fibrosis., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This review focuses on active clinical research in pediatric liver transplantation with special emphasis on areas that could benefit from studies utilizing the SPLIT infrastructure and data repository. Ideas were solicited by members of the SPLIT Research Committee and sections were drafted by members of the committee with expertise in those given areas. This review is intended to highlight priorities for clinical research that could successfully be conducted through the SPLIT collaborative and would have significant impact in pediatric liver transplantation., (© 2013 John Wiley & Sons A/S.)

This retrospective case series reviews our center's experience with sirolimus and a CNI as alternative therapy for the treatment of PTAH. It also characterizes regulatory T cells (Tregs) in PTAH. LT recipients with PTAH who had received or were receiving treatment with sirolimus were retrospectively identified (n = 12). Liver enzymes, immunohistochemistry, and histology were compared in all 12 patients. Immunophenotyping for Tregs in peripheral blood mononuclear cells was performed on LT recipients with PTAH on conventional therapy with CNI, azathioprine ± prednisone (CT) (n = 11), recipients with PTAH on sirolimus, CNI ± prednisone (n = 8), recipients without PTAH (n = 25), and pre-transplant patients (n = 5). Severity of necro-inflammatory changes markedly improved with sirolimus. Treg frequency and number were significantly lower in recipients with PTAH on CT compared to (i) those on sirolimus (p = 0.002 and p = 0.01, respectively), and (ii) recipients without PTAH (p = 0.07 and p = 0.009, respectively). Treg frequency was significantly higher in recipients with PTAH on sirolimus compared to recipients without PTAH under CNI therapy (p = 0.027). Sirolimus in addition to a CNI is successful in reversing inflammation in LT recipients with PTAH. This is associated with significantly higher circulating Tregs., (© 2012 John Wiley & Sons A/S.)

Current approaches to the management of immunosuppression are largely empiric and reactive rather than proactive due to our inability to predict accurately how the recipient immune system will respond to a given organ allograft. The validation of simple, reliable, non-invasive assays exploring allogeneic anti donor responsiveness or donor specific non-responsiveness are of interest for several reasons: (i) it would allow for early and non-invasive detection of acute or chronic allograft rejection such that intervention could be initiated before effector mechanisms and organ destruction occur, (ii) it would allow for individual immunosuppressive drug therapy thereby avoiding the unwanted consequences of over immunosuppression, and (iii) the identification of the immunological phenotype related to operational tolerance could allow for the complete cessation of immunosuppressants. This review will summarize in vitro assays of T cell reactivity that reflect allo-antigen-specific responses.

Acute liver failure in the newborn is relatively rare but often fatal. The broadest definition of acute liver failure is failure of the vital functions of the liver occurring within weeks or a few months of the onset of clinical liver disease. Therefore, by definition, any liver failure in the newborn can be construed to be acute liver failure. A second component of the general definition of acute liver failure is the lack of known preexisting liver disease. In the case of neonatal acute liver failure, preexisting disease would by definition be liver disease that affects the fetus. Almost nothing is known about fetal onset liver failure, and there is no literature addressing the subject. This review will address fetal liver disease that leads to liver failure in the fetus or newborn.