Pediatric Transplant Centers Research Articles

Multidisciplinary management of children with acute liver failure - Report on 104 children treated in single center.

Pediatric acute liver failure (PALF) is one of the most demanding emergencies in hepatology, intensive care, and for transplant team. This report describes the clinical pattern, diagnostic and therapeutic modalities in children with ALF considered at risk of death without liver transplantation, basing on a long-term experience of the pediatric transplant center. Between 1990 and 2022, 104 children aged 7 days-17 years (median 8 years), with body weight 3.1 to 77 kg (median 32 kg), were qualified for LT due to ALF, and finally 81 (78%) of them were transplanted (9% of all 899 LT performed in children in the same period). A total of 23 children were not transplanted: 15 (14.4%) died while awaiting transplantation. In 8 (7.7%) patients liver function recovered. Before transplantation 45 (43.3%) children developed circulatory failure, in 66 (63.5%) mechanical ventilation was necessary, 18 patients presented acute kidney injury (17.3%), and encephalopathy higher than stage I was present in 60 (57.7%) patients. In 63 children, various kidney/liver assist procedures were performed: CVVHD (continuous veno-venous hemodiafiltration in 22 (21.2%) patients, albumin dialysis (MARS; molecular adsorbent recirculating system) in 39 (37.5%) patients, therapeutic plasma exchange (TPE) in 13 (12.5%) patients. Twenty (24.7%) children died after LT including 15 (18.5%) in the early posttransplant period, and 5 (6.1%) in the late follow-up. Treatment of children with ALF in the peritransplant period is very difficult and require an experienced, multidisciplinary team. Despite continued advances in the care of children with ALF, patient survival remains lower than for elective indications for liver transplantation, and timely qualification and transplantation still are the most important factors of survival of these children.

Molecular Adsorbent Recirculating System for Acute Liver Failure in a New Pediatric-Based Extracorporeal Liver Support Program.

Acute liver failure (ALF) carries significant morbidity and mortality, for both pediatric and adult patients. Albumin dialysis via the molecular adsorbent recirculating system (MARS) is a form of extracorporeal liver support (ELS) that can reduce hepatic encephalopathy (HE), a main driver of mortality in ALF. However, data on MARS and its benefit on mortality have been inconsistent. We sought to report our experiences and patient outcomes from the first 2 years of operation of a new ELS program, within an established pediatric liver transplantation center. Retrospective review of outcomes in pediatric and adult patients treated with MARS therapy for ALF, from 2021 to 2022. Outcomes included reduction in HE and biochemical markers of ALF after MARS therapy, survival, and transplant-free survival. Comparisons were made via Wilcoxon signed-rank test. Five pediatric and two adult patients underwent MARS for ALF. Ages ranged from 2 to 29 years. Overall, 21 MARS runs were performed (median 3 runs per patient, 12.4 hr per run [interquartile range, IQR 10.1-17]). Overall survival was 85.7%, and transplant-free survival was 71.4%. There was a statistically significant reduction in HE score with MARS therapy (median 3 [IQR 3-4] to 1 [IQR 0-1], p = 0.03), and in ALF biomarkers including ammonia (256 µL/dL [195-265] to 75 µL/dL [58-101], p = 0.02), aspartate aminotransferase (6,362 U/L [920-8,305] to 212 U/L [72-431], p = 0.02), alanine aminotransferase (8,362 U/L [3,866-9,189] to 953 U/L [437-1,351], p = 0.02), and international normalized ratio (4.5 [3.3-6.7] to 1.3 [1.2-1.4], p = 0.02). MARS therapy for ALF was well tolerated by both pediatric and adult patients, and resulted in significant improvement in clinical and biochemical parameters. We demonstrated encouraging overall and transplant-free survival, suggesting that early initiation of MARS with relatively long and frequent cycle times may be of significant benefit to ALF patients, and is worthy of additional study in larger cohorts.

Criteria for immediate extubation after pediatric liver transplantation in a single pediatric liver transplant center in Japan.

This was a retrospective study. The records of all cases undergoing LT in our center from January 2016 to December 2020 were collected. We excluded cases>18 years old at the time of LT. Enrolled cases were divided into two groups: cases with immediate extubation (IE) or without immediate extubation (NIE). We compared preoperative conditions, intraoperative management, and postoperative courses. Finally, we classified NIE group patients into cases extubated at postoperative day 1 (early; E-NIE) and others (delayed; D-NIE) and compared their underlying diseases and postoperative courses. In the IE group, there were 81 cases, while the NIE group consisted of 185 cases. All patients in the IE group were successfully extubated without any instances of re-intubation due to respiratory failure. Within the E-NIE group, comprising 130 cases, all patients were ultimately extubated without the need for tracheostomy. However, in the D-NIE group, which encompassed 53 cases, seven patients required tracheostomy. In our center, the implementation of our anesthesia management protocol and the use of pre/postoperative case selection criteria have allowed for the safe practice of IE following pediatric LT. However, it should be noted that patients who cannot be extubated by Postoperative Day 1 (POD1) may be at an increased risk of requiring a tracheostomy. When contemplating IE, it is crucial to take into account the disease-specific physiological aspects and surgical site situations.

Outcome of pediatric living donor liver transplant: Experience from Pakistan; a resource limited setting.

Liver transplantation (LT) has emerged as a lifesaving modality for many liver diseases in children. Pediatric LT is an established treatment in the Western world but is relatively a new procedure in resource-limited countries like Pakistan. The study aims to highlight the outcomes and survival of pediatric recipients from the first pediatric liver transplant center in Pakistan. A retrospective analysis of pediatric LT was done from 2012 to 2019. The study was conducted in the Hepatobiliary and liver transplant department of Shifa International Hospital (SIH), Islamabad. A detailed analysis for indications for pediatric LT, survival, and complications was done. Forty-five patients under 18 years of age underwent Living donor liver transplant (LDLT) in SIH. Median age was 9 years and M:F of 2:1. Cryptogenic liver disease followed by Wilson disease were the two most common indications of LT. The majority of patients had chronic liver disease 34 (75%) while 11 (24%) had acute liver failure. The right lobe graft was the most common type of graft 19 (42.2%). Thirty days, 1-year, 3-year, and 5-year survival was 77.8%, 75.6%, 73.3%, and 60.6% respectively. Mortality was highest in patients with biliary atresia 4 (33%). Causes of death included pulmonary embolism, sepsis, surgical complications, and acute kidney injury. Mean survival was 88.850 months (±7.899) (CI 73.369-104.331). Pediatric LDLT has offered disease-free survival for patients. Survival can improve further with nutritional rehabilitation and anticipation and management of post-operative complications.

Safety and Immunogenicity of Live Viral Vaccines in a Multicenter Cohort of Pediatric Transplant Recipients

Live vaccines (measles-mumps-rubella [MMR] and varicella-zoster virus [VZV]) have not been recommended after solid organ transplant due to concern for inciting vaccine strain infection in an immunocompromised host. However, the rates of measles, mumps, and varicella are rising nationally and internationally, leaving susceptible immunocompromised children at risk for life-threating conditions. To determine the safety and immunogenicity of live vaccines in pediatric liver and kidney transplant recipients. This cohort study included select pediatric liver and kidney transplant recipients who had not completed their primary MMR and VZV vaccine series and/or who displayed nonprotective serum antibody levels at enrollment between January 1, 2002, and February 28, 2023. Eligibility for live vaccine was determined by individual US pediatric solid organ transplant center protocols. Exposure was defined as receipt of a posttransplant live vaccine. Transplant recipients received 1 to 3 doses of MMR vaccine and/or 1 to 3 doses of VZV vaccine. Safety data were collected following each vaccination, and antibody levels were obtained at 0 to 3 months and 1 year following vaccination. Comparisons were performed using Mann-Whitney U test, and factors associated with development of postvaccination protective antibodies were explored using univariate analysis. The cohort included 281 children (270 [96%] liver, 9 [3%] kidney, 2 [1%] liver-kidney recipients) from 18 centers. The median time from transplant to enrollment was 6.3 years (IQR, 3.4-11.1 years). The median age at first posttransplant vaccine was 8.9 years (IQR, 4.7-13.8 years). A total of 202 of 275 (73%) children were receiving low-level monotherapy immunosuppression at the time of vaccination. The majority of children developed protective antibodies following vaccination (107 of 149 [72%] varicella, 130 of 152 [86%] measles, 100 of 120 [83%] mumps, and 124 of 125 [99%] rubella). One year post vaccination, the majority of children who initially mounted protective antibodies maintained this protection (34 of 44 [77%] varicella, 45 of 49 [92%] measles, 35 of 42 [83%] mumps, 51 of 54 [94%] rubella). Five children developed clinical varicella, all of which resolved within 1 week. There were no cases of measles or rubella and no episodes of graft rejection within 1 month of vaccination. There was no association between antibody response and immunosuppression level at the time of vaccination. The findings suggest that live vaccinations may be safe and immunogenic after solid organ transplant in select pediatric recipients and can offer protection against circulating measles, mumps, and varicella.

Follow-up biopsies identify high rates of persistent rejection inpediatric kidney transplant recipients after treatment of T cell-mediated rejection.

Incomplete resolution of T cell-mediated rejection (TCMR) after treatment may not be detected with serum creatinine monitoring and is associated with donor-specific antibodies and chronic rejection. We evaluate the utility of follow-up biopsies (FUB) to identify and characterize rates of persistent TCMR after treatment in pediatric kidney transplant patients. Patients from two pediatric transplant centers performing standard of care FUB at 1.5-2 months after treatment for TCMR were included. FUB were evaluated for extent of rejection resolution (complete vs. incomplete) and grade. Clinical data at time of FUB and later were reported, where available. Fifty-eight patients underwent FUB, at mean of 1.7 months (SD 0.7) post-index biopsy. Rejection grade on index biopsy was Banff borderline (≥i1t1 and <i2t2) in 59% and Banff ≥1A (≥i2t2) in 41%. Acute rejection was persistent in 32 (55%) of FUB. Borderline rejection had higher rates of complete resolution of rejection compared to grade ≥1A (53% vs. 33%, p = .033). Incomplete resolution of rejection on FUB was re-treated in 25 (78%) of cases. Change in eGFR from index to FUB did not differ between those with complete and incomplete resolution (5.7 ± 32.2 vs. 13.1 ± 51.3, p = .28) and was not a sensitive marker of identifying persistent rejection. FUB were effective at detecting persistent rejection, which was common among pediatric transplant patients after standard TCMR treatment. Until more effective rejection treatments or sensitive biomarkers are available, FUB may be effectively utilized to identify patients with ongoing rejection who would benefit from further treatment.

No Additional Risk of Ampicillin Rash Among Pediatric Liver Transplant Recipients With Concurrent Epstein-Barr Virus Infection.

Epstein-Barr virus (EBV) infection frequently develops in children undergoing liver transplantation (LT) because of mandated immunosuppressive therapy. There is a risk of ampicillin rash when penicillin derivatives are used in patients with EBV-associated infectious mononucleosis. Hence, the administration of penicillin derivatives may raise concerns about ampicillin rash in patients with high EBV loads. However, no studies confirmed the risk of administering penicillin derivatives to EBV-infected children after LT. This retrospective study was conducted at the largest pediatric transplantation center in Japan. We investigated all pediatric liver transplant recipients who received penicillin derivatives within 2 years of LT between 2014 and 2020. We separated the cohort into EBV-positive and EBV-negative groups to assess the frequency of ampicillin and antibiotic-associated rash. Two hundred eighty-six liver transplant recipients were enrolled. There were 111 recipients in the EBV-positive group and 175 recipients in the EBV-negative group. In the EBV-positive group, 49 patients had high EBV DNA loads (≥1000 copies/µg DNA). None of the patients in either group developed ampicillin rash, and the frequency of antibiotic-associated rash did not differ [8/111 (7.2%) vs. 10/175 (5.7%), P = 0.797]. Additional subgroup analysis revealed no difference in the frequency of antibiotic-associated rashes regardless of the presence or absence of high EBV loads. In this study, ampicillin rash was not observed, and antibiotic-associated rash was not associated with concurrent EBV infection. Penicillin derivatives can be used safely, even in liver transplant recipients with persistent asymptomatic EBV infection.

Improving Safety in Living Liver Donation: Lessons From Intraoperative Adverse Events in 438 Donors Undergoing a Left Liver Resection.

Donor safety is paramount in living organ donation. Left liver resections are considered safer than right lobe hepatectomies. However, unexpected intraoperative adverse events (iAEs), defined as any deviation from the ideal intraoperative course, can also occur during left liver resections and may be life threatening or lead to postoperative complication or permanent harm to the donor and recipient. Records of 438 liver living donors (LDs) who underwent 393 left lateral sectionectomies (LLSs) and 45 left hepatectomies (LHs) between July 1993 and December 2018 in a pediatric living-donor liver transplantation center were reviewed for the appearance of iAEs that could have influenced the donor morbidity and mortality and that could have contributed to the improvement of the LD surgical protocol. Clinical characteristics of LLS and LH groups were comparable. Nine iAEs were identified, an incidence of 2%, all of them occurring in the LLS group. Seven of them were related to a surgical maneuver (5 associated with vascular management and 2 with the biliary tree approach). One iAE was associated with an incomplete donor workup and the last with drug administration. Each iAE resulted in subsequent changes in the surgical protocol. Donor outcome was at risk by 5 iAEs classed as type a, recipient outcome by 2 iAEs (type b) and both by 2 iAEs (type c). Postoperative complications occurred in 87 LDs (19.9%), with no differences between the LLS and LH groups (P = 0.227). No Clavien-Dindo class IVa or b complications or donor mortality (Clavien-Dindo class V) were observed. iAEs debriefings induced changes in our LD protocol and may have contributed to reduced morbidity and zero mortality. iAEs analysis can be used as a quality and safety improvement tool in the context of LD procedures, which may include right liver donation, laparoscopic, and robotic living liver graft procurement.

Vaccination practices in pediatric transplantation: A survey among member centers of the European reference network TransplantChild.

There is considerable variation in vaccination practices between pediatric transplant centers. This study aims to evaluate active immunization attitudes and practices among ERN-TransplantChild centers and identify potential areas of improvement that could be addressed by shared evidence-based protocols. A cross-sectional questionnaire of attitudes and practices toward immunization of pediatric SOT and HSCT candidates and recipients was sent to a representative member of multidisciplinary teams from 27 European centers belonging to the ERN-TransplantChild. A total of 28/62 SOT programs and 6/12 HSCT programs across 21 European centers participated. A quarter of centers did not have an on-site protocol for the immunizations. At the time of transplantation, pediatric candidates were fully immunized (80%-100%) in 57% and 33% of the SOT and HSCT programs. Variations in the time between vaccine administration and admission to the waiting list were reported between the centers, with 2 weeks for inactivated vaccines and variable time (2-4 weeks) for live-attenuated vaccines (LAVs). Almost all sites recommended immunization in the post-transplant period, with a time window of 4-8 months for the inactivated vaccines and 16-24 months for MMR and Varicella vaccines. Only five sites administer LAVs after transplantation, with seroconversion evaluated in 80% of cases. The immunization coverage of European pediatric transplant recipients is still inconsistent and far from adequate. This survey is a starting point for developing shared evidence-based immunization protocols for safe vaccination among pediatric transplant centers and generating new research studies.

Engaging Adolescent Heart Transplant Recipients Through In-App Messaging During Mobile Health Intervention.

Introduction: Adolescents heart transplant recipients experience difficulty with adherence to immunosuppressive medication leading to increased risk of organ rejection, hospitalization, and mortality. Few interventions have been successful to promote medication adherence in adolescent heart transplant patients as most fail to engage the patient in the behavioral change process and support patient-provider communication. The purpose of this study was to explore the nature and degree of in-app communication between adolescent heart transplant recipients and nursing staff during an asynchronous mobile video directly observed therapy intervention. Methods: A content analysis of 894 in-app messages exchanged between 10 adolescent patients and nurses during a 12-week mobile-based intervention was conducted. Two authors used an inductive, iterative process to guide a thematic analysis of the asynchronous in-app messages with high interrater reliability ranging from 81.5% to 100%. Findings: In-app messages fell under 3 broad content categories: (1) interpersonal support and rapport-building, (2) medically related questions and information, or (3) functional information about the intervention and the mHealth app. Results demonstrated the degree to which interpersonal engagement occurred during the intervention, the nature of these exchanges, and their relationship to medication adherence. Conclusions: The study provided insights into the feasibility and benefits of 2-way communication features of the directly observed therapy intervention in promoting engagement and in improving medication adherence among adolescent heart transplant patients. Continued research and clinical focus on patient engagement and impactful aspects of interpersonal communication could aid in the translation of this intervention into standard clinical care at pediatric transplant centers.

COVID-19 Disease in Pediatric Solid Organ Transplantation from Alpha to Omicron: A High Monocyte Count in the Preceding Three Months Portends a Risk for Severe Disease.

Planning for future resurgences in SARS-CoV-2 infection is necessary for providers who care for immunocompromised patients. to determine factors associated with COVID-19 disease severity in immunosuppressed children. a case series of children with solid organ transplants diagnosed with SARS-CoV-2 infection between 15 March 2020 and 31 March 2023. a single pediatric transplant center. all children with a composite transplant (liver, pancreas, intestine), isolated intestine transplant (IT), isolated liver transplant LT), or simultaneous liver kidney transplant (SLK) with a positive PCR for SARS-CoV-2. SARS-CoV-2 infection. We hypothesized that children on the most immunosuppression, defined by the number of immunosuppressive medications and usage of steroids, would have the most severe disease course and that differential white blood cell count in the months preceding infection would be associated with likelihood of having severe disease. The hypothesis being tested was formulated during data collection. The primary study outcome measurement was disease severity defined using WHO criteria. 77 children (50 LT, 24 intestine, 3 SLK) were infected with SARS-CoV-2, 57.4 months from transplant (IQR 19.7-87.2). 17% were ≤1 year post transplant at infection. 55% were male, 58% were symptomatic and ~29% had severe disease. A high absolute lymphocyte count at diagnosis decreased the odds of having severe COVID-19 disease (OR 0.29; CI 0.11-0.60; p = 0.004). Conversely, patients with a high absolute monocyte count in the three months preceding infection had increased odds of having severe disease (OR 30.49; CI 1.68-1027.77; p = 0.033). Steroid use, higher tacrolimus level, and number of immunosuppressive medications at infection did not increase the odds of having severe disease. The significance of a high monocyte count as predictor of severe disease potentially confirms the importance of monocytic inflammasome-driven inflammation in COVID-19 pathogenesis. Our data do not support reducing immunosuppression in the setting of infection. Our observations may have important ramifications in resource management as vaccine- and infection-induced immunity wanes.

Prediction of Outcomes After Heart Transplantation in Pediatric Patients Using National Registry Data: Evaluation of Machine Learning Approaches.

The prediction of posttransplant health outcomes for pediatric heart transplantation is critical for risk stratification and high-quality posttransplant care. The purpose of this study was to examine the use of machine learning (ML) models to predict rejection and mortality for pediatric heart transplant recipients. Various ML models were used to predict rejection and mortality at 1, 3, and 5 years after transplantation in pediatric heart transplant recipients using United Network for Organ Sharing data from 1987 to 2019. The variables used for predicting posttransplant outcomes included donor and recipient as well as medical and social factors. We evaluated 7 ML models-extreme gradient boosting (XGBoost), logistic regression, support vector machine, random forest (RF), stochastic gradient descent, multilayer perceptron, and adaptive boosting (AdaBoost)-as well as a deep learning model with 2 hidden layers with 100 neurons and a rectified linear unit (ReLU) activation function followed by batch normalization for each and a classification head with a softmax activation function. We used 10-fold cross-validation to evaluate model performance. Shapley additive explanations (SHAP) values were calculated to estimate the importance of each variable for prediction. RF and AdaBoost models were the best-performing algorithms for different prediction windows across outcomes. RF outperformed other ML algorithms in predicting 5 of the 6 outcomes (area under the receiver operating characteristic curve [AUROC] 0.664 and 0.706 for 1-year and 3-year rejection, respectively, and AUROC 0.697, 0.758, and 0.763 for 1-year, 3-year, and 5-year mortality, respectively). AdaBoost achieved the best performance for prediction of 5-year rejection (AUROC 0.705). This study demonstrates the comparative utility of ML approaches for modeling posttransplant health outcomes using registry data. ML approaches can identify unique risk factors and their complex relationship with outcomes, thereby identifying patients considered to be at risk and informing the transplant community about the potential of these innovative approaches to improve pediatric care after heart transplantation. Future studies are required to translate the information derived from prediction models to optimize counseling, clinical care, and decision-making within pediatric organ transplant centers.

Intraoperative fluid administration volumes during pediatric liver transplantation and postoperative outcomes: A multicenter analysis.

Fluid administration is an important aspect of the management of children undergoing liver transplantation and may impact postoperative outcomes. Our aim was to evaluate the association between volume of intraoperative fluid administration and our primary outcome, the duration of postoperative mechanical ventilation following pediatric liver transplantation. Secondary outcomes included intensive care unit length of stay and hospital length of stay. We conducted a multicenter, retrospective cohort study using electronic data from three major pediatric liver transplant centers. Intraoperative fluid administration was indexed to weight and duration of anesthesia. Univariate and stepwise linear regression analyses were conducted. Among 286 successful pediatric liver transplants, the median duration of postoperative mechanical ventilation was 10.8 h (IQR 0.0, 35.4), the median intensive care unit length of stay was 4.3 days (IQR 2.7, 6.8), and the median hospital length of stay was 13.6 days (9.8, 21.1). Univariate linear regression showed a weak correlation between intraoperative fluids and duration of ventilation (r2 = .037, p = .001). Following stepwise linear regression, intraoperative fluid administration remained weakly correlated (r2 = .161, p = .04) with duration of postoperative ventilation. The following variables were also independently correlated with duration of ventilation: center (Riley Children's Health versus Children's Health Dallas, p = .001), and open abdominal incision after transplant (p = .001). The amount of intraoperative fluid administration is correlated with duration of postoperative mechanical ventilation in children undergoing liver transplantation, however, it does not seem to be a strong factor. Other modifiable factors should be sought which may lead to improved postoperative outcomes in this highly vulnerable patient population.

Diagnostic yield and novel candidate genes by next generation sequencing in 166 children with intrahepatic cholestasis.

Cholestatic liver disease is a leading referral to pediatric liver transplant centers. Inherited disorders are the second most frequent cause of cholestasis in the first month of life. We retrospectively characterized the genotype and phenotype of 166 participants with intrahepatic cholestasis, and re-analyzed phenotype and whole-exome sequencing (WES) data from patients with previously undetermined genetic etiology for newly published genes and novel candidates. Functional validations of selected variants were conducted in cultured cells. Overall, we identified disease-causing variants in 31% (52/166) of our study participants. Of the 52 individuals, 18 (35%) had metabolic liver diseases, 9 (17%) had syndromic cholestasis, 9 (17%) had progressive familial intrahepatic cholestasis, 3 (6%) had bile acid synthesis defects, 3(6%) had infantile liver failure and 10 (19%) had a phenocopy of intrahepatic cholestasis. By reverse phenotyping, we identified a de novo variant c.1883G > A in FAM111B of a case with high glutamyl transpeptidase (GGT) cholestasis. By re-analyzing WES data, two patients were newly solved, who had compound heterozygous variants in recently published genes KIF12 and USP53, respectively. Our additional search for novel candidates in unsolved WES families revealed four potential novel candidate genes (NCOA6, CCDC88B, USP24 and ATP11C), among which the patients with variants in NCOA6 and ATP11C recapitulate the cholestasis phenotype in mice models. In a single-center pediatric cohort, we identified monogenic variants in 22 known human intrahepatic cholestasis or phenocopy genes, explaining up to 31% of the intrahepatic cholestasis patients. Our findings suggest that re-evaluating existing WES data from well-phenotyped patients on a regular basis can increase the diagnostic yield for cholestatic liver disease in children.

#6709 DONOR-DERIVED CELL-FREE DNA (DD-CDNA) AS A NON-INVASIVE BIOMARKER OF KIDNEY ALLOGRAFT REJECTION IN PEDIATRIC KIDNEY TRANSPLANTATION

Abstract Background and Aims Rejection remains the first cause of allograft loss in pediatric kidney transplant (pkTx) recipients. Detection of rejection currently relies on kTx biopsies performed either because of allograft dysfunction with the risk of late diagnosis or per surveillance protocols allowing early detection of subclinical rejection but resulting in many unnecessary biopsies. Dd-cfDNA was reported as a new non-invasive biomarker with the potential to improve rejection detection and guide biopsy indications. We aim to assess the association of dd-cfDNA levels with biopsy results in a large cohort of pediatric kTx recipients. Method All pediatric kTx patients with at least one dd-cfDNA assessment at the time of a biopsy at a single pediatric transplant center were included. Clinical, biological and histological data were collected from medical reports. Dd-cfDNA were retrospectively measured from plasma samples biobanked at the time of allograft biopsy between 2015 and 2020 or collected in patients who received regular dd-cfDNA testing as part as clinical care between 2021 and 2022. Results 170 cfDNA measurements in 132 pkTx recipients were available at the time of a biopsy, including 100 performed for surveillance. Mean age at biopsy was 16 years with a median time from kTx of 21 [11;38] months. Median eGFR was 62 [48;83] mL/min/1.73 m2, median UPCR 0,21 [0,14;0,36] g/g, and 20% had DSA at the time of the biopsy. Biopsy findings included: 109 normal, 30 borderline, 15 TCMR, 11 AMR and 5 mixed rejections. Median cfDNA level was 0,64 [0,31;1,80] %. We found a strong association between cfDNA levels and active tubule-interstitial and microvascular Banff lesions (Figure 1). cfDNA levels were significantly increased in cases with rejection (Figure 2). Using the proposed cut-off of 0.5%, performances of the test to detect rejection were Se 84%, Spe 51%, PPV 33%, NPV 92%. Among the borderline cases, 17 (57%) had cfDNA&amp;gt;0.5%. Conclusion We confirm in the largest pediatric kTx cohort to date, the association of dd-cfDNA levels with allograft rejection and its potential interest as a non-invasive biomarker in children. Further studies are needed to assess the added value of dd-cfDNA monitoring to the current standard of care and its ability to reduce unnecessary surveillance biopsies and improve outcomes.

History of Pediatric Nephrology in Türkiye.

This article analyzes the foundation, institutiona-lization, and development of pediatric nephrology in Türkiye. Erich Frank is the pioneer and inspiration for Turkish nephrologists. He pioneered the training of a new generation of modern physicians, the first generation of Turkish nephrologists, and the establishment of the discipline of nephrology. Turkish pediatricians closely followed these developments and tried to improve their knowledge, making an effort to study abroad. These physicians established pediatric nephrology departments in their universities, trained young pediatric nephrologists, initiated pediatric hemodialysis-peritoneal dialysis units, and realized renal transplantation in children. Another pioneer of pediatric nephrology is Prof. İhsan Doğramacı, who established the first pediatric nephrology department at the Ankara-Hacettepe Medical Center in the 1960s. He directed many physicians to pediatric nephrology and provided them education and research opportunities abroad. Pediatric nephrology became a subspecialty in pediatrics in 1983 in Türkiye. Over the years, the number of Turkish pediatric nephrologists has increased; in 1990, they established the Pediatric Nephrology Association. This gave momentum to the standardization of education, better patient care, and scientific studies. Renal biopsies were initiated in 1964, the first pediatric hemodialysis application was conducted in 1974, the first renal transplantation from the living donor was in 1975, and the first continuous peritoneal dialysis was in 1989. With regard to international collaborations, since 2000, a council member from Türkiye has continuously been elected to the executive board of the European Society for Pediatric Nephrology; currently, the European Society for Pediatric Nephrology is led by President Rezan Topaloğlu. Several Turkish pediatric nephrologists have worked in international associations. Today, Türkiye has 107 pediatric nephrology centers, 265 well-trained specialists, 28 hemodialysis units, 39 peritoneal dialysis units, and 26 pediatric transplant centers.

Early Detection of Epstein-Barr Virus as a Risk Factor for Chronic High Epstein-Barr Viral Load Carriage at a Living-donor-dominant Pediatric Liver Transplantation Center.

Epstein-Barr virus (EBV) infection and posttransplant lymphoproliferative disorders (PTLDs) after pediatric liver transplantation (LT) account for significant morbidity and mortality. Knowledge of EBV kinetics, epidemiology, and outcomes among pediatric living-donor LT cases is largely lacking. This study aims to provide clinical information related to EBV infection, chronic high EBV load (CHL) carriage, and PTLD at a living-donor-dominant pediatric LT center. A total of 5827 EBV load measurements from 394 LT recipients fulfilling inclusion criteria and their clinical data were analyzed. EBV loads >1000 copies/μg DNA (742 IU/μg DNA) were considered "high," and CHL was defined by persistence >6 mo. The highlighted results were as follows: (1) 94% of recipients underwent living-donor LT; (2) 80% of EBV seronegative recipients developed first EBV infection <2 y post-LT, and their EBV loads were consistently higher than those of seropositive recipients within <3 y post-LT but did not differ thereafter; (3) 61 (15%) recipients met CHL criteria, but none developed PTLD; (4) age <5 y, cytomegalovirus seronegative donors, and early development of EBV DNAemia <6 mo post-LT were independent risk factors for CHL; (5) the incidence of rejections after 1-y post-LT was comparably low among CHL carriers whose immunosuppression was minimized. Early detection of EBV following LT and CMV seronegative donors would facilitate risk stratification to prevent PTLD while titrating immunosuppression among pediatric LT recipients.

Quality care close to home: Objectives and early outcomes of a second paediatric heart transplant service in Australia.

We describe the experience of a new paediatric heart transplant (HT) centre in Australia. New South Wales offers quaternary paediatric cardiac services including comprehensive care pre- and post-HT; however, perioperative HT care has previously occurred at the national paediatric centre or in adult centres. Internationally, perioperative HT care is highly protocol-driven and a majority of HT occurs in low volume centres. Establishing a low volume paediatric HT centre in New South Wales offers potential for quality HT care close to home. Retrospective review of programme data for the first 12 months was undertaken. Patient selection was audited against the programme's intended initiation criteria. Longitudinal patient data on outcomes and complications were obtained from patient medical records. The programme's initial phase offered HT to children with non-congenital heart disease and no requirement for durable mechanical circulatory support. Eight patients met criteria for HT referral. Three underwent interstate transfer to the national paediatric centre. Five children (13-15 years, weight 36-85 kg) underwent HT in the new programme. Individual predicted 90-day mortality was 1.3-11.6%, with increased risk for recipients transplanted from veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and with restrictive/hypertrophic cardiomyopathies. Survival at 90 days and for duration of follow-up is 100%. Observed programme benefits include mitigation of family dislocation and improved continuity of care within a family-centred programme. Audit of the first 12 months' activity of a second paediatric HT centre in Australia demonstrates adherence to proposed patient selection criteria and excellent 90-day patient outcomes. The programme demonstrates feasibility of care close to home, providing continuity for all patients including those requiring increased rehabilitation and psychosocial support post-transplantation.

Allogeneic Hematopoietic Stem Cell Transplantation Activity in Inborn Errors of Immunity in Russian Federation.

Allogeneic hematopoietic stem cell transplantation (HSCT) is an established therapy for many inborn errors of immunity (IEI). The indications for HSCT have expanded over the last decade. The study aimed to collect and analyze the data on HSCT activity in IEI in Russia. The data were collected from the Russian Primary Immunodeficiency Registry and complemented with information from five Russian pediatric transplant centers. Patients diagnosed with IEI by the age of 18 years and who received allogeneic HSCT by the end of 2020 were included. From 1997 to 2020, 454 patients with IEI received 514 allogeneic HSCT. The median number of HSCTs per year has risen from 3 in 1997-2009 to 60 in 2015-2020. The most common groups of IEI were immunodeficiency affecting cellular and humoral immunity (26%), combined immunodeficiency with associated/syndromic features (28%), phagocyte defects (21%), and diseases of immune dysregulation (17%). The distribution of IEI diagnosis has changed: before 2012, the majority (65%) had severe combined immunodeficiency (SCID) and hemophagocytic lymphohistiocytosis (HLH), and after 2012, only 24% had SCID and HLH. Of 513 HSCTs, 48.5% were performed from matched-unrelated, 36.5% from mismatched-related (MMRD), and 15% from matched-related donors. In 349 transplants T-cell depletion was used: 325 TCRαβ/CD19+ depletion, 39 post-transplant cyclophosphamide, and 27 other. The proportion of MMRD has risen over the recent years. The practice of HSCT in IEI has been changing in Russia. Expanding indications to HSCT and SCID newborn screening implementation may necessitate additional transplant beds for IEI in Russia.

Solid Organ Transplantation for Children With Neurodevelopmental Disabilities—Ethical Considerations and a Call for Clarity

Pediatric transplant centers are faced with the difficult task of maximizing the benefit of organs donated for transplantation while also ensuring that all patients undergoing transplant evaluation are fairly considered for this life-saving therapy. Children with neurodevelopmental disabilities are a complex patient population that on occasion may face the need for a solid organ transplant. Several concerns exist regarding transplantation in this population, yet standard transplant inclusion and exclusion criteria do not exist. Here we explore important factors regarding organ transplantation for children with neurodevelopmental disorders, including patient outcomes, quality of life considerations, and the fundamental ethical principles underlying this complex medical decision-making.