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Introduction Guidelines for the treatment of steroid-dependent nephrotic syndrome (SDNS) and frequently relapsing nephrotic syndrome (FRNS) are lacking. Given the substantial impact of SDNS/FRNS on quality of life, strategies aiming to provide long-term remission while minimising treatment side effects are needed. Several studies confirm that rituximab is effective in preventing early relapses in SDNS/FRNS; however, the long-term relapse rate remains high (~70% at 2 years). This trial will assess the association of intravenous immunoglobulins (IVIgs) to rituximab in patients with SDNS/FRNS and inform clinicians on whether IVIg’s immunomodulatory properties can alter the course of the disease and reduce the use of immunosuppressive drugs and their side effects.Methods and analysis We conduct an open-label multicentre, randomised, parallel group in a 1:1 ratio, controlled, superiority trial to assess the safety and efficacy of a single infusion of rituximab followed by IVIg compared with rituximab alone in childhood-onset FRNS/SDNS. The primary outcome is the occurrence of first relapse within 24 months. Patients are allocated to receive either rituximab alone (375 mg/m²) or rituximab followed by IVIg, which includes an initial Ig dose of 2 g/kg, followed by 1.5 g/kg injections once a month for the following 5 months (maximum dose: 100 g).Ethics and dissemination The study has been approved by the ethics committee (Comité de Protection des Personnes) of Ouest I and authorised by the French drug regulatory agency (Agence Nationale de Sécurité du Médicament et des Produits de Santé). Results of the primary study and the secondary aims will be disseminated through peer-reviewed publications.Trial registration number NCT03560011.

Background: Severe respiratory complications following kidney transplantation have been reported, yet remain poorly understood in the pediatric population. This study aimed to document respiratory disease in this population., Methods: At annual follow-ups, patients completed a respiratory symptoms questionnaire and underwent pulmonary function tests (PFTs). We defined respiratory disease in children when they had clinical disorders and/or PFT abnormalities., Results: Among 236 children included, 110 (41%) exhibited respiratory involvement: 59 (53%) had only clinical disorders, 38 (35%) had only PFT abnormalities, and 13 (12%) had both. Of those with PFT abnormalities, 15 (7%) had obstructive impairment, 12 (6%) had restrictive impairment, and 30 (24%) showed decreased lung diffusion capacity for carbon monoxide (DLCO)/transfer coefficient for carbon monoxide (KCO). In the multivariate analysis, being over 3.5 years of age at the time of transplantation was associated with a reduced risk of respiratory involvement (OR 0.30, CI [0.14; 0.63], p = 0.002), such as induction with basiliximab (OR 0.39, CI [0.17; 0.90], p = 0.03). Conversely, history of immune deficiency, male gender, positive PCR for BK virus and diastolic hypertension were associated with an increased risk (OR 5.96, CI [2.15; 16.51], p = 0.0006, OR 1.97, CI [1.03; 3.77], p = 0.04, OR 3.77, CI [1.14; 12.52], p = 0.03 and OR 2.21, CI [1.13; 4.32], p = 0.02, respectively). Bronchial lesions, such as bronchiectasis, were predominantly observed on tomography., Conclusions: Given the risk of irreversible lung damage, we recommend systematic clinical and functional respiratory monitoring in case of respiratory symptoms, recurrent lower respiratory tract infections, and risk factors in their follow-up., Competing Interests: Declarations. Ethics approval: SPIROKID received approval from the Comité de Protection des Personnes (CPP) in compliance with French legislation regarding ethics, under IDRCB identifier 2018-A00956-49. All patients and their parents provided oral consent after receiving relevant written information. The study has been registered in the ClinicalTrials.gov database with identifier NCT03571542. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Dexmedetomidine is increasingly used for its ability to stabilise haemodynamic status during general anaesthesia. However, there is currently no data on paediatric kidney transplant recipients (pKTR). This study investigates the haemodynamic impact of dexmedetomidine administered perioperatively in pKTR., Methods: From 2019 to 2023, a retrospective study was conducted at Nantes University Hospital involving all pKTR under 18 years of age. The study compared intraoperative haemodynamic parameters between patients administered dexmedetomidine during kidney transplantation (DEX group) and those who did not receive it (no-DEX group). Mean arterial pressure (MAP) and heart rate (HR) were monitored throughout the duration of anaesthesia and compared. Graft function was assessed based on creatinine levels and glomerular filtration rate (GFR) at specific intervals. The perioperative use of fluids and vasoactive drugs, as well as their administration within 24 h post-surgery, were analysed., Results: Thirty-eight patients were enrolled, 10 in the DEX group and 28 in the no-DEX group. Intraoperative HR was similar between the groups; however, MAP was higher in the DEX group (mean difference 9, standard deviation (SD, 1-11) mmHg, p = 0.039). No differences were found regarding the use of fluid and vasoactive drug therapy between groups. GFR at 1 month post-transplantation was significantly elevated in the DEX group (p = 0.009)., Conclusions: pKTR receiving intraoperative dexmedetomidine exhibited higher perioperative MAP compared to those not administered dexmedetomidine. Additionally, the DEX group demonstrated superior graft function at 1 month. The direct impact of dexmedetomidine on immediate postoperative graft function in pTKR warrants further investigation in a prospective multicentre randomised study., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Introduction: Hepatocyte nuclear factor 1-beta ( HNF1B ) gene variants or the chromosome 17q12 deletion (17q12del) represent the most common monogenic cause of developmental kidney disease. Although neurodevelopmental disorders have been associated with the 17q12del, specific genotype-phenotype associations with respect to kidney function evolution have not yet been fully defined. Here, we aimed to determine whether 17q12del or specific HNF1B variants were associated with kidney survival in a large patient population with HNF1B disease., Methods: This was a retrospective observational study involving 521 patients with HNF1B disease from 14 countries using the European Reference Network for rare kidney diseases with detailed information on the HNF1B genotype ( HNF1B variants or the 17q12del). Median follow-up time was 11 years with 6 visits per patient. The primary end point was progression to chronic kidney disease (CKD) stage 3 (estimated glomerular filtration rate [eGFR] < 60 ml/min per 1.73 m 2 ). Secondary end points were the development of hypomagnesemia or extrarenal disorders, including hyperuricemia and hyperglycemia., Results: Progression toward CKD stage 3 was significantly delayed in patients with the 17q12del compared to patients with HNF1B variants (hazard ratio [HR]: 0.29, 95% confidence interval [CI]: 0.19-0.44, P  < 0.001). Progression toward CKD stage 3 was also significantly delayed when HNF1B variants involved the HNF1B Pit-1, Oct-1, and Unc-86 homeodomain (POU h ) DNA-binding and transactivation domains rather than the POU-specific domain (POU s ) DNA-binding domain (HR: 0.15 [95% CI: 0.06-0.37), P  < 0.001 and HR: 0.25 (95% CI: 0.11-0.57), P  = 0.001, respectively). Finally, the 17q12del was positively associated with hypomagnesemia and negatively associated with hyperuricemia, but not with hyperglycemia., Conclusion: Patients with the 17q12del display a significantly better kidney survival than patients with other HNF1B variants; and for the latter, variants in the POU s DNA-binding domain lead to the poorest kidney survival. These are clinically relevant HNF1B kidney genotype-phenotype correlations that inform genetic counseling., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Introduction: Rheumatoid purpura is the most common vasculitis in children, and its renal involvement determines the prognosis. To date, no national protocol exists for its management. A protocol was drafted for the French Grand Ouest inter-region in 2011 in order to standardize practices., Objectives: The main objective is to evaluate renal sequelae with a median follow-up of 2 years since the implementation of this protocol. The secondary objectives are to evaluate the different therapeutic and diagnostic management., Method: Inclusion of all children from 2006 to 2018 with nephropathy due to rheumatoid purpura followed in the university hospitals of Rennes, Nantes, Tours, Angers and Brest., Results: 169 patients were included, of whom 104 were treated accroding to protocol and 65 differently. Sequels at 2-year follow-up concerned 27.0% of patients with no significant difference according to whether or not the protocol was followed. A significant decrease of 26.1% in the number of renal biopsies was observed in the group that followed the protocol. The latter was performed with a median delay of less than 30 days., Conclusion: The protocol allowed a standardization of practices without deleterious consequences at 2 years of follow-up and a decrease in renal biopsy punctures. It is in agreement with the recommendations of KDIGO (Kidney Disease Improving Global Outcomes) and European experts. On the other hand, in view of recent studies and the physiopathology, immunosuppressive drugs other than corticosteroids could be introduced earlier in severe forms.

Background: IgA vasculitis (IgAV) is the most common vasculitis in children. IgAV long-term prognosis depends on kidney involvement or IgA vasculitis with nephritis (IgAVN). To date, steroid treatment (oral steroids or methylprednisolone pulses) has not proven to be formally efficient. This study aimed to assess the role of steroids on IgAVN outcome., Methods: All children with IgAVN diagnosed 2000-2019 in 14 French pediatric nephrology units with minimal follow-up of 6 months were retrospectively included. Outcomes of patients treated with steroids were compared with those of a control group of untreated patients matched for age, sex, proteinuria, eGFR, and histological features. The primary endpoint was IgAVN remission defined as urine protein-to-creatinine ratio < 20 mg/mmol without impaired eGFR one year after disease onset., Results: A total of 359 patients with IgAVN were included with a median follow-up time of 249 days (range 43-809). One hundred eight (30%) patients received oral steroids alone, 207 (51%) patients received three methylprednisolone pulses followed by oral steroids, and 44 patients (12.5%) did not receive steroids. Thirty-two children treated with oral steroids alone were compared with 32 matched control patients who did not receive steroids. One year after disease onset, IgAVN remission proportion was not different between these two groups: 62% versus 68%, respectively. Ninety-three children treated with oral steroids alone were compared with 93 matched patients treated with three methylprednisolone pulses followed by oral corticosteroids. IgAVN remission proportion was not different between these two groups: 77% versus 73%, respectively., Conclusion: The benefit of oral steroids alone and methylprednisolone pulses could not be established based on this observational study. Randomized controlled trials are thus required to determine the efficacy of steroids in IgAVN. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Introduction: Primary 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 Methods: All 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-)., Results: A 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)., Conclusion: Our 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Cheyssac, Savadogo, Lagoutte, Baudouin, Charbit, Novo, Sellier-Leclerc, Fila, Decramer, Merieau, Zaloszyc, Harambat and Roussey.)

Background: Cytomegalovirus (CMV) is one of the most frequent opportunistic infections in kidney transplant (KT) recipients and is a risk factor for patient and graft survival after KT. Center-to-center variation, optimal prevention and treatment strategies in pediatric KT are currently unknown. This survey aimed to assess current CMV prevention and treatment strategies used among French pediatric KT centers., Methods: A web-based survey was sent to all 13 French pediatric kidney transplantation centers., Results: Twelve (92%) centers responded to the survey. All centers used prophylaxis for the donor-positive/recipient-negative (D+/R-) group. For R + patients, 54% used prophylaxis, 37% used a pre-emptive strategy. In the low-risk group, D-/R-, 50% used a pre-emptive approach and 50% had no specific prevention strategy. The antiviral used by all centers for prophylaxis was valganciclovir (VGCV). The duration of prophylaxis varied from 3 to 7 months and the duration of viral load monitoring varied from 6 months to indefinitely. No center used a hybrid/sequential approach. For the treatment of CMV DNAemia, VGCV or intravenous GCV were used. Therapeutic drug monitoring of VGCV was performed in 5 centers (42%). Five centers reported drug resistance. Eight centers (67%) administered VGCV during the treatment of acute graft rejection., Conclusions: There is uniformity in CMV management in some areas among pediatric KT centers in France but not in others which remain diverse and are not up to date with current guidelines, suggesting unnecessary variation which could be reduced with better evidence to inform practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Madden, Baudouin, Charbit, Ranchin, Roussey, Novo, Garaix, Decramer, Fila, Merieau, Vrillon, Zaloszyc, Hogan and Harambat.)

Background: There seems to be a possible link between nephrotic syndrome (NS) and lymphoproliferative syndrome, but it remains poorly understood., Methods: This multicentric and retrospective study focuses on children, who developed idiopathic NS and malignant or benign proliferation between 2000 and 2021., Results: Eleven patients were included, with a median age of 4 years. Only one had a steroid-resistant nephrotic syndrome (SRNS). The maintenance therapy before the proliferation was in majority tacrolimus or mycophenolate mofetil (MMF), but three patients did not receive treatments. The proliferation was mainly a Hodgkin's lymphoma (45%) or a lymphoproliferative disease (36%), in a median time after the NS of two years. Viruses were found in seven cases (EBV in five cases and HHV-8 in two)., Conclusion: The association between proliferative syndrome and idiopathic NS may not be fortuitous, possibly with a common lymphocytic disturbance. Genetic analyses could improve the comprehension of these manifestations in the future. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2021. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Adeno-associated virus (AAV) gene therapies are highly promising, such as the onasemnogene abeparvovec (Zolgensma) in spinal muscle atrophy (SMA). We report the first case of fatal systemic thrombotic microangiopathy (TMA) following onasemnogene abeparvovec in a 6-month-old child with SMA type 1, carrying a potential genetic predisposition in the complement factor I gene. Other cases of TMA have recently been reported after onasemnogene abeparvovec and after AAV9 minidystrophin therapy in Duchenne muscular dystrophy. The risk-benefit ratio of this therapy must therefore be assessed. Early recognition of TMA and targeted immunotherapy are fundamental to ensure the safety of patients treated with AAV gene therapies., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Many centers accept a minimum body weight of 10 kg as threshold for kidney transplantation (Tx) in children. As solid evidence for clinical outcomes in multinational studies is lacking, we evaluated practices and outcomes in European children weighing below 10 kg at Tx., Methods: Data were obtained from the European Society of Paediatric Nephrology/European Renal Association and European Dialysis and Transplant Association Registry on all children who started kidney replacement therapy at <2.5 y of age and received a Tx between 2000 and 2016. Weight at Tx was categorized (<10 versus ≥10 kg) and Cox regression analysis was used to evaluate its association with graft survival., Results: One hundred of the 601 children received a Tx below a weight of 10 kg during the study period. Primary renal disease groups were equal, but Tx <10 kg patients had lower pre-Tx weight gain per year (0.2 versus 2.1 kg; P < 0.001) and had a higher preemptive Tx rate (23% versus 7%; P < 0.001). No differences were found for posttransplant estimated glomerular filtration rates trajectories (P = 0.23). The graft failure risk was higher in Tx <10 kg patients at 1 y (graft survival: 90% versus 95%; hazard ratio, 3.84; 95% confidence interval, 1.24-11.84), but not at 5 y (hazard ratio, 1.71; 95% confidence interval, 0.68-4.30)., Conclusions: Despite a lower 1-y graft survival rate, graft function, and survival at 5 y were identical in Tx <10 kg patients when compared with Tx ≥10 kg patients. Our results suggest that early transplantation should be offered to a carefully selected group of patients weighing <10 kg., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Kidney transplantation (KT) is the optimal treatment for children with end-stage kidney disease. The aim of this study was to evaluate the impact of preemptive kidney transplantation (PKT) and of pretransplant dialysis duration on graft survival among French pediatric kidney transplant recipients., Methods: We analyzed all first pediatric kidney-only transplantations performed in France between 1993 and 2012. A Cox multivariable model was used to investigate the association of PKT and pretransplant dialysis time with the hazard of graft failure defined as death, return to dialysis, or retransplant, whichever occurred first., Results: Patients (n = 1911) were included, of which 380 (19.8%) received a PKT. Median time of follow-up was 7.0 y. PKT was associated with a 55% reduction of the hazard of graft failure at any time after KT compared with patients transplanted after dialysis (hazard ratio, 0.45; 95% confidence interval, 0.33-0.62), after adjustment for recipient sex and age, primary kidney disease, donor age and type (living or deceased donor), number of HLA mismatches, cold ischemia time, and year of transplantation. A reduction of the hazard of graft failure was found in PKT whatever the compared duration of dialysis, even when <6 mo and whatever the dialysis modality. Results were similar in multiple sensitivity analyses., Conclusions: In France, PKT among pediatric patients is associated with a better graft survival when compared with KT after dialysis, even when <6 mo. Based on these findings, we suggest that PKT should be considered as the treatment of choice for children with end-stage kidney disease., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The prognosis of Henoch-Schönlein purpura (HSP), IgA vasculitis, depends on kidney involvement. There is no consensus on the initiation of treatment for HSP nephritis (HSPN). Some centres start treatment before performing a kidney biopsy (KB) while in others, treatment is dictated by the importance of the clinical, biological and histological signs. The aim of this study was to evaluate which of these two approaches is associated with a better kidney outcome at 5-year follow-up., Methods: This multicentre, retrospective, nonrandomised study included children treated for HSPN between 2006 and 2010 in a French paediatric nephrology unit. One group had an early KB at diagnosis (before starting treatment or in the 15 following days). In the second group, initial treatment was decided without performing a KB., Results: Among the 107 children included, 63.5% had an early KB at diagnosis. Follow-up at 5 years was completed in 44 children (28 KB at diagnosis, 16 no KB at diagnosis). Median urine protein/creatinine at 5 years was 2.5 mg/mmol in the early biopsy diagnosis group and 12.5 mg/mmol in the non-biopsy group. An antiproteinuric treatment was given, at 5 years, to 35.7% of the early biopsy at diagnosis children and in 62.5% of the non-biopsied children., Conclusions: Children with early KB at diagnosis seem to have a better renal outcome at 5 years compared to those without an early biopsy at diagnosis or biopsied later. However, this is a small patient cohort and data are missing. Further work is needed to build consensual guidelines on the management of HSPN in children., (© 2021. IPNA.)

Introduction: Socioeconomic status (SES) is recognized as an important determinant of kidney health. We aimed to evaluate the association of social deprivation with different indicators at kidney replacement therapy (KRT) initiation in the French pediatric metropolitan population., Methods: All patients with end-stage kidney disease (ESKD) who started KRT before 20 years old in France between 2002 and 2015 were included. We investigated different indicators at KRT initiation, which are as follows: KRT modality (dialysis vs. pre-emptive transplantation), late referral to a nephrologist, and dialysis modality (hemodialysis [HD] vs. peritoneal dialysis [PD], urgent vs. planned start of dialysis, use of catheter vs. use of fistula for HD vascular access). An ecological index (European Deprivation Index [EDI]) was used as a proxy for social deprivation., Results: A total of 1115 patients were included (males 59%, median age at dialysis 14.4 years, glomerular/vascular diseases 36.8%). The most deprived group represented 38.7% of the patients, suggesting pediatric patients with ESKD come from a more socially deprived background. The most deprived group was more likely to initiate KRT with dialysis versus kidney transplantation. Among patients on HD, the odds of starting treatment in emergency with a catheter was >2-fold higher for the most deprived compared with the least deprived children (adjusted odds ratio [aOR] 2.35, 95% CI 1.16-4.78)., Conclusion: Children from the most deprived area have lower access to pre-emptive transplantation, have lower access to PD, tend to be late referred to a nephrologist, and have more urgent initiation of HD with a catheter., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

Background: A new prolonged-release formulation of potassium citrate and potassium bicarbonate, ADV7103, has been shown to improve metabolic control, palatability, and gastrointestinal safety in patients with distal renal tubular acidosis (dRTA) when compared to standard of care (SoC) treatments. The present work evaluates safety and efficacy of ADV7103 during 24 months., Methods: Thirty pediatric and adult patients were included in an open-label extension study after a phase II/III trial. Safety and tolerability were assessed. Plasma bicarbonate and potassium levels, as well as urine parameters, were evaluated over time. Acceptability, adherence, and quality of life were also assessed. The evolution of clinical consequences of dRTA in the cohort was explored., Results: There were 104 adverse events (AEs) reported, but only 9 gastrointestinal events observed in five patients (17%) were considered to be related to ADV7103 treatment. There were no AEs leading to treatment discontinuation. Plasma bicarbonate and potassium levels were in the normal ranges at the different visits, respectively, in 69-86% and 83-93% of patients. Overall adherence rates were ≥ 75% throughout the whole study in 79% patients. An average improvement of quality of life of 89% was reported at 24 months of study., Conclusions: Common AEs concerned metabolism and gastrointestinal disorders; the former being related to the disease. Less than half of the gastrointestinal AEs were related to ADV7103 treatment and they were mostly mild in severity. Metabolic parameters were maintained in the normal ranges in most patients. Patient satisfaction was high and adherence to treatment was good and remained stable., Trial Registration Number: Registered as EudraCT 2013-003828-36 on the 3rd of September 2013.

Background: The renal transplantation is the best treatment for end-stage renal disease in children. We present the findings of an analysis of our institution's paediatric transplant outcomes comparing recipients under 15 kg, who represent this potentially higher risk group, to those above 15 kg., Methods: We retrospectively identified consecutive paediatric kidney transplants from a prospectively collected database for analysis. We included all recipients under the age of 18 years at the time of transplant between 2006 and 2018 without any exclusion criteria. The primary outcome was death-censored graft survival at 1 year, 5 years and 10 years., Results: 109 paediatric kidney transplants were performed in 100 children. Graft survival in the all population was 98%, 96% and 76% at 1 year, 5 years and 10 years, respectively. Recipient weight below 15 kg was not found to be a risk factor of graft loss. Overall, we found no individual factor to be statistically significantly associated with renal graft lost. The overall complication rate was 16% (18/109) with 12 early complications (11%) and 6 late ones (5%)., Conclusion: Kidney transplantation in children weighing < 15 kg seems safe and offers the same patient and graft survival outcomes as in other (> 15 kg) pediatric recipients with equally low complication rates., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

The study aimed to determine the effects of self-regulated and variable intensities sustained during short-term heat acclimation training on cycling performance. Seventeen competitive-level male athletes performed a 20-km cycling time trial before (TT-PRE), immediately after (TT-POST1) and one week after (TT-POST2) a 5-day acclimation training program, including either RPE-regulated intermittent (HA-HIT, N = 9) or fixed and low-intensity (HA-LOW, N = 8) training sessions in the heat (39 °C; 40% relative humidity). Total training volume was 23% lower in HA-HIT compared to HA-LOW. Physiological responses were evaluated during a 40-min fixed-RPE cycling exercise performed before (HST-PRE) and immediately after (HST-POST) heat acclimation. All participants in HA-LOW group tended to improve mean power output from TT-PRE to TT-POST1 (+8.1 ± 5.2%; ES = 0.55 ± 0.23), as well as eight of the nine athletes in HA-HIT group (+4.3 ± 2.0%; ES = 0.29 ± 0.31) without difference between groups, but TT-POST2 results showed that improvements were dissipated one week after. Similar improvements in thermal sensation and lower elevations of core temperature in HST-POST following HA-LOW and HA-HIT training protocols suggest that high intensity and RPE regulated bouts could be an efficient strategy for short term heat acclimation protocols, for example prior to the competition. Furthermore, the modest impact of lowered thermal sensation on cycling performance confirms that perceptual responses of acclimated athletes are dissociated from physiological stress when exercising in the heat., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Several models have been proposed to predict kidney graft failure in adult recipients but none in younger recipients. Our objective was to propose a dynamic prediction model for graft failure in young kidney transplant recipients., Methods: We included 793 kidney transplant recipients waitlisted before the age of 18 years who received a first kidney transplantation before the age of 21 years in France in 2002-13 and survived >90 days with a functioning graft. We used a Cox model including baseline predictors only (sex, age at transplant, primary kidney disease, dialysis duration, donor type and age, human leucocyte antigen matching, cytomegalovirus serostatus, cold ischaemia time and delayed graft function) and two joint models also accounting for post-transplant estimated glomerular filtration rate (eGFR) trajectory. Predictive performances were evaluated using a cross-validated area under the curve (AUC) and R2 curves., Results: When predicting the risk of graft failure from any time within the first 7 years after paediatric kidney transplantation, the predictions for the following 3 or 5 years were accurate and much better with the joint models than with the Cox model (AUC ranged from 0.83 to 0.91 for the joint models versus 0.56 to 0.64 for the Cox model)., Conclusion: Accounting for post-transplant eGFR trajectory strongly increased the accuracy of graft failure prediction in young kidney transplant recipients., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Distal renal tubular acidosis (dRTA), due to impaired acid secretion in the urine, can lead to severe long-term consequences. Standard of care (SoC) oral alkalizers, requiring several daily intakes, are currently used to restore normal plasma bicarbonate levels. A new prolonged-release formulation, ADV7103, has been developed to achieve a sustained effect with an improved dosing scheme., Methods: In a multicenter, open-label, non-inferiority trial (n = 37), patients with dRTA were switched from SoC to ADV7103. Mean plasma bicarbonate values and proportion of responders during steady state therapy with both treatments were compared, as were other blood and urine parameters, as well as acceptability, tolerability, and safety., Results: When switching from SoC to ADV7103, the number of daily intakes was reduced from a median of three to twice daily. Mean plasma bicarbonate was increased and non-inferiority of ADV7103 was demonstrated (p < 0.0001, per protocol), as was statistical superiority (p = 0.0008, intention to treat [ITT]), and the response rate increased from 43 to 90% with ADV7103 (p < 0.001, ITT). Urine calcium/citrate ratio was reduced below the threshold for risk of lithogenesis with ADV7103 in 56% of previously non-responders with SoC (p = 0.021, ITT). Palatability was improved (difference [95% CI] of 25 [10.7, 39.2] mm) and gastrointestinal discomfort was reduced (difference [95% CI] of - 14.2 [- 25.9, - 2.6] mm) with ADV7103., Conclusions: Plasma bicarbonate levels and response rate were significantly higher with ADV7103 than with SoC. Urine calcium/citrate ratio, palatability, and gastrointestinal safety were significantly improved, supporting the use of ADV7103 as first-line treatment for dRTA., Trial Registration: Registered as EudraCT 2013-002988-25 on the 1st July 2013 Graphical abstract.

Gain-of-function mutations in with no lysine (K) 1 (WNK1) and WNK4 genes are responsible for familial hyperkalemic hypertension (FHHt), a rare, inherited disorder characterized by arterial hypertension and hyperkalemia with metabolic acidosis. More recently, FHHt-causing mutations in the Kelch-like 3-Cullin 3 (KLHL3-CUL3) E3 ubiquitin ligase complex have shed light on the importance of WNK's cellular degradation on renal ion transport. Using full exome sequencing for a 4-generation family and then targeted sequencing in other suspected cases, we have identified new missense variants in the WNK1 gene clustering in the short conserved acidic motif known to interact with the KLHL3-CUL3 ubiquitin complex. Affected subjects had an early onset of a hyperkalemic hyperchloremic phenotype, but normal blood pressure values"Functional experiments in Xenopus laevis oocytes and HEK293T cells demonstrated that these mutations strongly decrease the ubiquitination of the kidney-specific isoform KS-WNK1 by the KLHL3-CUL3 complex rather than the long ubiquitous catalytically active L-WNK1 isoform. A corresponding CRISPR/Cas9 engineered mouse model recapitulated both the clinical and biological phenotypes. Renal investigations showed increased activation of the Ste20 proline alanine-rich kinase-Na+-Cl- cotransporter (SPAK-NCC) phosphorylation cascade, associated with impaired ROMK apical expression in the distal part of the renal tubule. Together, these new WNK1 genetic variants highlight the importance of the KS-WNK1 isoform abundance on potassium homeostasis.

Background: Relapsing nephrotic syndrome (NS) after transplantation can be a challenge to treat. The result of the consequent long-lasting proteinuria is the loss of the graft. Disease recurrence after renal transplantation occurs in around half of cases, and the efficacy of therapeutic strategies is often limited. Recently, ofatumumab, a second-generation and fully human anti-CD20 monoclonal antibody, has been shown to be effective in severe situations., Methods: We retrospectively collected data from the medical records of children with recurrence of NS after renal transplantation treated with ofatumumab in France, after failure of previous treatments., Results: Six patients were included in this study in five centers with a median duration of follow-up of 10.5 months. Two different ofatumumab regimens were administered. The primary outcome was proteinuria at 6 months after the last dose of ofatumumab. No patient achieved a complete remission, 3/6 had a partial remission, and 3/6 had no response to ofatumumab. Four patients exhibited a minor allergic reaction with the first infusion. One patient died of infection, as a consequence of multiple factors. No malignancies were observed; however, the time of follow-up was not sufficient to see such disease., Conclusions: Altogether, these results suggest ofatumumab has a poor efficacy in treating recurrence of NS after renal transplantation. However, it could be discussed in multidrug-resistant refractory NS, but infectious complications and overimmunosuppression have to be balanced. There is a need for further studies to confirm these findings and safety and to determine a standardized protocol in this indication.

In population exposed to cardiovascular risk, aortic stiffness is an important marker which is assessed by carotid-to-femoral pulse wave velocity (PWV). In childhood, the validated applanation tonometer SphygmoCor® can be used to measure PWV, but is limited in routine practice by the child's cooperation and operator's experience. An alternative device, the pOpmètre® is validated in adults and rapidly measures finger-to-toe PWV using 2 oxymeter-like sensors. The aim of this study is to validate the pOpmètre® device in children aged between 4 and 8 years. We compared simultaneous PWV measurements of the two devices, SphygmoCor® and pOpmètre®, in a training group, using the Bland-Altman method. Then we proposed an algorithm to correct pOpmètre® PWV (PWVpop). Finally, we validated this new algorithm in a validation group of children using the Bland-Altman method. This prospective study enrolled 26 children in the training group. Mean PWVpop was 3.919 ± 0.587 m/s and mean SphygmoCor® PWV was 4.280 ± 0.383 m/s, with a difference of -0.362(CI95%(-0.546;-0.178)) m/s. A new algorithm was defined using transit time (TTpop): corrected PWVpop (m/s) = 0.150/TTpop(s) + 1.381*Height(m) + 1.148. We enrolled 24 children in the validation group. Mean corrected PWVpop was 4.231 ± 0.189 m/s and mean SphygmoCor® PWV was 4.208 ± 0.296 m/s with a corrected difference of 0.023(CI95%(-0.086;0.131)) m/s. With this algorithm correction, we found an agreement between PWV measured by the SphygmoCor® and the pOpmètre®, with a difference of less than 10%. Using this algorithm, the pOpmètre® could be used in clinical or research practice in young children exposed to cardiovascular risk. (This study was registered as NCT02991703)., Competing Interests: There is no conflict of interest to report.

The prevalence of neurological involvement in patients with a deletion of or a variant in the HNF1B gene remains discussed. The aim of this study was to investigate the neuropsychological outcomes in a large cohort of children carrying either a HNF1B whole-gene deletion or a disease-associated variant, revealed by the presence of kidney anomalies. The neuropsychological development-based on school level-of 223 children included in this prospective cohort was studied. Data from 180 children were available for analysis. Patients mean age was 9.6 years, with 39.9% of girls. Among these patients, 119 carried a HNF1B deletion and 61 a disease-associated variant. In the school-aged population, 12.7 and 3.6% of patients carrying a HNF1B deletion and a disease-associated variant had special educational needs, respectively. Therefore, the presence of a HNF1B deletion increases the risk to present with a neuropsychiatric involvement when compared with the general population. On the other hand, almost 90% of patients carrying a HNF1B disease-associated variant or deletion have a normal schooling in a general educational environment. Even if these findings do not predict the risk of neuropsychiatric disease at adulthood, most patients diagnosed secondary to kidney anomalies do not show a neurological outcome severe enough to impede standard schooling at elementary school. These results should be taken into account in prenatal counseling.

Socioeconomic status is an important determinant of health. Its impact on kidney transplantation outcome has been studied among adults but data in children are scarce, especially in Europe. Here, we investigate the association between the level of social deprivation (determined by the continuous score European Deprivation Index) and graft failure risk in pediatric kidney transplant recipients. All patients listed under 18 years of age who received a first kidney transplant between 2002 and 2014 in France were included. Of 1050 kidney transplant recipients (males 59%, median age at transplantation 13.2 years, preemptive transplantation 23%), 211 graft failures occurred within a median followup of 5.9 years. Thirty-seven percent of these patients belong to the most deprived quintile, suggesting that deprivation is more frequent in pediatric patients with end-stage kidney disease (ESKD) than in the general population. Five- and ten-year graft survival were 85% and 69%, respectively, in the most deprived quintile vs. 90% and 83%, respectively, in the least deprived quintile. At any time after transplantation, patients in the most deprived quintile had almost a two-fold higher hazard of graft failure compared with the least deprived quintile, after adjustment for age at renal replacement therapy, duration of dialysis, primary kidney disease, and rural/urban living environment (hazard ratio 1.99; 95% confidence interval 1.20-3.28). The hazard of graft failure did not differ significantly between girls and boys. Thus, our findings suggest a lower socioeconomic status is independently associated with poor graft outcome in pediatric kidney transplantation., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: To describe the quality of life of adolescents initiating haemodialysis, to determine the factors associated with quality of life, and to assess coping strategies and their impact on quality of life., Methods: All adolescents initiating haemodialysis between September 2013 and July 2015 in French paediatric haemodialysis centres were included. Quality of life data were collected using the "Vécu et Santé Perçue de l'Adolescent et l'Enfant" questionnaire, and coping data were collected using the Kidcope questionnaire. Adolescent's quality of life was compared with age- and sex-matched French control., Results: Thirty-two adolescents were included. Their mean age was 13.9 ± 2.0 years. The quality of life score was lowest in leisure activities and highest in relationships with medical staff. Compared with the French control, index, energy-vitality, relationships with friends, leisure activities and physical well-being scores were significantly lower in haemodialysis population. In multivariate analyses, active coping was positively associated with quality of life and especially with energy-vitality, relationships with parents and teachers, and school performance. In contrast, avoidant and negative coping were negatively associated with energy-vitality, psychological well-being and body image for avoidant coping, and body image and relationships with medical staff for negative coping., Conclusions: The quality of life of haemodialysis adolescents, and mainly the dimensions of leisure activities, physical well-being, relationships with friends and energy-vitality, were significantly altered compared to that of the French population. The impact of coping strategies on quality of life seems to be important. Given the importance of quality of life and coping strategies in adolescents with chronic disease, health care professionals should integrate these aspects into care management.

Background and Objectives: Inherited complement hyperactivation is critical for the pathogenesis of atypical hemolytic uremic syndrome (HUS) but undetermined in postdiarrheal HUS. Our aim was to investigate complement activation and variants of complement genes, and their association with disease severity in children with Shiga toxin-associated HUS., Design, Setting, Participants, & Measurements: Determination of complement biomarkers levels and next-generation sequencing for the six susceptibility genes for atypical HUS were performed in 108 children with a clinical diagnosis of post-diarrheal HUS (75 Shiga toxin-positive, and 33 Shiga toxin-negative) and 80 French controls. As an independent control cohort, we analyzed the genotypes in 503 European individuals from the 1000 Genomes Project., Results: During the acute phase of HUS, plasma levels of C3 and sC5b-9 were increased, and half of patients had decreased membrane cofactor protein expression, which normalized after 2 weeks. Variants with minor allele frequency <1% were identified in 12 Shiga toxin-positive patients with HUS (12 out of 75, 16%), including pathogenic variants in four (four out of 75, 5%), with no significant differences compared with Shiga toxin-negative patients with HUS and controls. Pathogenic variants with minor allele frequency <0.1% were found in three Shiga toxin-positive patients with HUS (three out of 75, 4%) versus only four European controls (four out of 503, 0.8%) (odds ratio, 5.2; 95% confidence interval, 1.1 to 24; P =0.03). The genetic background did not significantly affect dialysis requirement, neurologic manifestations, and sC5b-9 level during the acute phase, and incident CKD during follow-up. However, the only patient who progressed to ESKD within 3 years carried a factor H pathogenic variant., Conclusions: Rare variants and complement activation biomarkers were not associated with severity of Shiga toxin-associated HUS. Only pathogenic variants with minor allele frequency <0.1% are more frequent in Shiga toxin-positive patients with HUS than in controls., (Copyright © 2019 by the American Society of Nephrology.)

Background: Recommendations for management of Finnish-type congenital nephrotic syndrome (CNS) followed by many teams include daily albumin infusions, early bilateral nephrectomy, dialysis and transplantation. We aimed to assess the treatment and outcome of patients with CNS in France., Methods: We conducted a nationwide retrospective study on 55 consecutive children born between 2000 and 2014 treated for non-infectious CNS., Results: The estimated cumulative incidence of CNS was 0.5/100 000 live births. The underlying defect was biallelic mutations in NPHS1 (36/55, 65%), NPHS2 (5/55, 7%), PLCE1 (1/55, 2%), heterozygous mutation in WT1 (4/55, 7%) and not identified in nine children (16%). Fifty-three patients (96%) received daily albumin infusions from diagnosis (median age 14 days), which were spaced and withdrawn in 10 patients. Twenty children (35%) were managed as outpatients. Thirty-nine patients reached end-stage kidney disease (ESKD) at a median age of 11 months. The overall renal survival was 64% and 45% at 1 and 2 years of age, respectively. Thirteen children died during the study period including four at diagnosis, two of nosocomial catheter-related septic shock, six on dialysis and one after transplantation. The remaining 13 patients were alive with normal renal function at last follow-up [median 32 months (range 9-52)]. Renal and patient survivals were longer in patients with NPHS1 mutations than in other patients. The invasive infection rate was 2.41/patient/year., Conclusions: Our study shows: (i) a survival free from ESKD in two-thirds of patients at 1 year and in one-half at 2 years and (ii) a significant reduction or even a discontinuation of albumin infusions allowing ambulatory care in a subset of patients. These results highlight the need for new therapeutic guidelines for CNS patients., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Despite major technical improvements in the care of children requiring renal replacement therapy (RRT) before 2 years of age, the management of those patients remains challenging and transplantation is generally delayed until the child weighs 10 kg or is 2 years old. In this national cohort study, we studied patient and graft survival in children starting RRT before 2 years of age to help clinicians and parents when deciding on RRT initiation and transplantation management., Methods: All children starting RRT before 24 months of age between 1992 and 2012 in France were included through the national Renal Epidemiology and Information Network (REIN) registry. The primary endpoints were patient survival on dialysis and 10-year graft survival., Results: A total of 224 patients were included {62% boys, median age 10.5 months [interquartile range (IQR) 5.8-15.6]}. The 10-year survival rate was 84% (IQR 77-89). Suffering from extrarenal comorbidities was the only factor significantly associated with both an increased risk of death on dialysis [hazard ratio 5.9 (95% confidence interval 1.8-19.3)] and a decreased probability of being transplanted. During follow-up, 174 renal transplantations were performed in 171 patients [median age at first transplantation 30.2 (IQR 21.8-40.7) months]. The 10-year graft survival was 74% (IQR 67-81). Factors associated with graft loss in multivariate analysis were the time spent on dialysis before transplantation, donor/recipient height ratio with an increased risk for both small and tall donors and presenting two human leucocyte antigen-antigen D-related mismatches., Conclusions: This study confirms the good outcome of children starting RRT before 2 years of age. The main question remains when and how to transplant those children. Our study provides data on the optimal morphological and immunological matching in order to help clinicians in their decisions.

Introduction: The study aimed to investigate how a distortion of perceived exertion in the heat may affect, during a self-paced cycling exercise preceded by prior cognitive task, the thermal perception and the subsequent regulation of power output in high level athletes., Methods: Eleven endurance trained male athletes completed four experimental sessions including a 30-min fixed-RPE (15-Hard) cycling exercise in neutral (TMP-22 °C) and hot (HOT-37 °C) conditions, following a 60-min incongruent Stroop task (EXP) or passively watching documentary films (CON). Central and peripheral performances of the knee extensors were assessed before the cognitive task and after the exercise., Results: Although mental demand and effort were higher in EXP (P < 0.05), no effect of prior cognitive task was observed on subjective feelings of mental fatigue or decline in power output at a fixed RPE. Average exercise intensity was lower in HOT than TMP (3.14 ± 0.09 W⋅kg -1 vs. 3.42 ± 0.10 W⋅kg -1 respectively, P < 0.05). Skin temperature and warmth sensations were higher in HOT throughout the exercise (P < 0.05) but not thermal comfort. Central and peripheral parameters were not affected more in HOT than in TMP., Conclusion: Although the effects of combined stressors on the distortion of perceived exertion could not be verified, the greater decline in power output recorded in HOT than TMP suggest a high contribution of both perceptual and cardiovascular responses in the regulation of work rate when the subject is in mild hyperthermia., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Context: Limited data exist regarding uropathogen resistance in randomized controlled trials of urinary tract infection (UTI) prevention and antibiotic prophylaxis., Objective: To assess the effect of prophylaxis on developing a multidrug-resistant first recurrent UTI among children with vesicoureteral reflux., Data Sources: Cochrane Kidney and Transplant Specialized Register through May 25, 2017., Study Selection: Randomized controlled trials of patients ≤18 years of age with a history of vesicoureteral reflux being treated with continuous antibiotic prophylaxis compared with no treatment or placebo with available antibiotic sensitivity profiles., Data Extraction: Two independent observers abstracted data and assessed quality and validity per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Adjusted meta-analyses were performed by using a mixed-effects logistic regression model., Results: One thousand two hundred and ninety-nine patients contributed 224 UTIs. Patients treated with prophylaxis were more likely to have a multidrug-resistant infection (33% vs 6%, P < .001) and were more likely to receive broad-spectrum antibiotics (68% vs 49%, P = .004). Those receiving prophylaxis had 6.4 times the odds (95% confidence interval: 2.7-15.6) of developing a multidrug-resistant infection. One multidrug-resistant infection would develop for every 21 reflux patients treated with prophylaxis., Limitations: Variables that may contribute to resistance such as medication adherence and antibiotic exposure for other illnesses could not be evaluated., Conclusions: Prophylaxis increases the risk of multidrug resistance among recurrent infections. This has important implications in the risk-benefit assessment of prophylaxis as a management strategy and in the selection of empirical treatment of breakthrough infections in prophylaxis patients., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Background: Primary focal segmental glomerulosclerosis (FSGS) frequently recurs after kidney transplantation (KTx) in children. This can lead to delayed graft loss. As the management of children with recurrent FSGS is not well established, apheresis strategies could be a cornerstone to control the disease. Immunoadsorption (IA) is a recent apheresis therapy. There have been few studies examining IA in this setting. We report the results of IA for management of recurrent FSGS after KTx in children in France., Methods: We included all children treated with IA for early FSGS recurrence after KTx between January 2011 and June 2014 in France. We excluded genetic forms of FSGS. Patients' characteristics and technical data on IA were retrospectively collected. Recurrence was defined as nephrotic proteinuria during the post-transplantation period. Partial and complete remissions were defined when urine protein:creatinine ratios were less than 0.2 and 0.05 g/mmol, respectively., Results: Twelve patients, from six paediatric KTx units, presenting with FSGS recurrence between 0 and 21 days after KTx were treated with IA. Ten of 12 children were responders: 2 achieved partial remission and 8 complete remission. The decrease of proteinuria rapidly occurred within the first 10 sessions after initiating IA. After 3 months of IA, two patients maintained remission without IA and eight became IA dependent. No severe side effects were reported., Conclusions: Our study reports on the efficacy of IA in the recurrence of FSGS after KTx in children. Further prospective controlled studies are required to confirm these results and to optimize the management of FSGS recurrence after paediatric KTx.

Treatment of SRNS is a challenge. Antiproliferative agents and depleting antibodies have been reported to be effective. However, these agents are not always successful, and use of ofatumumab could provide a different treatment option. Our patient was diagnosed with a SRNS at 5 years of age. She developed ESRD, with FSGS. This was cause for a first renal transplantation. The NS relapsed, leading to loss of the graft, and a second renal transplantation was performed. Due to the recurrence of the NS, IAds were initiated and led to a complete remission. Our patient remained dependent on IAds, however, despite treatments with calcineurin inhibitors, corticosteroids, rituximab, and abatacept. Ofatumumab was introduced and led to a remission, thus allowing cessation of the IAd treatment. Another infusion of ofatumumab was administered 8 months after the last one, due to the recurrence of the NS and a renewed increase in B cells. Although it did not result in a complete remission, the proteinuria was stabilized in the absence of IAds. Ofatumumab may be an alternative treatment for post-transplantation rituximab-resistant SRNS, although this needs to be confirmed by further studies., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Bartter syndrome type 3 is a clinically heterogeneous hereditary salt-losing tubulopathy caused by mutations of the chloride voltage-gated channel Kb gene ( CLCNKB ), which encodes the ClC-Kb chloride channel involved in NaCl reabsorption in the renal tubule. To study phenotype/genotype correlations, we performed genetic analyses by direct sequencing and multiplex ligation-dependent probe amplification and retrospectively analyzed medical charts for 115 patients with CLCNKB mutations. Functional analyses were performed in Xenopus laevis oocytes for eight missense and two nonsense mutations. We detected 60 mutations, including 27 previously unreported mutations. Among patients, 29.5% had a phenotype of ante/neonatal Bartter syndrome (polyhydramnios or diagnosis in the first month of life), 44.5% had classic Bartter syndrome (diagnosis during childhood, hypercalciuria, and/or polyuria), and 26.0% had Gitelman-like syndrome (fortuitous discovery of hypokalemia with hypomagnesemia and/or hypocalciuria in childhood or adulthood). Nine of the ten mutations expressed in vitro decreased or abolished chloride conductance. Severe (large deletions, frameshift, nonsense, and essential splicing) and missense mutations resulting in poor residual conductance were associated with younger age at diagnosis. Electrolyte supplements and indomethacin were used frequently to induce catch-up growth, with few adverse effects. After a median follow-up of 8 (range, 1-41) years in 77 patients, chronic renal failure was detected in 19 patients (25%): one required hemodialysis and four underwent renal transplant. In summary, we report a genotype/phenotype correlation for Bartter syndrome type 3: complete loss-of-function mutations associated with younger age at diagnosis, and CKD was observed in all phenotypes., (Copyright © 2017 by the American Society of Nephrology.)

Background: The risk of graft failure in young kidney transplant recipients has been found to increase during adolescence and early adulthood. However, this question has not been addressed outside the United States so far. Our objective was to investigate whether the hazard of graft failure also increases during this age period in France irrespective of age at transplantation., Methods: Data of all first kidney transplantation performed before 30 years of age between 1993 and 2012 were extracted from the French kidney transplant database. The hazard of graft failure was estimated at each current age using a 2-stage modelling approach that accounted for both age at transplantation and time since transplantation. Hazard ratios comparing the risk of graft failure during adolescence or early adulthood to other periods were estimated from time-dependent Cox models., Results: A total of 5983 renal transplant recipients were included. The risk of graft failure was found to increase around the age of 13 years until the age of 21 years, and decrease thereafter. Results from the Cox model indicated that the hazard of graft failure during the age period 13 to 23 years was almost twice as high as than during the age period 0 to 12 years, and 25% higher than after 23 years., Conclusions: Among first kidney transplant recipients younger than 30 years in France, those currently in adolescence or early adulthood have the highest risk of graft failure.

Background: Peritoneal dialysis (PD) remains the modality of choice in children, but there is no clear evidence to support a better outcome in children treated with PD. We aimed to assess factors that have an impact on the choice of dialysis modality in children and young adults in France and sought to determine the roles of medical factors and center practices., Methods: We included all patients aged <20 years at the start of renal replacement therapy (RRT), recorded in the French RRT Registry between 2002 and 2013. Hierarchical logistic regression models were used to study the association between the patient/center characteristics and the probability of receiving PD as the first dialysis modality., Results: We included 806 patients starting RRT in 177 centers, 23 of which were specialized pediatric centers. Six hundred and one patients (74.6 %) started with hemodialysis (HD), whereas 205 (25.4 %) started with PD. A greater probability of PD was found in younger children, whereas starting the treatment in an emergency setting was associated with a low use of PD. We found a significant variability among centers that accounted for 43 % of the total variability. The probability of PD was higher in adult centers and was proportional to the rate of PD in the center., Conclusions: Center practices are a major factor in the choice of dialysis modality. This raises concerns about patient and family choices and to what extent doctors may influence the final decision. Further pediatric studies focusing on children's and parents' wishes are needed to provide care as close as possible to patients' and families' expectations.

Objectives: Acute kidney injury (AKI) is a severe complication of prematurity, with currently unknown consequences for renal function in childhood. The objective of this study was to search for signs of reduced nephron number in children aged 3-10 years who had been born preterm with neonatal AKI and compare this group to control children., Methods: IRENEO was a prospective, controlled study conducted in 2013 in Nantes University Hospital. Children who were born at less than 33 weeks gestational age (GA) and included in the LIFT cohort were eligible for entry. Twenty-five children with AKI (AKI-C) and 49 no-AKI children were matched on a propensity score of neonatal AKI and age. AKI was defined as a serum creatinine level higher than critical values: 1.6 mg/dl (GA 24-27 weeks), 1.1 mg/dl (28-29) and 1 mg/dl (GA 30-32). Renal function was evaluated during childhood., Results: Mean age of the children at the time of the study was 6.6 years. No difference in microalbuminuria, estimated glomerular filtration rate (GFR) or pulse wave velocity was observed between the two groups. Renal volume was lower in the AKI-C group (57 vs. 68; p = 0.04). In the entire cohort, 10.8 % had a microalbuminuria, and 23 % had a diminished GFR (median 79 ml/min/1.73 m 2 ). The GFR was lower in children with very low birth weight of <1000 g (99 vs. 107 ml/min/1.73 m 2 ; p = 0.04)., Conclusion: In children born preterm, neonatal AKI does not seem to influence renal function. However, independent ofAKI, a large proportion of very preterm infants, especially those with very low birth weight, presented with signs of nephron reduction, thus requiring follow-up with a nephrologist.

Background: Patients with HNF1B mutations develop progressive chronic renal failure, diabetes mellitus (40-50%), and liver tests abnormalities (40-70%). In HNF1B patients who reach end-stage renal disease, single kidney transplantation (SKT) or combined kidney-pancreas transplantation can be considered., Methods: A retrospective multicenter study including 18 HNF1B patients receiving SKT or kidney-pancreas transplantation, and in vitro experiments including the characterization of the HNF1B expression after calcineurin inhibitor (CNI) exposure., Results: After SKT, 50% of the HNF1B patients develop early posttransplantation diabetes mellitus, whereas 40% experience new-onset or severe worsening of preexisting abnormalities of liver tests, including severe cholestasis. In liver biopsies, disorders of the cholangiocytes primary cilium and various degrees of bile duct paucity and dysplasia were identified. In vitro studies combining CNI exposure and siRNA-mediated inhibition of NFATc revealed that calcineurin inhibition decreases HNF1B expression in epithelial cells but independent of NFATc., Conclusions: Because HNF1B-related disease is a heterozygous condition, CNIs used to prevent rejection may induce reduced expression of the nonmutated allele of HNF1B leading to a superimposed defect of HNF-1β transcriptional activity. Taking into account the specific risk of posttransplantation diabetes mellitus and liver disorders in HNF1B patients, these findings advocate for in-depth characterization of pathways that regulate HNF1B and plead for considering individually tailored graft management that may include a CNI-free immunosuppressive regimen. Interventional studies will have to confirm this individualized approach.

Prenatal forms of autosomal dominant polycystic kidney disease (ADPKD) are rare but can be recurrent in some families, suggesting a common genetic modifying background. Few patients have been reported carrying, in addition to the familial mutation, variation(s) in polycystic kidney disease 1 (PKD1) or HNF1 homeobox B (HNF1B), inherited from the unaffected parent, or biallelic polycystic kidney and hepatic disease 1 (PKHD1) mutations. To assess the frequency of additional variations in PKD1, PKD2, HNF1B, and PKHD1 associated with the familial PKD mutation in early ADPKD, these four genes were screened in 42 patients with early ADPKD in 41 families. Two patients were associated with de novo PKD1 mutations. Forty patients occurred in 39 families with known ADPKD and were associated with PKD1 mutation in 36 families and with PKD2 mutation in two families (no mutation identified in one family). Additional PKD variation(s) (inherited from the unaffected parent when tested) were identified in 15 of 42 patients (37.2%), whereas these variations were observed in 25 of 174 (14.4%, P=0.001) patients with adult ADPKD. No HNF1B variations or PKHD1 biallelic mutations were identified. These results suggest that, at least in some patients, the severity of the cystic disease is inversely correlated with the level of polycystin 1 function., (Copyright © 2016 by the American Society of Nephrology.)

Background: Identification of patient groups by risk of renal graft loss might be helpful for accurate patient counselling and clinical decision-making. Survival tree models are an alternative statistical approach to identify subgroups, offering cut-off points for covariates and an easy-to-interpret representation., Methods: Within the European Society of Pediatric Nephrology/European Renal Association-European Dialysis and Transplant Association (ESPN/ERA-EDTA) Registry data we identified paediatric patient groups with specific profiles for 5-year renal graft survival. Two analyses were performed, including (i) parameters known at time of transplantation and (ii) additional clinical measurements obtained early after transplantation. The identified subgroups were added as covariates in two survival models. The prognostic performance of the models was tested and compared with conventional Cox regression analyses., Results: The first analysis included 5275 paediatric renal transplants. The best 5-year graft survival (90.4%) was found among patients who received a renal graft as a pre-emptive transplantation or after short-term dialysis (<45 days), whereas graft survival was poorest (51.7%) in adolescents transplanted after long-term dialysis (>2.2 years). The Cox model including both pre-transplant factors and tree subgroups had a significantly better predictive performance than conventional Cox regression (P < 0.001). In the analysis including clinical factors, graft survival ranged from 97.3% [younger patients with estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m(2) and dialysis <20 months] to 34.7% (adolescents with eGFR <60 mL/min/1.73 m(2) and dialysis >20 months). Also in this case combining tree findings and clinical factors improved the predictive performance as compared with conventional Cox model models (P < 0.0001)., Conclusions: In conclusion, we demonstrated the tree model to be an accurate and attractive tool to predict graft failure for patients with specific characteristics. This may aid the evaluation of individual graft prognosis and thereby the design of measures to improve graft survival in the poor prognosis groups., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

♦ OBJECTIVES: Assess the stability of several antibiotics in peritoneal dialysis (PD) solutions under common conditions of use in pediatrics, particularly in automated PD. ♦ METHODS: Amoxicillin, cefazolin, cefepime, ceftazidime, imipenem, cotrimoxazole, tobramycin, vancomycin, and the association of ceftazidime + vancomycin and ceftazidime + tobramycin, were tested in 3 different PD solutions: bicarbonate/lactate solution with 2 glucose concentrations (Physioneal 1.36 and 3.86%; Baxter Healthcare Corporation, Deerfield, IL, USA) and an icodextrin-containing solution (Extraneal; Baxter Healthcare Corporation, Deerfield, IL, USA). Concentrations were those recommended in guidelines for the treatment of peritonitis in pediatrics. Physioneal bags were incubated at 37°C for 24 hours, whereas Extraneal bags were stored 12 hours at room temperature (22 ± 2°C) and then 12 hours at 37°C. Drug concentrations were determined using high performance liquid chromatography (HPLC). Each measure was taken in triplicate. Stability of antibiotics was defined as less than 10% degradation of the drug over time. ♦ RESULTS: Cefazolin, cotrimoxazole, tobramycin, and vancomycin were stable under studied conditions. Ceftazidime was stable 24 hours in icodextrin, 12 hours in Physioneal 1.36% and 6 hours in Physioneal 3.86%. The association of tobramycin or vancomycin did not influence the stability of ceftazidime. Cefepime and amoxicillin were stable 6 h, 4 h, and 8 h in Physioneal 1.36%, 3.86% and Extraneal, respectively. The stability of imipenem was very low: 2 h in Physioneal and 6 h in Extraneal. Moreover, an increasingly yellow coloration was observed with the use of imipenem, whereas no color change or precipitation occurred in other bags. ♦ CONCLUSION: Cefazolin, tobramycin, cotrimoxazole, and vancomycin are stable in PD solutions up to 24 hours and can be administered in the PD bag for the treatment of peritonitis, even in automated PD under studied conditions. However, amoxicillin, cefepime, ceftazidime, and imipenem must be used with caution due to their lack of stability., (Copyright © 2016 International Society for Peritoneal Dialysis.)

In the folate cycle MTHFD1, encoded by MTHFD1, is a trifunctional enzyme containing 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase activity. To date, only one patient with MTHFD1 deficiency, presenting with hyperhomocysteinemia, megaloblastic anaemia, hemolytic uremic syndrome (HUS) and severe combined immunodeficiency, has been identified (Watkins et al J Med Genet 48:590-2, 2011). We now describe four additional patients from two different families. The second patient presented with hyperhomocysteinemia, megaloblastic anaemia, HUS, microangiopathy and retinopathy; all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid. The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia, and was successfully treated with a regime that included and was eventually reduced to folic acid. The other two, elder siblings of the third patient, died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis and had MTFHD1 deficiency diagnosed retrospectively. We identified a missense mutation (c.806C > T, p.Thr296Ile) and a splice site mutation (c.1674G > A) leading to exon skipping in the second patient, while the other three harboured a missense mutation (c.146C > T, p.Ser49Phe) and a premature stop mutation (c.673G > T, p.Glu225*), all of which were novel. Patient fibroblast studies revealed severely reduced methionine formation from [(14)C]-formate, which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid. These additional cases increase the clinical spectrum of this intriguing defect, provide in vitro evidence of disturbed methionine synthesis and substantiate the effectiveness of folic or folinic acid treatment.

Circulating vitamin D is found in various forms: 25-hydroxyvitamin D or calcidiol, majority circulating form, is a "pro-hormon" which will be converted to 1,25-dihydroxyvitamin D or calcitriol, hormone corresponding to vitamin D active form. While determination of 25-hydroxyvitamin D serum levels reflects vitamin D status of patients, determination of 1,25-dihydroxyvitamin D serum level is only indicated in rare cases of suspected hypersensitivity vitamin D in children or of sarcoidosis in adults. There are too many confusion between these two vitamin forms, resulting in inappropriate prescription of 1,25-dihydroxyvitamin D. Here, we describe a case of hypersensitivity to vitamin D by mutation of CYP24A1. We propose to review the interest of 1,25-dihydroxyvitamin D assay in different pathologies, to describe the assay techniques and remind the good prescribing practices of this parameter.

Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal failure, and variable manifestations of other proximal tubule dysfunctions. It often progresses over a few decades to chronic renal insufficiency, and therefore molecular characterization is important to allow appropriate genetic counseling. Two genetic subtypes have been described to date: Dent disease 1 is caused by mutations of the CLCN5 gene, coding for the chloride/proton exchanger ClC-5; and Dent disease 2 by mutations of the OCRL gene, coding for the inositol polyphosphate 5-phosphatase OCRL-1. Herein, we review previously reported mutations (n = 192) and their associated phenotype in 377 male patients with Dent disease 1 and describe phenotype and novel (n = 42) and recurrent mutations (n = 24) in a large cohort of 117 Dent disease 1 patients belonging to 90 families. The novel missense and in-frame mutations described were mapped onto a three-dimensional homology model of the ClC-5 protein. This analysis suggests that these mutations affect the dimerization process, helix stability, or transport. The phenotype of our cohort patients supports and extends the phenotype that has been reported in smaller studies., (© 2015 WILEY PERIODICALS, INC.)

Loss-of-function mutations of CYP24A1, the enzyme that converts the major circulating and active forms of vitamin D to inactive metabolites, recently have been implicated in idiopathic infantile hypercalcemia. Patients with biallelic mutations in CYP24A1 present with severe hypercalcemia and nephrocalcinosis in infancy or hypercalciuria, kidney stones, and nephrocalcinosis in adulthood. We describe a cohort of 7 patients (2 adults, 5 children) presenting with severe hypercalcemia who had homozygous or compound heterozygous mutations in CYP24A1. Acute episodes of hypercalcemia in infancy were the first symptom in 6 of 7 patients; in all patients, symptoms included nephrocalcinosis, hypercalciuria, low parathyroid hormone (PTH) levels, and higher than expected 1,25-dihydroxyvitamin D levels. Longitudinal data suggested that in most patients, periods of increased sunlight exposure tended to correlate with decreases in PTH levels and increases in calcemia and calciuria. Follow-up of the 2 adult patients showed reduced glomerular filtration rate and extrarenal manifestations, including calcic corneal deposits and osteoporosis. Cases of severe PTH-independent hypercalcemia associated with hypercalciuria in infants should prompt genetic analysis of CYP24A1. These patients should be monitored carefully throughout life because they may be at increased risk for developing chronic kidney disease., (Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Renovascular hypertension accounts for 5-10 % of hypertension cases in children; there is currently no consensus on treatment. Here, we report on our clinical experience with this disease and outline the different pathways in which to investigate it. We report retrospectively on ten children diagnosed with renovascular hypertension at the University Hospital of Nantes from 2001 to 2012. The main findings were obtained by fortuitous screening of children aged 2 months to 14 years old with neurofibromatosis (n = 2) and fibromuscular dysplasia (n = 8). The hypertension was always severe yet asymptomatic. Lesions were complicated in nine out of ten cases and included bilateral, multiple, mid-aortic syndrome and aneurysm. Doppler ultrasound associated with computed tomography allowed for a precise diagnosis in seven out of ten cases. Where ambiguities persisted, they were highlighted by arteriography, the gold standard investigation. Medical treatment was insufficient, leading to invasive procedures in nine out of ten children: 2 nephrectomies, 2 autotransplantations, and 21 repetitive percutaneous transluminal angioplasties. After invasive procedures, blood pressure control improved in four cases and was resolved in three., Conclusion: Arteriography remains to be the gold standard technique for renovascular hypertension in children and can be combined with angioplasty when medical treatment is rendered obsolete. The role of computed tomography is controversial. Despite the heterogeneity of the children studied, we present a general medical and therapeutic management pathway for the treatment of this disease.