Kidney transplantation requires the anastomosis of the graft’s kidney vein to the recipient's iliac vein or inferior vena cava (IVC). The venous reconstruction can be challenging in case of extended ilio-caval thrombosis. We report the case of a child with Denis Drash syndrome, with right Wilms tumor and intra-caval tumoral extension, left nodules of nephroblastomatosis on a horseshoe kidney, proteinuria, and progressive kidney failure, resulting in bilateral nephrectomy and iliac veins and vena cava thrombosis extended to the retro-hepatic IVC. At the age of 7 years, 32 months after the end of the oncological treatment, she underwent kidney transplantation. Venous reconstruction was achieved by using the donor IVC as a venous conduit anastomosed to the recipient's retro-hepatic IVC at the level of the hepatic veins. Postoperative course was uneventful, and the child is alive and well, free of tumor and with normal kidney function, 5 years after the end of oncological treatment, and 32 months after transplantation. This technique appears as a safe and physiological alternative to previously described venous anastomoses to the portal system or pelvic varices, preventing chronic venous hypertension of the graft.

BACKGROUND:The effectiveness of therapeutic drug monitoring (TDM) of mycophenolic acid (MPA) trough levels in children with steroid-dependent or frequently relapsing nephrotic syndrome (SDNS/FRNS) treated with mycophenolate mofetil (MMF) has not been adequately assessed. METHODS:We performed an international, retrospective study including children with SDNS/FRNS, treated with MMF as the first-line steroid-sparing agent, and a follow-up of more than six months. Patients were categorized into two groups: TDM, if MPA trough levels were monitored, and No-TDM, if not. In the TDM group, MMF doses were adjusted to maintain MPA trough levels of more than 3 µg/ml, unless toxicity occurred. The primary outcome was relapse-free survival. RESULTS:A total of 167 patients were observed, 90 in the TDM and 77 in the No-TDM group. Relapse-free survival over the total follow-up was significantly longer in the TDM group (p=0.001, log-rank test) with an estimated relapse-free survival at six months of 73% for the TDM and 55% for the No-TDM group. After correcting for potential confounders, the association remained statistically significant (p<0.001). TDM patients also received lower doses of prednisone after MMF introduction. In the TDM group, children were more likely to modify their initial dose (90% vs 9%; p<0.001). While MMF dose was not associated with relapse (median 1186 vs 1298 mg/m 2 ; p=0.14), MPA trough levels were significantly higher in children who did not relapse (4.0 vs 2.7 µg/ml, p=0.001). Among children maintaining mean MPA levels more than 2.9 µg/ml, relapse-free survival at 6 months was 86%. Reported side effects were similar in both groups. CONCLUSIONS:Monitoring MPA trough levels was associated with an approximately 20% higher MMF effectiveness in maintaining remission at six months in children with SDNS/FRNS. Personalized MMF dosing, adjusted to maintain MPA levels more than 2.9 µg/ml, was both safe and effective. We recommend including MPA trough level monitoring in future studies comparing MMF with other steroid-sparing agents in SDNS/FRNS children.

BackgroundEpstein-Barr virus (EBV) is a herpesvirus linked to nine different human tumors and lymphoproliferative disorders. Immunosuppression promotes EBV-driven malignancies. The most frequent EBV-induced malignancies are lymphomas and nasopharyngeal carcinoma. By promoting smooth muscle proliferation, EBV can induce EBV-associated smooth muscle tumors (EBV-SMT). EBV-SMT is a rare oncological entity for which no current guideline for diagnosis or management exists. Data on posttransplant EBV-SMT (PT-SMT) are scarce in kidney transplant recipients.MethodsWe conducted a national multicentric retrospective study and collected cases among transplantation centers in France. Kidney transplant recipients experiencing histologically proven PT-SMT were included. We collected data on demographic characteristics of patient, history of kidney transplantation, history of PT-SMT, evolution of graft function, and patient survival.ResultsEight patients were included. The median age at PT-SMT diagnosis was 31 years (range 6.5-40). PT-SMT occurred after a median delay of 37.8 months after transplantation (range 6-175). PT-SMT management consisted in immunosuppressive regimen minimization in all patients. Introduction of mTOR inhibitors was performed in two patients. Four patients (50%) needed chemotherapy. Surgical resection was performed in four patients. At last follow-up after PT-SMT diagnosis (median 33 months (range 17-132)), five patients were considered in complete remission, and two patients had died. Two patients experienced graft rejection; two resumed dialysis (25%). All patients with available data presented with impaired graft function at last follow-up.ConclusionPT-SMT is a subacute and progressive disease during kidney transplantation. Even if the risk of developing PT-SMT is low in kidney transplant recipients (0.07% in our cohort), PT-SMT is associated with significant graft loss, possibly due to reduced immunosuppression. Developing guidelines could help transplantation teams better manage these patients.

Autoimmune polyendocrine syndrome type-1 (APS-1) is caused by mono- or biallelic loss-of-function variants of the autoimmune regulator gene AIRE underlying early-onset multiorgan autoimmunity and the production of neutralizing autoantibodies against cytokines, accounting for mucosal candidiasis and viral diseases. Medical intervention is essential to prevent or attenuate autoimmune manifestations. Ruxolitinib is a JAK inhibitor approved for use in several autoimmune conditions. It is also used off-label to treat autoimmune manifestations of a growing range of inborn errors of immunity. We treated three APS-1 patients with ruxolitinib and followed them for at least 30 months. Tolerance was excellent, with no medical or biological adverse events. All three patients had remarkably positive responses to ruxolitinib for alopecia, nail dystrophy, keratitis, mucosal candidiasis, steroid-dependent autoimmune hepatitis, exocrine pancreatic insufficiency, renal potassium wasting, hypoparathyroidism, and diabetes insipidus. JAK inhibitors were therefore considered an effective treatment in three patients with APS-1. Our observations suggest that JAK/STAT pathways are involved in the pathogenesis of APS-1 autoimmune manifestations. They also suggest that JAK inhibitors should be tested in a broader range of APS-1 patients.

IntroductionPrimary infection or reactivation of Epstein-Barr Virus (EBV) is a significant cause of morbidity and mortality in pediatric kidney transplantation. Valganciclovir (VGC) treatment is recommended for prophylaxis of cytomegalovirus infection, but its role for the prevention of EBV infection remains controversial.Patients and methodsAll pediatric kidney transplant recipients aged <18 years old were considered for inclusion in this retrospective study. EBV negative recipients with an EBV positive donor (a group at risk of primary infection) or EBV positive recipients (a group at risk of reactivation) were included. Severe infection was defined by post-transplant lymphoproliferative disorder (PTLD), symptomatic EBV infection or by asymptomatic EBV infection with a viral load >4.5 log/ml. Outcomes were compared between patients receiving VGC prophylaxis (group P+) and those not receiving VGC prophylaxis (group P−).ResultsA total of 79 patients were included, 57 (72%) in the P+ group and 22 (28%) in the P− group; 25 (31%) were at risk of primary infection and 54 (69%) at risk of reactivation. During the first year post-transplant, the occurrence of severe EBV infection was not different between the P+ group (n = 13, 22.8%) and the P− group (n = 5, 22.7%) (p = 0.99). Among patients at risk of primary infection, the rate of severe EBV infection was not different between the two groups (42.1% in P+ vs. 33.3% in P−). A higher frequency of neutropenia was found in the P+ group (66.6%) than in the P− group (33.4%) (p < 0.01).ConclusionOur observational study suggests no effect of VGC for the prevention of EBV infection in pediatric kidney transplant recipients, irrespective of their EBV status. Adverse effects revealed an increased risk of neutropenia.

T-helper 17 (Th17) cell differentiation and downstream interleukin-17 (IL-17) production and signaling is critical for neutrophil granulocyte recruitment and activation and subsequent host defense against Candida and Staphylococcus1. This was highlighted by the description of specific defects of this pathway, such as autosomal recessive IL17RA or autosomal dominant IL17F deficiencies, in patients with chronic mucocutaneous candidiasis and staphylococcal skin disease2,3. Of interest, in the kidney, IL-17 also plays a significant role in the defense against these pathogens4, with IL-17 signaling in renal tubular epithelial cells, rather than hematopoietic cells, acting as a crucial player in disseminated candidiasis immune response.

In this retrospective cohort study, we analyze the early humoral and cellular response in 64 adolescents KTx recipients, after two or three doses of mRNA vaccine BNT162b2 against different variants of COVID-19. After 2 doses, 77.8% % of children with no history of infection had a positive humoral response with a median anti-S IgG level of 1107 (IQR, 593-2,658) BAU/mL. All the patients with a history of infection responded with a higher median IgG level (3,265 (IQR, 1,492-8,178) BAU/mL). In non-responders after 2 doses, 75% responded after a third dose with a median Ab titer at 355 (IQR, 140-3,865 BAU/mL). Neutralizing activity was significantly lower against the delta and the omicron variants compared to the wild-type strain and did not improve after a 3rd dose, while infection did provide higher levels of neutralizations against the variants. T cell specific response correlated with humoral response and no patient displayed a cellular response without a humoral response. Adolescent KTx recipients exhibit a high seroconversion rate after only two doses. A third injection, induces a response in the majority of the non-responders patients but did not counterbalance the strong decrease in neutralizing antibody activities against variants highlighting the need for boosters with specific vaccines.

Whole-genome sequencing (WGS) now allows identification of multiple variants in non-coding regions. The large number of variants identified by WGS however complicates their interpretation. Through identification of the first deep intronic variant in NPHS2, which encodes podocin, a protein implicated in autosomal recessive steroid resistant nephrotic syndrome (SRNS), we compare herein three different tools including a newly developed targeted NGS-based RNA-sequencing to explore the splicing effect of intronic variations. WGS identified two different variants in NPHS2 eventually involved in the disease. Through RT-PCR, exon-trapping Minigene assay and targeted RNA sequencing, we were able to identify the splicing defect in NPHS2 mRNA from patient kidney tissue. Only targeted RNA-seq simultaneously analyzed the effect of multiple variants and offered the opportunity to quantify consequences on splicing. Identifying deep intronic variants and their role in disease is of utmost importance. Alternative splicing can be predicted by in silico tools but always requires confirmation through functional testing with RNA analysis from the implicated tissue remaining the gold standard. When several variants with potential effects on splicing are identified by WGS, a targeted RNA sequencing panel could be of great value.

www.transplantjournal.com 549 French Recommendations for a National Competency Framework of Therapeutic Patient Education in Solid Organ Transplantation Caroline Monchaud, PharmD, PhD, Claire Villeneuve, PhD, Stéphanie Belaiche, PharmD, PhD, Marina Charbit, MD, PhD, Charlotte Colosio, MD, Pauline Houssel, MD, Aurélie Meurette, MD, Karine Nubret, MD, Adrien Tissot, MD, Marion Albouy, MD, and Laure Esposito, MD

Glucocorticoids are 1 of the primary treatments in paediatric kidney transplantation. The aims of this study were: (i) to build a population pharmacokinetics (PPK) model of free prednisolone, which is the active form of prednisone, in paediatric kidney transplant recipients; (ii) to identify covariates accounting for interindividual variability (IIV) of pharmacokinetics (PK) parameters; and (iii) to investigate drug exposure–safety relationships.