Pediatric Liver Transplant Recipients Research Articles

Prediction Model of the T Cell-mediated Rejection After Liver Transplantation in Children and Adults: a Case-controlled Study.

T cell-mediated rejection (TCMR) is a major concern following liver transplantation (LT), and identifying its predictors could help improve post-transplant prognosis. This study aimed to develop a model to predict the risk of TCMR in children and adults after LT. Pre-transplant demographic characteristics, intraoperative parameters, and especially early post-transplant laboratory data for 1,221 LT recipients (1,096 adults and 125 children) were obtained from Hospital, University, between 1 January 2015, and 1 January 2022. These data were analyzed to develop the prediction model. The incidence of TCMR was higher in pediatric LT recipients than in adults (17.6% vs. 6.4%, p < 0.001). In adult recipients, seven predictors were identified: donor sex, recipient age, recipient height, and post-transplant levels of serum direct bilirubin, urea, platelets, and neutrophil-to-lymphocyte ratio. In pediatric recipients, four predictors were identified: post-transplant levels of serum monocyte percentage, direct bilirubin, albumin, and gamma-glutamyl transferase. The area under the model's curve incorporating these variables for predicting TCMR after LT was 0.713 (95% CI: 0.655-0.770) in adults and 0.786 (95% CI: 0.675-0.896) in children. Decision curve analyses demonstrated the clinical significance of the model. This study developed a prediction model that may be useful in identifying high-TCMR-risk populations in both adult and pediatric LT recipients.

Finding Value in Pediatric Liver Transplantation: When Does Volume Matter?

Pediatric liver transplantation provides substantial survival benefit. An emphasis on value-based practices has become a central theme in many surgical fields, but have not been well-studied in pediatric transplantation. Given an increasing focus on optimizing outcomes while containing costs, defining value in pediatric liver transplantation warrants investigation. Pediatric end-stage liver disease -era deceased donor pediatric liver transplant recipients from 2/2002 to 2/2019 were identified using the United Network for Organ Sharing Standard Transplant Analysis file data (n=5770). Liver centers were divided into volume tertiles (small, medium, and large), and recipients were stratified by age (0-4, 5-11, and 12-18y). The value for the index transplant episode was defined as % graft survival ≥1y divided by mean post-transplant length of stay. Nearest-neighbor Mahalanobis metric matching was used to account for confounding when assessing the impact of center volume on value. Compared to small centers, large centers delivered better outcomes (1-y graft survival 93.7% versus 89.4%, P=0.017) without increased resource utilization (length of stay 20.8±15.6d versus 19.6±17.0, P=0.281) during the 17-y study period. Mahalanobois-matched cohorts demonstrated a volume-value relationship (higher value care with better outcomes and decreased resource utilization) in the 0-4 age group, but not in older recipients. The 0-4 age group comprised the largest proportion of status 1B patients (21.8%, P<0.001) and the highest utilization rate of partial liver allografts (40.9%, P<0.001). There is value in liver transplant volume in very young (0-4y) deceased donor pediatric patients. Given improved survival of these patients in higher volume centers, regionalization of care may benefit this specific population of recipients.

Cerebral tissue oxygen saturation and its potential relationship with neurodevelopmental delay in pediatric liver transplant recipients.

To discover the potential association between diminished intraoperative average SctO2 levels and postoperative neurodevelopmental delays among patients after pediatric living-donor liver transplantation. Patients undergoing living-donor liver transplantation were recruited for this trial. The neurodevelopment status of patients was assessed using the Ages Stages Questionnaires. The primary outcome was the occurrence of neurodevelopmental delay among patients at different intervals following pediatric liver transplantation. Secondary outcomes included the duration of mechanical ventilation, rates of re-intubation, length of ICU stay, postoperative hospitalization, and intraoperative comparisons of mean arterial pressure (MAP), arterial partial pressure of oxygen (PaO2), arterial partial pressure of carbon dioxide (PaCO2), and hemoglobin (Hb) concentration. A total of 119 patients were included in the statistical analysis and assigned to high saturation group (HS) and low saturation group (LS) according to the average intraoperative cerebral tissue oxygen saturation values. Following adjustment for PELD scores, significant differences between the two groups were observed for the incidence of neurodevelopmental delay in communication at 1 and 3 months follow-up (P = 0.019 and P = 0.020, respectively), fine motor at six months follow-up (P = 0.014), and problem-solving abilities at one year follow-up (P = 0.047). Moverover, the length of ICU stay (P = 0.009) and postoperative hospitalization (P = 0.029) in LS group were also significant prolonged. This prospective observational study revealed that the patients with low average SctO2 values were more predisposed to experiencing postoperative neurodevelopment delays, suggesting a potential association between decreased average SctO2 and neurodevelopmental delay.

Factors influencing 25-year survival in Pediatric Liver Transplant Recipients

Factors influencing 25-year survival in Pediatric Liver Transplant Recipients

Intestinal Insufficiency Predicts Early Death in Pediatric Liver Transplant Recipients

Intestinal Insufficiency Predicts Early Death in Pediatric Liver Transplant Recipients

Material economic hardships are associated with adverse 1-year outcomes after pediatric liver transplantation: Prospective cohort results from the multicenter SOCIAL-Tx Study.

Pediatric liver transplant outcomes exhibit disparities, necessitating the identification of modifiable risk factors to develop targeted interventions. We characterized associations between household material economic hardship (eg, financial barriers to housing or food) and pediatric liver transplant outcomes. We recruited pediatric recipients of liver transplants <18 years at the time of transplant across 8 US centers. Our primary exposure was ≥1 household material economic hardship (ie, food insecurity, housing instability, transportation challenges, or utility concerns), measured using the Accountable Healthcare Communities screening tool. Outcomes included 90-day and 1-year (1) total inpatient bed-days, and (2) episodes of T-cell-mediated rejection. Of the 77 participants (36% female), 34% reported household material economic hardship. Such hardship was associated with increased total inpatient bed-days within 90 days (ratio estimate: 1.45, 95% CI: 1.08, 1.96); the association persisted after adjusting for health literacy, insurance, and transplant center (ratio estimate: 1.37, 95% CI: 1.02, 1.84). Household material economic hardship was associated with total inpatient bed-days within 1 year after transplant (ratio estimate: 3.2, 95% CI: 1.1, 10.1); associations diminished in multivariable analyses (ratio estimate: 2.2, 95% CI: 0.7, 6.9). Household material economic hardship was associated with increased risk of T-cell-mediated rejection within 1 year of transplant (relative risk: 2.1, 95% CI: 1.1, 4.2); the association diminished in propensity-score matched analyses (relative risk: 1.4, 95% CI: 0.9, 2.3). Our findings highlight the adverse influence of household material economic hardship on pediatric liver transplant outcomes within the first year. Targeted social risk assistance and adjustment strategies offer actionable avenues to mitigate these challenges and enhance outcomes in pediatric recipients of liver transplants.

The trend of Epstein-Barr virus DNA loads and CD8+ T lymphocyte numbers can predict the prognosis of pediatric liver transplant recipients with PTLD

Abstract Objectives Epstein-Barr virus (EBV) can cause lymphoproliferative disorders (PTLD) in immunodeficiency individuals. The pathogenesis of EBV infection depends on its effective recognition and elimination. Our study investigated the effect of peripheral lymphocyte subsets (PLS) on the elimination of EBV. Methods A retrospective single-center study included 63 patients with 17 pediatric liver transplant recipients with EBV-induced PTLD (PTLD group) and 46 patients diagnosed with EBV-induced mononucleosis (IM group). Dynamic monitoring of PLS with EBV-DNA loads was performed. Results EBV-DNA replicated at a high level (5.2E3∼5.93E7 copies/mL in PBMC) before treatment in all patients in PTLD group. B lymphocytes were the main infected cells. After treatment with Rituximab, the EBV-DNA loads decreased below the lower limit of detection in 10 patients (PTLD-stable disease, PTLD-SD group), and the viral loads replicated at lower level in six patients (PTLD-partial response, PTLD-PR group). In the PTLD-SD group, the percentage of CD3+CD8+ T lymphocytes increased beyond the normal range with the ascending of EBV-DNA loads, then it decreased to the normal range accompanied by the clearance of EBV. In the PTLD-PR group, the CD3+CD8+ T lymphocytes kept in the normal range, while the EBV kept on replication. Conclusions The increased number of CD3+CD8+ T lymphocytes occurred in parallel with the decline in EBV-DNA loads, which is the most useful index in estimating the host capacity of immuno-surveillance against EBV.

Early Hospital Readmission After Pediatric Liver Transplant: A Retrospective Analysis of the Society of Pediatric Liver Transplantation (SPLIT) Database.

Incidence of and risk factors for early hospital readmission (EHR) are poorly defined in pediatric liver transplant recipients. Therefore, we evaluated EHR incidence and risk factors for pediatric liver recipients in a nationally representative sample. Using the Society of Pediatric Liver Transplantation database, we retrospectively analyzed 2808 pediatric liver-only recipients transplanted 2011-2022. Recipient-, donor-, and center-level characteristics were evaluated as possible risk factors for EHR within 30 days of hospital discharge using multivariable modified Poisson regression. Overall, 23% (N = 642) of pediatric recipients experienced EHR. Independent risk factors for EHR include diabetes (adjusted relative risk [aRR] 2.33, 95% CI: 1.41-3.86, p = 0.001), history of malignancy (aRR 1.59, 95% CI: 1.19-2.11, p = 0.002), and shorter length of transplant hospitalization. Recipients in the shortest length of stay quartile (median [IQR] 8 [7-9] days) had a ninefold increased risk for EHR compared with recipients in the longest length of stay quartile (34 [28-48] days) (aRR 8.86, 95% CI: 5.68-13.81, p < 0.001). Incidence of EHR did not vary by transplant center and was not associated with other characteristics of the donor (DCD vs. not DCD), recipient (age, race, sex, and diagnosis), procedure (whole vs. split liver, ischemic time), or transplant center. We found the 30-day readmission rate for pediatric liver transplant recipients was 23%. Shorter hospital stays were a major risk factor for EHR, highlighting that longer initial transplant hospital stays may be beneficial for predischarge optimization and coordination of their complex care.

Bridging the Gap: A Review of Pediatric to Adult Transition of Care in Liver Transplantation.

With improvements in long-term graft function and survival, an increasing population of pediatric liver transplant (LT) recipients now require adult care. A process to successfully transition young adults to adult LT centers is supported in the literature with discussions on the rationale for health care transition (HCT), barriers to transition, stakeholder perspectives, and transfer readiness (TR). Results of outcomes studies are difficult to generalize and there remains no standard of care for HCT in LT. Of concern is that the youth's increasing independence occurs during a period of developmental vulnerability, with a threat to graft function due to risk-taking behaviors, specifically nonadherence, that may lead to rejection, graft loss, and death. The purpose of this comprehensive literature review is to discuss current knowledge, practices, and outcomes of HCT for LT recipients with additional support from literature in solid organ transplant (SOT) and pediatric-onset chronic conditions literature. Recent position statements in LT and SOT express a greater awareness of the importance of HCT with broad agreement that reflects a similarity in approach in endorsing HCT as an essential process that should be initiated in early adolescence with TR as a primary determinant of transfer; however, standardization with consistent outcomes measurement is lacking. The literature supports transition as an esential component of care that should be initated in early adolescence with programs that address knowlege, skill-development, and advocacy. The engagement of all stakeholders in LT is essential to program development. There is increasing awareness among the multidisciplinary team of the importance and role of the adult provider in extending transitional care into the adult setting as executive functioning skills mature. Outcome measures need to be clearly defined and standardized. Regulatory agency involvement to validate and support the need for TOC programs is crucial and should promote outcomes research for best practice program standardization.

Effectiveness of hepatitis A immunisation after paediatric liver transplantation: A retrospective observational analysis.

This retrospective study aimed to investigate the response to hepatitis A virus (HAV) immunisation following liver transplantation. We analysed, 234 vaccination records of 284 children who underwent liver transplantation between January 2003 and July 2021, including annual serological results. Of the 120 HAV-naïve patients, approximately 71% and 83% showed seroconversion after receiving one and two vaccine doses, respectively. The third dose increased the seroconversion rate to 93%. In multivariable logistic regression analysis, the number of vaccine doses and age at first vaccine dose were independently associated with seroconversion. In contrast, additional immunosuppression with mycophenolate mofetil (MMF) was negatively associated with seroconversion. In Cox regression analysis of all 96 seroconverted children, younger age at first vaccination and additional immunosuppression with either MMF or prednisolone were identified as independent risk factors for the early loss of HAV immunity. In summary, HAV immunisation with the three-dose vaccination series is recommended for paediatric liver transplant recipients. Antibody testing and booster vaccinations, if necessary, are recommended, especially for those living in endemic areas or with additional immunosuppressive treatments.

Clinical outcomes of Omicron infection and vaccine acceptance among pediatric liver transplant recipients: insights from a cross-sectional survey

ObjectivesOur study aims to explore the clinical characteristics of Omicron infection in pediatric liver transplant recipients (PLTRs), after the national COVID-19 outbreak. Additionally, we will investigate changes in vaccine coverage and parental attitudes towards vaccinating their children after this current outbreak.MethodsWe conducted a web-based questionnaire survey to gather information on Omicron infection, vaccination status, and guardian attitude among PLTRs. Besides, utilized valid questionnaire and long-term follow-up information processing techniques, and performed statistical analysis of relevant parameters.Results528 valid questionnaires were collected, among which, 251 responses replied Omicron infection status. The Omicron infection rate in Chinese PLTRs was 56.2% (141/251), similar to the report in the normal population (around 60%). 99.3% of infected PLTRs presented mild symptoms, mostly with fever (78.0%), followed by Cough (76.6%), with a mean RTPCR conversion time of 7 days; the overall PLTRs’ vaccination rate in this study was 13.3%, similar to that of our previous study (9.4%). Besides, we found no significant differences of either infection rate or clinical symptoms between the vaccinated and unvaccinated groups. Moreover, the study showed 61.6% of guardians supported COVID-19 inoculation despite the outbreak of Omicron status.ConclusionsThe symptoms of Omicron infection in Chinese PLTRs were relatively mild, vaccine immunization had a limited effect on PLTRs’ defense against Omicron infection, besides, their guardians supported the inoculation policy with a caution.Clinical trial registrationhttp://www.chictr.org.cn, identifier ChiCTR2200055968.

Less is more: The use of single biodegradable stenting to treat biliary anastomotic strictures in pediatric liver transplantation.

This study reports our experience of using biodegradable biliary stents (BBSs) for anastomotic biliary strictures (ABSs) in pediatric patients undergoing liver transplants. It involves the analysis of a retrospective data collection from January 2014 to January 2023, including all pediatric recipients of liver transplants in our center treated for ABSs with BBSs. In phase 1 (2014-2019), there was an initial percutaneous transhepatic cholangiography with anastomotic dilatation followed 2 weeks after a second percutaneous transhepatic cholangiography with BBS insertion. In phase 2 (2019-2023), the BBS was placed shortly after ABS dilatation, requiring only 1 percutaneous transhepatic cholangiography. All patients were followed up with routine tests and ultrasound. Forty-six ABSs were diagnosed in 43 pediatric recipients of liver transplants with a median of 6.7 months after liver transplantation (0.1-246.8mo). Eight out of 46 ABSs (17.4%) treated with BBSs relapsed (median recurrence time: 6.5mo; 1.6-17.0mo). Four resolved with further BBS placement; only 4 needed surgical revision (8.7%) after a median follow-up time of 43.9 months (0.3-106.3). There were no differences in ABS recurrence rate, time between stent placement and recurrence, or the presence of cholangitis based on whether the BBS was deployed in 1 or 2 steps. Patients with end-to-end anastomosis had a higher ABS recurrence (OR 10.8; 1.4-81.3, p = 0.008) than those with bilioenteric anastomosis. The use of biodegradable stents could be a good option for treating ABSs in pediatric patients undergoing liver transplants, with our series showing a success rate of over 90% and an average follow-up of 43.9 months.

Neighborhood-Level Deprivation Impacts Graft and Patient Outcomes Among Pediatric Liver Transplant Recipients.

The impact of social determinants of health (SDOH) on pediatric liver transplant outcomes has not been extensively investigated. The purpose of this study was to examine the effect of neighborhood-level deprivation on graft and patient survival among pediatric liver transplant recipients. This is a single-center observational study among children who received a primary liver transplant from March 1996 to March 2023. The Childhood Opportunity Index (COI) score was used to measure the degree of neighborhood deprivation. A total of 252 children were included, half (52.8%) were female and the majority were non-Hispanic White (71%). Half (53.6%) of the children had private insurance, and the median COI score was 64. A total of 28 children were transplanted from a very low-to-low COI area. Children in very low-to-low COI areas had worse patient (HR = 4.90, 95% CI = 1.41-17.04, p = 0.01) and graft (HR = 3.41, 95% CI = 1.19-9.75, p = 0.02) survival outcomes compared to children in moderate-to-very high areas when adjusting for clinical characteristics. COI score remained a significant predictor of graft survival after adjusting for race and insurance type (HR = 3.41, 95% CI = 1.12-10.40, p = 0.03). Pediatric liver transplant recipients from very low-to-low COI score areas have worse graft outcomes when accounting for clinical factors, race/ethnicity, and insurance status. Future research should investigate the impact of multiple, intersecting SDOH factors, rather than solely a collection of isolated variables.

A blood-based PT-LIFE (Pediatric Liver Transplantation-LIver Fibrosis Evaluation) biomarker panel for noninvasive evaluation of pediatric liver fibrosis after liver transplantation: A prospective derivation and validation study

Allograft fibrosis is increasingly detected in graft biopsies as the postoperative period extends, potentially emerging as a pivotal determinant of long-term graft function and graft survival among pediatric recipients. Currently, there is a paucity of noninvasive diagnostic tools capable of identifying allograft fibrosis in pediatric recipients of liver transplants. This study involved 507 pediatric liver transplant patients and developed a novel blood-based diagnostic assay, Pediatric Liver Transplantation-Liver Fibrosis Evaluation (PT-LIFE), to noninvasively distinguish allograft fibrosis using blood samples, clinical data, and biopsy outcomes. The PT-LIFE assay was derived from a matrix of 23 variables and validated in 2 independent cohorts. It integrates 3 biomarkers (LECT2, YKL-40, FBLN3) with an area under the receiver operating characteristic curve of 0.91. In the pooled analysis, a PT-LIFE score lower than 0.12 identified liver allograft fibrosis semiquantitative scores 0 to 2 with a sensitivity of 91.9%, whereas scores above 0.29 indicated liver allograft fibrosis semiquantitative scores 3 to 6, with a specificity of 88.4%. The PT-LIFE assay presents as a promising noninvasive diagnostic tool for the detection of allograft fibrosis in pediatric liver transplant recipients.

Cytomegalovirus prophylaxis in pediatric liver transplantation: A comparison of strategies across the Society of Pediatric Liver Transplantation consortium

Although cytomegalovirus (CMV) is a common complication after pediatric liver transplantation (PLT), the optimal method for CMV prevention is uncertain and lacks multicentered investigation. We compared the effectiveness of short (<120 days) vs long (>180 days) CMV primary antiviral prophylaxis to prevent CMV disease in PLT, through a prospective cohort study of primary PLT (aged <18 years) recipients enrolled in the Society of Pediatric Liver Transplantation registry from 2015 to 2019 with either donor or recipient CMV seropositivity. Participants were grouped into short or long prophylaxis based on their center’s practice and intended duration. In total, 199 PLT recipients were enrolled including 112 (56.3%) short and 87 (43.7%) long prophylaxis. End-organ disease was rare and similar between groups (2.7% and 1.1%; P = .45). CMV DNAemia and syndrome were more common in the short compared with those in long prophylaxis (26.8% vs 13.8%; P = .03; 18.8% vs 6.9%; P = .02). Neutropenia occurred more commonly with long prophylaxis (55.2% vs 16.1%; P < .001). Graft and patient survival were similar. Consideration of a short prophylaxis must weigh increased risk of CMV syndrome/DNAemia against medication burden and neutropenia of longer prophylaxis.

Transient Elastography for Noninvasive Evaluation of Posttransplant Liver Graft Fibrosis in Turkish Children, Ege University Children Hospital Experience.

The influence of advancing fibrosis on graft survival in the context of pediatric liver transplantation accentuates the critical role of protocol-driven liver biopsies, a practice adopted by numerous medical centers. Consequently, the exigency for noninvasive methodologies to assess graft fibrosis assumes heightened importance when conventional clinical and laboratory parameters fail to reveal signs of liver damage. This study aimed to assess the reliability of transient elastography (TE) in pediatric liver transplant recipients to detect graft fibrosis and compare the results of TE in patients who underwent biopsy. This prospective cohort study included liver transplanted children who underwent biopsy at Ege University Children's Hospital between October 1, 2021, and October 31, 2022, and a healthy control group. According to TE, fibrosis was detected in 40 patients, and no fibrosis was detected in 50. The median time to develop fibrosis was 100 months (95% CI [83.1-116.8]). A statistically significant positive correlation existed between LSM and METAVIR fibrosis score (r = 0.562, p = 0.001). There was a statistically significant difference in LSM between patients with F2 fibrosis (7.8-8.8kPa ± 3.2) compared to patients with F0 fibrosis (5.2kPa ± 0.7) (p = 0.005) and F1 fibrosis (6.1kPa ± 1.5) (p = 0.041), on ANOVA. Liver allograft fibrosis is common in long-term follow-up in children who have undergone liver transplantation. Abnormal TE may guide physicians to consider liver biopsy to detect late allograft fibrosis in these children.

Risk Factors for Returning of Pediatric Liver Transplant Recipients to the Intensive Care Unit

Objective To explore the risk factors for the returning of pediatric liver transplant recipients to the intensive care unit (ICU) and provide reference for the clinical decision-making after surgery. Methods A retrospective analysis was conducted with the information of all the pediatric patients who underwent liver transplantation in Ren Ji Hospital,Shanghai Jiao Tong University School of Medicine and were returned to the ICU from 2019 to 2021.The patients returned to the ICU during hospitalization and the reasons for the return were recorded.Each patient of ICU return was matched with three pediatric patients who did not return to the ICU during hospitalization.The basic information,the vital signs and laboratory indicators on the day of transfer from ICU,immunosuppressants and drug concentrations were compared between the two groups.Multivariate Logistic regression analysis was performed to explore the risk factors for the returning of pediatric liver transplant recipients to the ICU. Results The returning rate of pediatric liver transplant recipients to the ICU was 4.36%,and it was 16.00% within 48 h.The main reasons for the return included respiratory complications,abdominal infections,and hepatic vascular occlusion.Multivariate Logistic regression analysis showed that post-operative red blood cell transfusion (OR=4.554,95%CI=1.743-11.901,P=0.002) and high serum level of uric acid (OR=1.005,95%CI=1.001-1.009,P=0.014) were the risk factors for returning to the ICU.High diastolic blood pressure (OR=0.922,95%CI=0.885-0.960,P<0.001) and high total protein level (OR=0.937,95%CI=0.891-0.986,P=0.012) were the protective factors for returning to the ICU. Conclusion Post-operative red blood cell transfusion and high serum level of uric acid are independent risk factors for the returning of pediatric liver transplant recipients to the ICU.

Optimizing Piperacillin Dosing in Pediatric Liver Transplant Recipients: A Case Series.

Pathophysiological changes post-liver transplantation impact the pharmacokinetics and pharmacodynamics of antibiotics. Piperacillin, often used in combination with tazobactam, is a key antibiotic after transplantation to its broad-spectrum activity, but there is a lack of specific pharmacokinetic data in this population. This study aims to describe the pharmacokinetic parameters and target attainment of piperacillin in pediatric liver transplant recipients. Patients with preserved renal function (estimated glomerular filtration rate > 50 mL/min/1.73 m2) receiving intravenous piperacillin-tazobactam at 112.5 mg/kg every 8 h (100 mg piperacillin/12.5 mg tazobactam), with a rapid infusion (0.5-1 h), were included. Two blood samples per child were collected during the same interval within 48 h of starting therapy. A Bayesian approach was applied to estimate individual pharmacokinetic parameters and perform dosing recommendations against Enterococcus spp., Enterobacterales and Pseudomonas aeruginosa. Eight patients with median age of 8 months were included. Median piperacillin clearance and central volume of distribution for the cohort were 11.11 L/h/70 kg and 9.80 L/70 kg, respectively. Seven patients (87.5%) presented with concentrations below the target of 100% fT > MIC. Simulations suggested that these patients required more frequent dosing and extended duration of infusion to ensure target attainment. One patient (12.5%) had trough concentrations that exceed 16 mg/L and could receive a lower daily dose. This case series highlights the importance of personalized therapy in pediatric liver transplant recipients due to the unpredictable and highly variable piperacillin pharmacokinetics in this population.

Role of mTOR Inhibitors in Pediatric Liver Transplant Recipients: A Systematic Review.

Immunosuppressive medications play a crucial role in determining both organ and patient survival following liver transplantation (LT). Typically, immunosuppressive protocols for pediatric LT patients rely on calcineurin inhibitors (CNIs). While inhibitors of mammalian target of rapamycin (mTOR) have demonstrated beneficial outcomes in adult recipients of liver allografts, such as improved renal function post-LT, their application in pediatric liver transplant recipients is a subject of debate due to uncertain efficacy and potential adverse effects. This review evaluates the potential roles of mTOR inhibitors in the context of pediatric LT patients. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol for conduct and reporting. Databases until 31 August 2023 were searched using specific terms and keywords. All clinical studies focusing on mTOR inhibitors in pediatric LT were included. Out of 888 identified articles, 30 studies, involving 386 children who had undergone liver transplantation and received mTOR-inhibitor-based immunosuppressive regimens, met the inclusion criteria. The beneficial impacts of switching from a CNI to an mTOR inhibitor or adding an mTOR inhibitor to CNI-reduced immunosuppression in LT pediatric patients with impaired kidney function are controversial, and high-powered clinical studies are need. It appears that enhancing immunosuppression by adding an mTOR inhibitor to CNI is helpful for pediatric LT recipients who are experiencing refractory acute rejection or chronic rejection. mTOR-inhibitor-containing regimens failed to reduce the occurrence of post-transplant lymphoproliferative disorders (PTLD) among children with LT that may be due to concomitant high CNI concentration among studied patients. The effectiveness of mTOR inhibitors in treating PTLD remains uncertain; however, in patients with PTLD who are at high risk of rejection, mTOR inhibitors may be administered. Conversion to or the addition of mTOR inhibitors to maintenance immunosuppression seems to be suitable for pediatric patients who received a transplant due to hepatic malignancies such as hepatoblastoma or hepatocellular carcinoma or for those with post-transplant primary or recurrent malignancies. Switching to an mTOR inhibitor may improve some CNI-related adverse effects such as gingival hyperplasia, neurotoxicity, nephropathy, hypertrophic cardiomyopathy, or thrombotic microangiopathy. Although the exact role of mTOR inhibitors among pediatric patients who have received a liver transplant needs further study, two algorithms are presented in this review to guide conversion from CNIs to mTOR inhibitors or the addition of mTOR inhibitor to a CNI-minimization immunosuppressive regimen for pediatric patients who may benefit from this class of drugs. This review mainly consisted of retrospective studies with inadequate sample sizes and lacked a control group, which represents the main limitation of this study.

Human leukocyte antigen compatibility and incidence of donor-specific antibodies in pediatric liver transplant recipients.

Antibody-mediated rejection following liver transplantation (LT) has been increasingly recognized, particularly with respect to the emergence of de novo donor-specific antibodies (DSAs) and their impact on graft longevity. While substantial evidence for adult populations exists, research focusing on pediatric LT outcomes remains limited. To investigate the prevalence of human leukocyte antigen (HLA) mismatches and DSA and evaluate their association with rejection episodes after pediatric LT. A cohort of pediatric LT recipients underwent HLA testing at Santa Casa de Porto Alegre, Brazil, between December 2013 and December 2023. Only patients who survived for > 30 days after LT with at least one DSA analysis were included. DSA classes I and II and cross-matches were analyzed. The presence of de novo DSA (dnDSA) was evaluated at least 3 months after LT using the Luminex® single antigen bead method, with a positive reaction threshold set at 1000 MFI. Rejection episodes were confirmed by liver biopsy. Overall, 67 transplanted children were analyzed; 61 received grafts from living donors, 85% of whom were related to recipients. Pre-transplant DSA (class I or II) was detected in 28.3% of patients, and dnDSA was detected in 48.4%. The median time to DSA detection after LT was 19.7 [interquartile range (IQR): 4.3-35.6] months. Biopsy-proven rejection occurred in 13 patients at follow-up, with C4d positivity observed in 5/13 Liver biopsies. The median time to rejection was 7.8 (IQR: 5.7-12.8) months. The presence of dnDSA was significantly associated with rejection (36% vs 3%, P < 0.001). The rejection-free survival rates at 12 and 24 months were 76% vs 100% and 58% vs 95% for patients with dnDSA anti-DQ vs those without, respectively. Our findings highlight the importance of incorporating DSA assessment into pre- and post-transplantation protocols for pediatric LT recipients. Future implications may include immunosuppression minimization strategies based on this analysis in pediatric LT recipients.