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Background: The risk of early surgical complications of liver transplantation (LT) is higher in children when compared with adults. The aims of the present retrospective study from a single center cohort/single surgeon were to identify the predictive factors for surgical complications after pediatric LT., Methods: All children receiving a first LT from October 1990 to October 2010 in our center were included., Results: Included 151 children (boys 55.0%), with a mean age of 4.8 ± 4.8 years, and a mean weight of 17.9 ± 14.4 kg. Thirty-seven patients were transplanted within the first year, and 59 patients had a body weight below 10 kg. The main initial liver disease was biliary atresia (49.0%). Living donor LT was performed in 39 cases (25.8%), cadaveric whole liver LT in 50 cases (33.1%), and cadaveric partial liver LT in 62 cases (41.1%). Early surgical complications included reoperation (37.8%), vascular complications (8.6%), i.e. arterial (3.3%) or portal thrombosis/stenosis (7.3%) within the first month, and biliary complications in the first 90 days occurred in 22.5% of the cases. The main indications for surgical revision were abdominal bleeding, treatment of a biliary complication, and bowel perforation. Multivariate analysis disclosed that only graft type (split and moreover from a living donor) was significantly and independently associated with the occurrence of biliary complication, and that indication for LT, period, graft type, and operative time were significantly and independently associated with the necessity of surgical revision., Conclusion: Our results emphasize that surgical complications are frequent and strongly depend on patient/graft characteristics., Competing Interests: Declaration of Competing Interest None of the authors have any conflict of interest disclosures to make., (Copyright © 2023. Published by Elsevier Masson SAS.)

Background: The role of protocol liver biopsies (PLB) in the follow-up of pediatric liver transplant recipients remains questionable. This single-center retrospective study aimed to evaluate their clinical impact on the long-term management of pediatric liver transplant recipients., Methods: We described histopathological lesions and clinical consequences for patient management of PLB performed 1, 5, 10, 15, 20, and 25 years after pediatric liver transplantation (LT)., Results: A total of 351 PLB performed on 133 patients between 1992 and 2021 were reviewed. PLB found signs of rejection in 21.7% of cases (76/351), and moderate to severe fibrosis in 26.5% of cases (93/351). Overall, 264 PLB (75.2%) did not cause any changes to patient care. Immunosuppression was enhanced after 63 PLB, including 23 cases of occult rejection. The 1-year PLB triggered significantly more changes, while biopsies at 15, 20, and 25 years produced the lowest rates of subsequent modifications. PLB had a significantly higher probability of inducing therapeutic changes if the patient had abnormal biological or imaging results (odds ratio [OR] 2.82 and 2.06), or a recent history of rejection or bacterial infection (OR 2.22 and 2.03)., Conclusion: Our results suggest that, although it often does not prompt any treatment changes, PLB could be performed because of its ability to detect silent rejection requiring an increase in immunosuppression. PLB could be carried out 1, 5, and 10 years after LT and then every 10 years in patients with normal biological and imaging results and no recent complications, while other patients could be kept on a 5-year protocol., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Liver transplantation (LT) is a standard-of-care therapeutic modality for selected patients with life-threatening liver disease, including children. In addition to specific clinical characteristics of pediatric LT recipients due to initial liver disease (and related comorbidities) and level of liver failure, early postoperative outcome may be dependent on the surgical technique used, related to the type of organ donor and graft. Therefore, the aims of the present retrospective study from a large single centre cohort were to identify the prognostic factors for both 1-year patient and graft survival., Methods: Between October 1990 and October 2010, 151 children underwent a first LT in our centre., Results: The mean age was 5.3 ± 7.4 years, and the main indication was biliary atresia (BA) (49.0%). Living donor liver transplantation (LDLT) was performed in 39 cases (25.8%). Cadaveric liver graft was a whole liver in 50 cases (33.1%) and a partial liver (reduced or split) in 62 cases (41.1%). One-year patient and graft survival rates were 88.7% and 86.1%, respectively. Multivariate analysis disclosed that initial liver disease, location at time of LT, donor/recipient (D/R) delta age, early post-transplant hemodialysis and initial immunosuppression (induction) were significantly associated with patient survival and that D/R delta age, primary non-function, early post-transplant hemodialysis and initial immunosuppression (induction) were significantly associated with graft survival., Conclusion: The results of our single-centre experience of pediatric LT emphasize that early patient and graft survivals depend on pre-operative/operative factors such as initial liver disease, D/R delta age and immunosuppressive regimen. Awareness of these factors can help in the decision making for children requiring LT., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

There are limited clinical data regarding prolonged-release tacrolimus (PR-T) use in pediatric transplant recipients. This Phase 2 study assessed the efficacy and safety of PR-T in stable pediatric kidney, liver, and heart transplant recipients (aged ≥5 to ≤16 years) over 1 year following conversion from immediate-release tacrolimus (IR-T), on a 1:1 mg total-daily-dose basis. Endpoints included the incidence of acute rejection (AR), a composite endpoint of efficacy failure (death, graft loss, biopsy-confirmed AR, and unknown outcome), and safety. Tacrolimus dose and whole-blood trough levels (target 3.5-15 ng/ml) were also evaluated. Overall, 79 patients (kidney, n = 48; liver, n = 29; heart, n = 2) were assessed. Following conversion, tacrolimus dose and trough levels remained stable; however, 7.6-17.7% of patients across follow-up visits had trough levels below the target range. Two (2.5%) patients had AR, and 3 (3.8%) had efficacy failure. No graft loss or deaths were reported. No new safety signals were identified. Drug-related treatment-emergent adverse events occurred in 28 patients (35.4%); most were mild, and all resolved. This study suggests that IR-T to PR-T conversion is effective and well tolerated over 1 year in pediatric transplant recipients and highlights the importance of therapeutic drug monitoring to maintain target tacrolimus trough levels., (© 2019 Astellas Pharma Europe. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)

Background: Risk factors for the development of anti-HLA antibodies include blood transfusion, organ transplantation, and pregnancy. Humoral rejection, mediated by donor-specific anti-HLA antibodies (DSA), has been studied in all kind of solid organ transplantations, and several studies have suggested that post-liver transplantation (LT) DSA may play a role in acute and chronic rejection., Objective: The aim of the present study was to assess the impact of pregnancy on the occurrence of DSA and the impact of DSA in a large population of young female LT recipients., Methods: This single center retrospective study included all female patients who underwent a first LT between January 1990 and December 2010 and who were of childbearing age during post-LT follow-up (i.e. 18 to 40 years old)., Results: The study population consisted in 73 patients, and the mean age at LT was 20.9 years (0.6-39.9); 32 patients were transplanted during childhood. The global incidence of de novo DSA was 42.5% (31/73), after a median delay of 15.5 years (1-25) of follow-up after LT. Most de novo DSA were anti-class II alone (90.3%), and included anti-DQ for 80.6%. From the 73 patients, 33 presented at least one pregnancy after LT (45.2%) and before DSA screening. Multivariate analysis disclosed that history of pregnancy (OR = 6.37; 95%CI, 2.17-18.63, p = 0.001) and younger age at LT (OR = 0.96; 95%CI:0.92-0.99, p = 0.033) were significantly associated with de novo DSA. Among the 31 patients who had de novo DSA, the diagnosis of antibody-mediated rejection was made in 8 patients (25.8%), after a median delay of 74 months after LT; 6/8 (75.0%) had history of pregnancy. During follow-up, 3 of these 8 patients lost their liver graft and died., Conclusion: The results of the present study suggest that close monitoring of DSA in young women with history of pregnancy should be recommended regarding the risk of DSA-mediated rejection., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This study was a Phase II, open-label, multicenter, single-arm, cross-over study comparing the pharmacokinetics (PK) of tacrolimus in stable pediatric kidney, liver, or heart allograft recipients converted from immediate-release tacrolimus (IR-T) to prolonged-release tacrolimus (PR-T). In Days -30 to -1 of screening period, patients received their IR-T-based regimen; during Days 1-7, patients received study IR-T (same dose as screening). On Day 7, the first 24-hours PK profile was taken; patients were then converted to PR-T (1 mg:1 mg), with a second 24-hours PK profile taken on Day 14. The primary end-point was tacrolimus area under the blood concentration-time curve over 24 hours (AUC 24 ); secondary end-points were maximum concentration C max and concentration at 24 hours C 24 . The predefined similarity interval for confidence intervals (CIs) of least squares mean (LSM) ratios was 80%-125%. The PK analysis set comprised 74 pediatric transplant recipients (kidney, n = 45; liver, n = 28; heart, n = 1). PR-T:IR-T LSM ratio (90% CI) was similar overall for AUC 24 , max , and C 24 , and for kidney and liver recipients for AUC 24 (LSM ratio, kidney 91.8%; liver 104.1%) and C 24 (kidney 90.5%; liver 89.9%). Linear relationship was similar between AUC 24 and C 24 , and between PR-T and IR-T (rho 0.89 and 0.84, respectively), suggesting that stable pediatric transplant recipients can be converted from IR-T to PR-T at the same total daily dose, using the same therapeutic drug monitoring method., (© 2019 The Authors. Pediatric Transplantation published by Wiley Periodicals, Inc.)

Background: The prevalence and clinical impact of anti-HLA donor-specific antibodies (DSA) after liver transplantation (LT) have not been extensively studied, especially in pediatric population., Methods: The present cross-sectional study included 100 patients who underwent a first LT in childhood. Anti HLA immunization study was performed at a single time point during routine follow-up using Luminex® single antigen tests with classical anti-IgG conjugate and anti-C3d conjugate., Results: The main indication for LT was biliary atresia (52%) and median age at LT was 4.6years. The median time between LT and DSA assessment was 7.8years (range 1-21years). DSA was identified in twenty-four patients (24%) after LT, with a prevalence of 8%, 28%, 33%, 50%, respectively 0-5years, 5-10years, 10-15years and >15years after LT. DSA were mainly class II (23/24) with a mean MFI of 9.731±5.489 and 18 (79.3%) were C3d-binding DSA. Multivariate analysis disclosed that time elapsed since LT (p<0.01) and history of fulminant hepatitis (p=0.04) were significantly associated with a higher rate of DSA. Liver function tests (at time of DSA assessment) were not different according to the presence or not of DSA (or C3d-binding DSA). Regarding histology, the DSA group had a higher rate of chronic rejection, cirrhosis and centrilobular fibrosis or cirrhosis. In addition, patients with C3d-binding DSA and high MFI (>10,000) had a significant poorer long-term graft survival (p=0.03)., Conclusion: In our pediatric cohort of LT, prevalence of DSA was high and increased regularly with time. Presence of C3d positive-DSA with high MFI was associated with a higher rate of graft loss., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This first observation of donor-transmitted coccidioidomycosis in a pediatric liver-transplant recipient underlines a rare condition in transplanted patients in a nonendemic area. This transmission was observed after a liver split, the patient being contaminated by the left liver while the right-liver recipient was not.

Background: Experience in combined liver-kidney transplantation (CLKT) in children is limited., Methods: We conducted a retrospective study of all pediatric CLKTs performed at our medical institution between 1992 and 2013., Results: We identified 18 pediatric patients (9 girls) who had undergone CLKT at our institution during the study period. The median age [range] and body weight [range] of this patient group was 3.6 [1.0-18.6] years and 13 [10-40] kg, respectively; 11 patients weighed <15 kg at the time of CLKT. Indications for CLKT were primary hyperoxaluria (PH1; n = 14), association of hepatic fibrosis and end-stage renal disease (n = 3) and methylmalonic acidemia (n = 1). In the early postoperative period, eight patients required dialysis. Median stay in the pediatric intensive care unit was 10 [6-29] days. One patient died from cardiovascular disease 10 years after CLKT. There were no liver graft losses despite six acute liver rejection episodes, whereas four kidney grafts were lost. At last follow-up (6 [0.5-21] years) for patients with a functioning renal graft, the glomerular filtration rate was 71 [26-146] mL/min/1.73 m(2). In PH1 patients, urine oxalate normalized in six patients within 3 years after CLKT, but three patients still presented with elevated oxaluria at 1, 2 and 3 years after CLKT., Conclusions: Pediatric CLKT provides encouraging results in the long term, even in the youngest patients.

Cardiovascular diseases induce long-term morbidity and mortality of adult LT recipients. The aim of this retrospective study was to assess CVRF, lipid abnormalities, and atherosclerosis (appraised by c-IMT), more than 10 yr after pediatric LT. Thirty-one children who underwent LT between December 1990 and December 2000 were included. Median age at LT was 14 months (range 4-64), and median follow-up after LT was 11.9 yr (range 9.0-17.3). In our cohort, obesity (9.7%) and treated hypertension (9.7%) were rare. None of the patients was smoker or diabetic. High TC and TG were both observed in 6.5% of the patients. The mean c-IMT for male patients was 1.22 ± 1.55 and 1.58 ± 1.23 mm in female patients. Seven patients (22%) had a mean c-IMT above +2 s.d. Values below the 5th percentile were noted for LDL-cholesterol (58.1%), HDL-cholesterol (25.8%), apolipoprotein B (40%), and apolipoprotein A1 (20%). LDL-cholesterol and apolipoprotein B levels were significantly lower in patients treated by tacrolimus in comparison with CsA (p < 0.05). In conclusion, our results suggest that pediatric LT patients do not present significant CVRF; moreover, instead of hyperlipidemia, hypocholesterolemia (LDL-C) is frequent and immunosuppressive therapy is probably the cause., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose of Review: The experience of combined liver-kidney transplantation (CLKT) is limited in pediatric populations. This strategy is, however, required in specific diseases such as metabolic diseases (namely primary hyperoxaluria type one and methylmalonic acidemia), autosomal recessive polycystic kidney disease, miscellaneous ciliopathies and atypical hemolytic uremic syndrome., Recent Findings: Different series and registry studies have confirmed the feasibility of pediatric CLKT with encouraging results in the long term, even in the youngest and smallest patients, provided that highly trained multidisciplinary teams are involved in this global management. As such, the long-term outcomes after CLKT are currently comparable to that of isolated liver or kidney transplantations, even though the immediate postoperative period remains challenging., Summary: Some questions remain nevertheless unanswered, such as the respective place of combined versus sequential liver-kidney transplantation, especially in primary hyperoxaluria and autosomal recessive polycystic kidney disease. The aim of this review was therefore to provide a 2015 update on pediatric CLKT. In the future, international collaborative studies and registries may help to improve our knowledge of this rare and still highly challenging technique.

Background: Hepatitis E is an emerging disease in developed countries and is usually asymptomatic, particularly in children. Chronic infection is possible in immunocompromised individuals. In the context of a liver transplant, it can simulate a rejection. In this case, antiviral therapy may be considered, thus highlighting the need to diagnose hepatitis E virus (HEV) infection in this population., Objectives: Given the lack of data in France, we have studied the the prevalence of antibodies to HEV in the paediatric liver transplant population., Study Design: This was a retrospective study, carried out in Lyon between 1st January 2010 and 31 May 2013. HEV serology (anti-HEV IgM &IgG) and HEV PCR were studied in 96 children who had undergone liver transplants (84 isolated liver and 12 combined liver and kidney transplants)., Results: Eight patients (8.3%; 62.5% girls; mean age:12.3 years) were HEV seropositive. The mean period since their transplantation was 10 years (range:2-21.8 years). Biliary atresia was the principal indication for transplantation. Seven of these eight children had received liver transplants. There were no differences between the epidemiological and clinical data concerning these patients and the remainder of the study population, particularly with respect to immunosuppression(7/8 tacrolimus; 50% dual immunosuppression). No cases of chronic hepatitis E were found, but 1/8 had chronic cytolysis(EBV&adenovirus infection). In all the patients tested(4/8), seroconversion had occurred after the transplant. There was no significant differences between the age groups in this study., Conclusions: This study showed that in France, the prevalence of antibodies to HEV in paediatric liver and combined liver and kidney transplant patients is 8.3%, as has been found by other European authors., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Epstein-Barr virus (EBV) is known to establish latent infections in B-lymphocytes that can cause lymphoproliferative disorders particularly in immunocompromised patients. More recently, the development of rare EBV-associated smooth muscle tumors has been reported in transplant recipients. We herein describe 2 new cases of EBV-associated post-transplant smooth muscle tumors (EBV-PTSMT), including the first in a facial composite tissue graft recipient. Among the striking features shared by these 2 patients were their young ages, the fact that they were naïve for EBV before the transplantation, that they developed a post-transplant lymphoproliferative disorder before the diagnosis of EBV-PTSMT, and that they responded favorably to reduction of immunosuppression. Radiological and histologic features of EBV-PTSMT are shown. Finally, pathophysiology and therapeutic management of EBV-PTSMT are discussed based on a comprehensive review of the literature., (© 2013 John Wiley & Sons A/S.)

We assessed quality of life in children after liver transplantation (LT) for at least 5years and in their parents, taking into account the physical, psychological, and social components, then compared the results of the patients with those of the general population and investigated the association between quality of life and somatic and psychosocial factors. Thirty-three patients, aged 8 to 18years and with a mean follow-up of 11.4years were included. Quality of life was assessed using generic self-administered questionnaires in 3 versions depending on age (pre-teens, teens, parents): the AUQUEI, OK Ado, and SQLP, respectively. Patient quality of life improved with age for all components and adolescent patients could exceed that of the general population. There was a negative impact of LT on parental quality of life, but family cohesion was strengthened. The parameters associated with patient quality of life were primarily psychosocial parameters, with special consideration for siblings and school. The somatic parameters related to LT had little impact on the quality of life of the patients but were strongly correlated with parental scores, especially when there were complications related to LT or immunosuppression. Quality-of-life assessment is complementary to clinical and laboratory data and is essential to optimize patient monitoring. Parental assessment is essential because of the long-term impact of LT on these families. A regular assessment of the quality of life of young liver transplant recipients is necessary to determine whether the encouraging results are confirmed on a larger cohort., (Copyright © 2012. Published by Elsevier SAS.)

Despite the increasing use of mycophenolate mofetil (MMF) in pediatric liver transplantation recipients, data on MMF pharmacokinetics in this population are relatively scattered. This pilot study was performed to explore whether recipient age-related factors, in conjunction with donor factors, can explain variability in mycophenolic acid (MPA) exposure. Thirty-four MPA pharmacokinetic profiles were performed in 20 stable pediatric liver transplantation recipients (median age, 12 years; range, 1-18 years; median delay after liver transplant, 88 months; range, 3-179 months). Ten children were converted to MMF; the others received MMF as a primary immunosuppressive regimen. MMF was used in combination with tacrolimus. Plasma MPA concentrations were analyzed samples collected at 0, 1, 3, and 6 hours after MMF administration using the enzyme multiplied immunotechnique immunoassay. The median MMF dose was 431 mg/m2 per day (range, 189-833 mg/m2 per day) leading to a median estimated MPA-AUC0-12h of 27 mg/h/L (range, 17-79 mg/h/L). Dose-normalized MPA-AUCs were characterized by high interpatient variability. Young children receiving a liver from a pediatric donor had lower MPA exposure compared with those receiving liver from an adult donor. No correlation was seen between MPA-C0 and MPA-AUC 0-6h in infants, whereas this correlation was significant but moderate in older children. The interpatient variability of MPA exposure observed with this pilot study is an argument for developing therapeutic drug monitoring-based dose adaptation strategies in pediatric liver transplantation recipients. A marked MPA underexposure was observed among young children receiving livers from pediatric donors, indicating that higher doses (mg/m2 of body surface area) might be required to reach the same MPA exposure as in adolescents.

Background: Renal impairment is a frequent complication after orthotopic liver transplantation (OLT). However, most studies in children use inaccurate renal assessment based on serum creatinine, and long-term follow-up data are lacking. The purpose of this study was to determine incidence, determinants, and progression of long-term chronic renal insufficiency (CRI) in a single-center series of pediatric liver transplant recipients., Methods: The true glomerular filtration rate was measured by inulin clearance before and serially after OLT in 69 consecutive patients followed more than 2 years after transplantation. Cumulative incidence of CRI (glomerular filtration rate<60 mL/min/1.73 m2) was determined using a Kaplan-Meier method. A Cox proportional hazard model was performed to identify predictors of CRI., Results: The median age at OLT was 3.2 years. The median follow-up time after OLT was 9.3 years (interquartile range 6.3-11.9). At 10 years post-OLT, the cumulative incidence of CRI was 25%. In a multivariate Cox regression model, arterial hypertension during follow-up as time dependant variable (P=0.03), cyclosporine as primary immunosuppression (P=0.048), and liver diseases with potential renal involvement including inborn errors of metabolism, Alagille syndrome, and hepatic fibrosis (P=0.003) were associated with CRI., Conclusions: Renal function is a major concern long after OLT in children. Renal dysfunction post-OLT may be reduced by optimal control of arterial hypertension, immunosuppression protocols adapted to primary liver disease, and calcineurin inhibitor sparing regimen.