Surveillance biopsy is essential to detect graft rejection that remains silent to conventional liver function tests (LFTs), allowing tailored immunosuppression. The benefit of detecting subclinical biopsy-proven acute rejection (BPAR) comes at the cost of subjecting all pediatric recipients to an invasive procedure, including those who could potentially be safely spared if accurately identified as low risk of rejection using sensitive and noninvasive biomarkers of graft injury. We evaluated the ability of donor-derived cell-free DNA (dd-cfDNA) to rule out BPAR in pediatric liver transplant (LT) patients and its role in biopsy decision-making when used alongside LFTs. A clinical decision-making process combining LFTs and dd-cfDNA to identify low-risk rejection patients was developed using data from 98 patients under surveillance and 40 patients who underwent for-cause biopsy. Sixty BPAR events were recorded, and almost half of them (46.7%) were classified as subclinical BPAR (subBPAR). Only dd-cfDNA distinguished subBPAR from BPAR-free cases ( p =0.02), demonstrating a sensitivity of 96.7% (95% CI, 88.6-99.4) and a specificity of 34.6% (95% CI, 25.0-45.7) at a threshold of 1.9%. According to the decision-making process, patients with LFTs below the upper limit of normal and dd-cfDNA <1.9% would be spared from liver biopsy. Considering a BPAR prevalence of 43.4% in the study cohort, the negative and positive predictive values were 93.1% and 53.2%, respectively. In this large pediatric study, we demonstrate for the first time that low dd-cfDNA levels can reliably identify liver transplant patients at low risk of rejection, improving the tailoring of surveillance biopsies when used alongside LFTs.

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.

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.

Avoidance of steroids in pediatric liver transplantation may reduce toxicity and morbidity. The aim of this study was to analyze the feasibility of a steroid-free tacrolimus-basiliximab immunosuppression scheme, the risk factors associated with steroid requirement, and safety parameters. Patients who underwent liver transplantation for biliary atresia between 2011 and 2019 were included and followed for 6 months after transplantation. Immunosuppression consisted of tacrolimus-based treatment with basiliximab induction. Steroid-free survival was estimated, and risk factors for steroid requirement were evaluated using multivariate Cox regression analysis. A total of 76 patients were included, of whom 42 (55.3%) required steroids (>14 d) due to biopsy-proven acute rejection (47.6%, n = 20), instability in liver function tests (35.7%, n = 15), tacrolimus-related adverse drug reactions (14.3%, n = 6), or other reasons (bronchospasm episode, n = 1). Steroid-free survival was 45.9% (95% CI, 35.9–58.8). Independent factors associated with steroid requirement included tortuosity in tacrolimus trough levels (≥1.76 vs. <1.76: HR 5.8, 95% CI, 2.6–12.7; p < 0.001) and mean tacrolimus trough levels (≥ 6.4 ng/mL vs. < 6.4 ng/mL: HR 0.4, 95% CI, 0.2–0.7; p = 0.002). The rate of bacterial and viral infections was comparable between patients with and without steroids, although in the former group, cytomegalovirus infection developed earlier ( p = 0.03). Patients receiving steroids had higher total cholesterol, LDL, and HDL levels ( p < 0.05) during follow-up, but no changes in the height Z-score were observed 1 year after transplantation. Basiliximab induction in combination with tacrolimus-based treatment avoided steroid requirements in 45% of the patients. Tacrolimus variability and trough levels below 6.4 ng/mL independently increased the risk of steroid requirement. Further efforts should be focused on personalizing immunosuppressive treatment.

Background: Liver transplantation is considered a valid option for children with terminal acute or chronic liver diseases. However, it has significant morbidity and mortality, and the factors that influence patient and graft survival are less studied in pediatric recipients. Methods: We present our series of 950 consecutive pediatric liver transplants performed in Garrahan Pediatric Hospital in Argentina from 1992 to 2022. To analyze two different periods through time, transplants were divided into two eras (era I from 1992 to 2005, and era II from 2005 to 2022). Primary outcomes included one-year patient and graft survival. Kaplan Meier curves were compared using Log Rank test. Uni and multivariate analysis were made to analyze the impact on one year patient mortality and graft loss. Results: Graft survival at one year improved from 66.9 % in era 1 to 81.9 % in era 2 (log rank test 0.0001), while patient survival at one year went from 70.9 % to 86.9 % (log rank test 0.0001). Predictors of mortality and graft loss at one year were arterial graft, arterial thrombosis, prolonged ischemia time and weight under 10 kg, while the variables associated with better survival were era 2 and having a whole graft. The era was found to be an effect modifier, as children under 10 kg had higher risk of dying in the first era but not in the second. Conclusions: The improvements achieved are comparable to international standards and reflect the continuous improvements and experience of an interdisciplinary team.

Aims Pharmacokinetics of tacrolimus after sublingual administration is not characterized in paediatric liver transplant patients. Therefore, we aimed to develop a population pharmacokinetic model of sublingually administered tacrolimus in patients who cannot swallow the capsules due to their age, sedation status and/or mechanical ventilation during the first weeks post‐transplantation. Methods Demographic, clinical and pharmacological variables, including tacrolimus whole blood concentrations obtained from therapeutic drug monitoring and data from dense‐sampling pharmacokinetic profiles, were recorded in 26 paediatric patients with biliary atresia who underwent liver transplantation between 2016 and 2021. Population pharmacokinetic analysis was performed with NONMEM v7.4. Results Disposition of tacrolimus was best characterized by a 2‐compartment model with clearance achieving half of the maximum elimination capacity (CL MAX = 4.1 L/h) at 4.6 days post‐transplantation (T 50 ). Compared to sedated patients, nonsedated status showed an increased first‐order absorption rate constant (1.1 vs . 0.1 h −1 ) and a 24% reduction in bioavailability (F NS ) at 14 days post‐transplant. The model was able to explain the oral absorption pattern in nonsedated patients as the result of gut bioavailability (0.9) and hepatic extraction ratio, with the latter being responsible for first‐pass effects. Estimates of interindividual variability remained moderate (25.9% for the gut bioavailability) to high (79.8% for the apparent volume of distribution of the central compartment, and 101% for T 50 ). Conclusion A population pharmacokinetic model of sublingually administered tacrolimus in paediatric patients was developed to characterize different absorption mechanisms. Once the model is externally validated, the effect of post‐transplant time on clearance and the sedation status may be considered in routine dosing management.

Background: Patients with biliary atresia (BA) and portal hypoplasia have a higher risk of developing portal complications. The objective of this work is to analyze the results before and after the implementation of longitudinal portoplasty (LP) during liver transplantation (LT) in our center. Methods: Retrospective cohort study including all pediatric patients transplanted due to BA with portal hypoplasia was conducted. Results were analyzed before and after the introduction of the LP in 2016. Primary endpoints were the occurrence of early portal vein thrombosis and portal vein thrombosis. Secondary endpoints were patient survival and portal complications. Results: 60 patients were transplanted before the implementation of LP and 60 patients after the new technique was used. Baseline characteristics did not differ among groups. Portal vein thrombosis decreased from 26.7 % in the first period, to 3.3 % in the second (p 0.001), and early portal thrombosis from 20 % to 1.7 % (p 0.002). An association was found between portal vein thrombosis and the period in which LP was implemented (OR 0.095, 95 %CI 0.021 0.43, p=0.002), showing a lower risk in the occurrence of thrombosis in the second period. Patient survival at 12 and 24 months in the first group was 79.6 % and 76.0 %, while in the second group was 93.1 % and 93.1 %, with a log rank test 0.01. Conclusions: The routine use of LP could possibly minimize the occurrence of portal complications and could be considered in these cases with good results. Level of evidence: II.

Objective: Biliary atresia (BA) represents the most frequent cause of liver transplantation (LT) in the pediatric population. An association between BA and portal hypoplasia has been previously described, making this group at higher risk of portal complications, which could eventually lead to portal hypertension, graft failure or even graft loss. The main objective of this work is to analyze and compare the results before and after the implementation of longitudinal portoplasty (LP) as the technique of choice during LT for patients with BA and hypoplasic portal vein in our center. Materials and Methods: Retrospective study including all patients transplanted due to BA and a preoperative diagnosis of portal hypoplasia (diameter measured by doppler ultrasound or CT scan less or equal to 5 mm). Results were analyzed before (group 1) and after the introduction of the new reconstruction technique in 2016 (group 2). Primary endpoints were the occurrence of early portal vein thrombosis (within 30 days of transplantation) and patient survival. Secondary endpoints were the occurrence of portal complications. Results: A total of 100 patients (out of 346 transplants, 78.1% of patients with BA) had a preoperative diagnosis of BA with portal hypoplasia and were included (50 patients in each group). Baseline characteristics did not differ among groups. Reduced grafts were used in 96% of the cases, and living donors in 43%. Overall rate of portal early thrombosis was 22% (n=11) in the first group and 2% (n=2) in the second (p= 0.002). An association between early portal early thrombosis and LP was found (p: 0.025 OR: 0.089 95% CI: 0.011-0.74). With regard to the technique used, portal early thrombosis was found in 12.7% (n=6) of end to end anastomosis, in 41.7% (n=5) of graft interposition and in 2.4% (n=1) of LP (p: 0.001). Patient survival at 12 and 24 months in the first group was 79.5% and 77.3%, while in the second group was 92% and 92% (log rank test 0.048). Median follow-up was 2 years. No statistical significant difference between survival and LP was found (p: 0.06 HR: 0.34 95% CI: 0.11-1.05). Overall rate of portal complications was 28%. With the implementation of LP there was a decrease of 24% in portal complications (p: 0.008). No statistical difference was found for stenosis among groups. Conclusion: Since the implementation of LP, a decrease in early portal thrombosis was seen. Limitations of this study are the fact that it is a retrospective and single institution study. Although results showed favorable trends towards LP, survival did not reach statistical significance yet, possibly due to lack of power in this context of limited cases to analyze. Larger sample size and longer follow-up studies are required to confirm these findings in the future. In conclusion, the routine use of LP could possibly minimize the occurrence of portal complications in patients with BA and portal hypoplasia, and could be considered in these cases with good results.

Introduction: The pediatric population of Argentina, especially those under 12 years old, access to liver transplantation through the MELD score exception. This fact might cause inequities since young adult’s recipients are at high risk factor for worse graft survival after liver transplantation. In this study we evaluated liver transplantation waitlist and post-transplant outcomes in those aged 18 to 24 years compared to younger waitlist registrants and recipients. Method: we performed a multivariate logistic regression to examinate the association between age at listing (0-5, 6-11,12-17 and 18 -24 years [the reference category]) and waitlist outcomes: drop out and transplantation. The model included the following features: emergency category, whether an exception score was granted, serum albumin, ABO blood group, and insurance payer status. The database used was the Information Registry and Management System of Argentina (SINTRA). Graft and patient survival were stratified by these age categories using Kaplan Meier curves to perform the analysis of transplant outcomes. Results: between 2006 and 2020, 1842 on first time transplants registrants and 794 recipients were included. Registrants aged 0 to 17 were less likely to experience dropout from the waiting list compared with those aged 18 to 24 years (adjusted hazard ratio, 0-5: OR 0.21 (0.16-0.30); 6-11: OR 0.36 (0.22-0.59); 12-17: 0.57 (0.39-0.86); 18-24: 1.00), and better transplant probability (adjusted hazard ratio, 0-5: OR 4.20 (3.03-5.82); 6-11: OR 2.10 (1.33-3.31);12-17: 1.36 (0.90-2); 18-24: 1.00). In post-liver transplant survival analysis, recipients aged 18 to 24 years had a similar risk of graft failure and death compared with all other groups. Conclusion: This study showed that there was not differences in liver graft failure and death between young adults ages 18 to 24 years and children. However, younger age liver transplant patients had had higher probability of drop out from the waitlist and less probability of being transplanted compared to younger age groups.

Introduction: Advances in pediatric liver transplantation have led to an increasing number of patients reaching adolescence in whom poor adherence rate increases, becoming a prevalent risk factor for rejection and other adverse outcomes. Being a modifiable factor, its monitoring is a common practice in long-term follow-up and interventions on it are a priority for transplant programs. However, improvements in adherence do not correlate with long-term clinical results, these being the objective variables of graft functionality. The objective of this study is to correlate adherence measurement by both objective and subjective methods, with graft dysfunction and/or pathological liver biopsy, and to measure long-term clinical results as ideal transplant (single transplant, monodrug, no clinical complications associated with immunosuppression and normal growth). Methods: Measurement and analysis of adherence using objective (variability in drug levels, >2 SD) and subjective methods (SMAQ questionnaire and medical impression) in 62 adolescents with liver transplantation who came for a follow up visit from August 2019 to March 2020 at Garrahan Hospital. Association was searched between the different adhesion methods and chronic graft injury (defined as three months or more of increased transaminases and/or pathological liver biopsy -rejection or fibrosis >2 on the Knodell-Ishak scale) using univariate logistic regression models. A p<0.05 was considered as significant, and STATA 15 was used. Results: Of the patients surveyed, 50% were female, median age of 15.8 years (10.6-18.5), 10 patients received a retransplant (16%) and 40 had more than 10 years post-transplant (64.5%). 55.7% lived in CABA/AMBA and 40.9% in the rest of the country. No statistically significant association was seen between any of the adherence measurement methods with graft dysfunction and/or pathological liver biopsy (p 0.66 and 0.53 for variability, 0.96 and 0.11 for SMAQ questionnaire and 0.35 and 0.19 for subjective opinion). A total of 13 patients (21%) with ideal transplant results were obtained with a mean follow-up of 12.37 years. Conclusion: With the data collected, it is not possible to correlate in a statistically significant way the measurement of poor adherence with graft dysfunction and/or pathological biopsies. Potential biases of this study are sample size, follow-up time and the population studied (adherent group that attends control). However, since variability is an objective method and is related to adverse effects related to immunosuppression, we consider that drug measurement and its variability is the best method. Measurement of adherence is necessary since it allows evaluating interventions aimed at improving it, despite the fact that it is not directly related to clinical results. The focus on long-term transplant care has shifted to long-term consequences of immunosuppressive treatment, and it should be measured with objective variables (“ideal transplant”).