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Keywords:ATG; HUS; MMF; relapse; transplantation [ABSTRACT FROM PUBLISHER]

Background: Pediatric kidney transplantations are rarely performed, and there is limited knowledge about the diversity in current clinical practices across Europe. This study aims to explore the utility of clinical snapshot studies in identifying these disparities, establishing a foundation for future snapshot studies and standardization efforts., Methods: A pilot clinical snapshot study was conducted, with invitations extended to all 109 pediatric kidney transplant centres in Europe. Each participating centre provided pre-, peri-, and postoperative data concerning their most recent thirty transplantations. The primary outcomes encompassed the evaluation of disparities in donor-recipient selection, surgical techniques, post-operative drainage procedures, and immunosuppressive therapy protocols. Secondary outcomes involved the analysis of rejection rates, incidence of infections, and graft survival., Results: The study involved 439 patients from fifteen centres (14%) in twelve countries, with varying transplant volumes (range 1-29 transplantations per year) and follow-up periods. Significant differences were found among centres in terms of donor types, cold and warm ischemia time, pre-emptive transplant rates, and kidney transplant drainage methods. The rate of living donors varied between 3% and 90% and the median duration of cold ischemia ranged was 770 min after deceased donation and 147 min after living donation. Basiliximab was the dominant induction therapy, yet steroid withdrawal varied widely. Infection, rejection, and graft survival rates also varied significantly between centres., Conclusion: This study revealed substantial variation in clinical practices among European centres performing pediatric kidney transplantations. These findings could serve as a stimulus for international dialogue and collaboration., 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., (© 2024 Oomen L, Bootsma-Robroeks, Bouts, Carbonell Pradas, Gander, Kienzl-Wagner, König, Pereira, Dunand, Mosca, Pac, Podracka, Prytula, Sangermano, Vitkevic, Zieg, van der Zanden, Feitz and de Wall.)

Aims: Prednisolone is the cornerstone of treatment for idiopathic nephrotic syndrome in children, but is associated with marked side-effects. Therapeutic drug monitoring using saliva would be a patient-friendly option to monitor prednisolone treatment. To assess the feasibility of saliva monitoring, we described the pharmacokinetics (PK) of unbound prednisolone in plasma and saliva of children with first onset steroid-sensitive nephrotic syndrome (SSNS)., Methods: Children (age 2-16 years) with SSNS participating in a randomized, placebo-controlled trial with levamisole were treated with an 18-week tapering schedule of prednisolone. Five serial samples were collected at 4 (saliva) and 8 weeks (saliva and plasma) after first onset. A nonlinear mixed-effects model was used to estimate the PK parameters of unbound prednisolone and the saliva-to-plasma ratio. Monte Carlo simulations were performed to assess the predictive performance of saliva monitoring., Results: From 39 children, 109 plasma and 275 saliva samples were available. Estimates (relative squared error) of unbound plasma clearance and volume of distribution were 93 (5%) L h -1 70 kg -1 and 158 (7%) L 70 kg -1 , respectively. Typical saliva-to-plasma ratio was 1.30 (8%). Monte Carlo simulations demonstrated that on basis of 4 saliva samples and a single plasma sample unbound plasma area-under-the-concentration-time curve can be predicted within 20% imprecision in 79% of the patients compared to 87% based on 4 plasma samples., Conclusion: Saliva proved to be a reliable and patient-friendly option to determine prednisolone plasma exposure in children with SSNS. This opens opportunities for further PK and pharmacodynamics studies of prednisolone in a variety of paediatric conditions., (© 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes ( CREBBP , EP300 ) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP ; RTS2: EP300 ), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Steroid-sensitive nephrotic syndrome (SSNS) is associated with a relapsing-remitting course that can be stressful for parents. As little is known of parental distress at the first onset of SSNS, this study aims to describe parental distress and everyday problems in mothers and fathers of a child with newly diagnosed SSNS participating in a randomized controlled trial of levamisole added to corticosteroids., Methods: To assess distress, the Distress Thermometer for Parents (DT-P) was used, which includes questions on distress (thermometer score 0-10, ≥ 4 "clinical distress") and presence of everyday problems in six domains: practical, social, emotional, physical, cognitive, and parenting. The DT-P was completed 4 weeks after the onset of SSNS. Total sum and individual items of everyday problems were compared with reference data from mothers and fathers of the Dutch general population., Results: There was no difference in clinically elevated parental distress between SSNS mothers (n = 37) and fathers (n = 25) and reference parents. Compared to reference fathers, fathers of a child with SSNS scored significantly higher on emotional problems (P = 0.030), while mothers experienced more parenting problems (P = 0.002). Regression analyses showed that lower parental age and having a girl with SSNS were significantly associated with more practical problems and higher distress thermometer scores, respectively., Conclusions: Four weeks after onset, SSNS mothers and fathers experience equal distress as reference parents. However, both parents endorsed significantly more everyday problems. Therefore, monitoring parental distress, even in the first weeks of the disease, could contribute to timely interventions and prevent worsening of problems., Clinical Trial Registry: Dutch Trial Register ( https://onderzoekmetmensen.nl/en/trial/27331 ). A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s).)

Levamisole (LMS) is a small molecule used in the treatment of idiopathic nephrotic syndrome (INS). The pathogenesis of INS remains unknown, but evidence points toward an immunological basis of the disease. Recently, LMS has been shown to increase the relapse-free survival in INS patients. While LMS has been hypothesized to exert an immunomodulatory effect, its mechanism of action remains unknown. Here, we show that LMS decreased activation and proliferation of human T cells. T-cell activation-associated cytokines such as IL-2, TNF-α, and IFN-γ were reduced upon LMS treatment, whereas IL-4 and IL-13 were increased. Gene expression profiling confirmed that the suppressive effects of LMS as genes involved in cell cycle progression were downregulated. Furthermore, genes associated with p53 activation were upregulated by LMS. In agreement, LMS treatment resulted in p53 phosphorylation and increased expression of the p53 target gene FAS. Accordingly, LMS sensitized activated T cells for Fas-mediated apoptosis. LMS treatment resulted in a mid-S phase cell cycle arrest accompanied by γH2AX-foci formation and phosphorylation of CHK1. Our findings indicate that LMS acts as an immunosuppressive drug that directly affects the activation and proliferation of human T cells by induction of DNA damage and the activation of a p53-dependent DNA damage response., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Objectives: Rituximab (RTX), used for treatment in paediatric immune-mediated diseases, can lead to hypogammaglobulinaemia and thus to an increased risk of infection, but data on these adverse effects in children are scarce. We aimed to describe the pharmacodynamics of RTX by time to B cell repopulation in paediatric immune-mediated diseases and to assess whether low post-RTX immunoglobulin levels were associated with frequency and severity of infections., Methods: Data of children with autoimmune diseases (AID), immune dysregulation (ID), haematological diseases (HD) and renal diseases (RD), including immunoglobulin levels pre-/post-RTX and occurrence of infections, who had received RTX at our centre were retrospectively collected. B cell depletion was defined as B cells <10 cells/μl., Results: Post-RTX B cell depletion was achieved in 45/49 patients. In 30/45 patients with B cell repopulation, median time to repopulation was 166 days (IQR 140-224): AID group (n=9) (183 days (IQR 156-239), ID group (n=6) 170 days (IQR 128-184), HD group (n=7) 139 days (IQR 127-294), RD group (n=7) 160 days (IQR 121-367). Severe infections leading to hospitalisation occurred in 7/52 (13.5%) patients: ID (n=3), HD (n=1), RD (n=3). After RTX treatment, 13/52 patients (25%) had low IgG levels for their age at least once, 11/13 had an infection during low IgG but only 2/13 had a severe infection. Low IgG was not associated with severe infection (p=0.459)., Conclusions: Time to B cell repopulation post-RTX ranged individually but did not significantly differ between paediatric patient groups. Severe infections were non-frequent and not associated with low (post-RTX) IgG levels.

Background: The aetiology of idiopathic nephrotic syndrome (INS) remains partially unknown. Viral infections have been associated with INS onset. Since we observed fewer first onset INS cases during the Covid-19 pandemic, we hypothesised that lower INS incidence was the result of lockdown measures. Therefore, the aim of this study was to evaluate the incidence of childhood INS before and during the COVID-19 pandemic in two independent European INS cohorts., Methods: Children with new INS in the Netherlands (2018-2021) and Paris area (2018-2021) were included. We estimated incidences using census data for each region. Incidences were compared using two proportion Z-tests., Results: A total of 128 and 324 cases of first onset INS were reported in the Netherlands and Paris area, respectively, corresponding to an annual incidence of 1.21 and 2.58 per 100,000 children/year. Boys and young children (< 7 years) were more frequently affected. Incidence before and during the pandemic did not differ. When schools were closed, incidence was lower in both regions: 0.53 vs. 1.31 (p = 0.017) in the Netherlands and 0.94 vs. 2.63 (p = 0.049) in the Paris area. During peaks of hospital admissions for Covid-19, no cases were reported in the Netherlands or Paris area., Conclusions: Incidence of INS before and during the Covid-19 pandemic was not different, but when schools were closed during lockdown, incidence was significantly lower. Interestingly, incidences of other respiratory viral infections were also reduced as was air pollution. Together, these results argue for a link between INS onset and viral infections and/or environmental factors. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s).)

This study assessed HRQoL and emotional and behavioral difficulties (EBD) and associated variables in children with first onset SSNS. While relapsing steroid-sensitive nephrotic syndrome (SSNS) in children is associated with lower health-related quality of life (HRQoL), little is known about first onset. Four weeks after onset, children (2-16 years) and/or their parents who participated in a randomized placebo-controlled trial, completed the Pediatric Quality of Life Inventory 4.0 (PedsQL) and Strengths and Difficulties Questionnaire (SDQ) to measure HRQoL and EBD, respectively. Total and subscale scores and the proportion of children with impaired HRQoL (> 1 SD below the mean of the reference group) or SDQ clinical scores (< 10 th and > 90 th percentile) were compared to the Dutch general population (reference group). Regression analyses were used to identify associated variables. Compared to the reference group, children 8-18 years reported significantly lower total HRQoL, and physical and emotional functioning. A large proportion (> 45%) of these children had impaired HRQoL. There were no differences in HRQoL between children 2-7 years and the reference group, except for higher scores on social functioning (5-7 years). Similar proportions of SSNS and reference children scored within the clinical range of SDQ subscales. Age, sex, and steroid side-effects were negatively associated with HRQol and/or EBD.   Conclusion: This study showed that HRQoL and EBD are affected in children of different ages with first onset SSNS. This calls for more awareness from healthcare providers and routinely monitoring of HRQoL and EBD in daily clinical care to prevent worsening of symptoms.   Clinical trial registry: Netherlands Trial Register ( https://trialsearch.who.int/ ; NTR7013), date of registration: 02 June 2018. What is Known: •  Health-related quality of life (HRQoL) is lower and emotional and behavioral difficulties (EBD) is more affected in children with frequently-relapsing and steroid-dependent nephrotic syndrome. What is New: •  HRQoL and EBD are affected in children with first onset steroid-sensitive nephrotic syndrome compared to a reference group of the Dutch general population. • To what extent HRQoL and EBD are affected depends on the age of the patient., (© 2023. The Author(s).)

Background: A prediction model for graft survival including donor and recipient characteristics could help clinical decision-making and optimize outcomes. The aim of this study was to develop a risk assessment tool for graft survival based on essential pre-transplantation parameters., Methods: The data originated from the national Dutch registry (NOTR; Nederlandse OrgaanTransplantatie Registratie). A multivariable binary logistic model was used to predict graft survival, corrected for the transplantation era and time after transplantation. Subsequently, a prediction score was calculated from the β-coefficients. For internal validation, derivation (80%) and validation (20%) cohorts were defined. Model performance was assessed with the area under the curve (AUC) of the receiver operating characteristics curve, Hosmer-Lemeshow test and calibration plots., Results: In total, 1428 transplantations were performed. Ten-year graft survival was 42% for transplantations before 1990, which has improved to the current value of 92%. Over time, significantly more living and pre-emptive transplantations have been performed and overall donor age has increased ( P  < .05).The prediction model included 71 829 observations of 554 transplantations between 1990 and 2021. Other variables incorporated in the model were recipient age, re-transplantation, number of human leucocyte antigen (HLA) mismatches and cause of kidney failure. The predictive capacity of this model had AUCs of 0.89, 0.79, 0.76 and 0.74 after 1, 5, 10 and 20 years, respectively ( P  < .01). Calibration plots showed an excellent fit., Conclusions: This pediatric pre-transplantation risk assessment tool exhibits good performance for predicting graft survival within the Dutch pediatric population. This model might support decision-making regarding donor selection to optimize graft outcomes., Trial Registration: ClinicalTrials.gov Identifier: NCT05388955., Competing Interests: All the authors declared no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Introduction: The introduction of eculizumab has improved the outcome in patients with atypical hemolytic uremic syndrome (aHUS). The optimal treatment strategy is debated. Here, we report the results of the CUREiHUS study, a 4-year prospective, observational study monitoring unbiased eculizumab discontinuation in Dutch patients with aHUS after 3 months of therapy., Methods: All pediatric and adult patients with aHUS in native kidneys and a first-time eculizumab treatment were evaluated. In addition, an extensive cost-consequence analysis was conducted., Results: A total of 21 patients were included in the study from January 2016 to October 2020. In 17 patients (81%), a complement genetic variant or antibodies against factor H were identified. All patients showed full recovery of hematological thrombotic microangiopathy (TMA) parameters after the start of eculizumab. A renal response was noted in 18 patients. After a median treatment duration of 13.6 weeks (range 2.1-43.9), eculizumab was withdrawn in all patients. During follow-up (80.7 weeks [0.0-236.9]), relapses occurred in 4 patients. Median time to first relapse was 19.5 (14.3-53.6) weeks. Eculizumab was reinitiated within 24 hours in all relapsing patients. At last follow-up, there were no chronic sequelae, i.e., no clinically relevant increase in serum creatinine (sCr), proteinuria, and/or hypertension in relapsing patients. The low sample size and event rate did not allow to determine predictors of relapse. However, relapses only occurred in patients with a likely pathogenic variant. The cost-effectiveness analysis revealed that the total medical expenses of our population were only 30% of the fictive expenses that would have been made when patients received eculizumab every fortnight., Conclusion: It is safe and cost-effective to discontinue eculizumab after 3 months of therapy in patients with aHUS in native kidneys. Larger data registries are needed to determine factors associated with suboptimal kidney function recovery during eculizumab treatment, factors to predict relapses, and long-term outcomes of eculizumab discontinuation., (© 2022 Published by Elsevier Inc. on behalf of the International Society of Nephrology.)

Background: In pediatric patients treated with levamisole to prevent relapses of idiopathic nephrotic syndrome (INS), a transient and non-progressive rise in creatinine levels has been observed. It has been suggested that levamisole affects tubular secretion of creatinine. However, other potential mechanisms - nephrotoxicity and interference with the analytical assay for creatinine - have never been thoroughly investigated., Methods: In three steroid-sensitive nephrotic syndrome (SSNS) patients with elevated plasma creatinine levels, treated with levamisole 2.5 mg/kg every other day, serum cystatin C was determined. The glomerular filtration rate (GFR) was estimated using the full age spectrum for creatinine and the full age spectrum for cystatin C equations. Interference of levamisole with the enzymatic creatinine assay was tested using spare human plasma of different creatinine concentrations spiked with levamisole (4, 20, and 100 µM)., Results: Three patients who received levamisole with elevated plasma creatinine levels had normal serum cystatin C levels and corresponding estimated GFR. There was no assay interference., Conclusion: Levamisole increases plasma creatinine levels, which is most probably due to impaired tubular secretion of creatinine since there was no assay interference and patients had normal eGFR based on serum cystatin C. However, interference of metabolites of levamisole could not be excluded. To monitor GFR, cystatin C in addition to creatinine should be used and be measured before and during levamisole use., (© 2022. The Author(s).)

Introduction: The recurrence of proteinuria after kidney transplantation in patients with focal segmental glomerulosclerosis (FSGS) is considered proof of the presence of circulating permeability factors (CPFs). The aim of this study is to demonstrate the presence of plasma CPFs using series of in vitro assays., Methods: Podocytes and endothelial cells (glomerular microvascular endothelial cells [GMVECs]) were incubated with plasma from FSGS patients with presumed CPFs in relapse and remission and from steroid-resistant nephrotic syndrome (SRNS), steroid-sensitive nephrotic syndrome (SSNS), membranous nephropathy (MN), and healthy controls (hCtrls). Cell viability, podocyte actin cytoskeleton architecture, and reactive oxygen species (ROS) formation with or without ROS scavenger were investigated by Cell Counting Kit-8 assay, immunofluorescence staining, and CM-H2DCFDA probing, respectively., Results: Presumed CPF-containing plasma causes a series of events in podocytes but not in GMVECs. These events include actin cytoskeleton rearrangement and excessive formation of ROS, which results in podocyte loss. These effects were solely observed in response to CPF plasma collected during relapse, but not in response to plasma of hCtrls, or patients with SRNS, SSNS, and MN. The copresence of dimethylthiourea, a scavenger of ROS, abolished the aforementioned effects of CPF plasma., Conclusion: We provide a panel of in vitro bioassays to measure podocyte injury and predict the presence of CPFs in plasma of patients with nephrotic syndrome (NS), providing a new framework for monitoring CPF activity that may contribute to future NS diagnostics or used for disease monitoring purposes. Moreover, our findings suggest that the inhibition of ROS formation or facilitating rapid ROS scavenging may exert beneficial effects in patients with CPFs., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

(1) Background: Health-related quality of life (HRQoL) is lower in patients with chronic kidney disease (CKD) compared to the general population. In 2011, the KLIK PROM portal was implemented in the Emma Children's Hospital to monitor and discuss HRQoL in daily care. This study describes and assesses the implementation and use of the KLIK PROM portal in the pediatric nephrology department. (2) Methods: CKD patients (self-report, if 8-18 years of age) and their parents (proxy-report, if 1-8 years) were invited to complete HRQoL patient-reported outcome measures (PROMs): TNO-AZL Preschool children Quality Of Life (TAPQOL) or Pediatric Quality of Life Inventory for Children (PedsQL). The PROMs were completed before and discussed during outpatient consultations. The adaptation rate-the proportion of patients/parents who were invited and completed at least one PROM-was calculated. Reported HRQoL scores of CKD patients were compared to the general population. (3) Results: In total, 142 patients (proxy- and self-report) were invited, 112 patients completed at least one PROM (adaptation rate 79%). Patients ( n = 84 with informed consent for scientific use) with CKD reported lower HRQoL and HRQoL was more often impaired compared to the general Dutch population. (4) Conclusions: The implementation of KLIK was successful and its use is feasible for daily care. Using KLIK, HRQoL problems can be easily identified and monitored.

Background: C3 glomerulopathy (C3G) is a rare kidney disorder characterized by predominant glomerular depositions of complement C3. C3G can be subdivided into dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). This study describes the long-term follow-up with extensive complement analysis of 29 Dutch children with C3G., Methods: Twenty-nine C3G patients (19 DDD, 10 C3GN) diagnosed between 1992 and 2014 were included. Clinical and laboratory findings were collected at presentation and during follow-up. Specialized assays were used to detect rare variants in complement genes and measure complement-directed autoantibodies and biomarkers in blood., Results: DDD patients presented with lower estimated glomerular filtration rate (eGFR). C3 nephritic factors (C3NeFs) were detected in 20 patients and remained detectable over time despite immunosuppressive treatment. At presentation, low serum C3 levels were detected in 84% of all patients. During follow-up, in about 50% of patients, all of them C3NeF-positive, C3 levels remained low. Linear mixed model analysis showed that C3GN patients had higher soluble C5b-9 (sC5b-9) and lower properdin levels compared to DDD patients. With a median follow-up of 52 months, an overall benign outcome was observed with only six patients with eGFR below 90 ml/min/1.73 m 2 at last follow-up., Conclusions: We extensively described clinical and laboratory findings including complement features of an exclusively pediatric C3G cohort. Outcome was relatively benign, persistent low C3 correlated with C3NeF presence, and C3GN was associated with higher sC5b-9 and lower properdin levels. Prospective studies are needed to further elucidate the pathogenic mechanisms underlying C3G and guide personalized medicine with complement therapeutics., (© 2021. The Author(s).)

Objectives: Rituximab (RTX) is a chimeric monoclonal CD20-antibody. Lack of efficacy has been suggested to be related to the presence of anti-drug antibodies (ADA). The aims of this study were to determine if ADA impact the pharmacokinetics (PK) and pharmacodynamics (PD) of RTX in children, whether the formation of ADA differs between various immune-mediated diseases and if it is related to the occurrence of infusion-related reactions (IRR)., Methods: All children <18 years who had received RTX treatment in our centre between December 2006 and February 2020 with known ADA/RTX-levels, were retrospectively included. The presence of ADA was defined as a titre >8 AU/ml., Results: Of twenty-six children treated with RTX for various immune-mediated diseases, six patients were ADA-positive (23.1%). In all ADA-positive patients, RTX concentrations were undetectable in contrast to ADA-negative patients (median RTX concentration 3.1 μg/ml; IQR 0.57-12.0; p<0.001). Failure of B cell depletion was found in 5/6 ADA-positive and 1/19 ADA-negative patients (p=0.003). In SLE-patients, 50.0% (n=4/8) had developed RTX-ADA. Severe anaphylaxis (n=3) occurred only in the ADA-positive group., Conclusions: In our cohort of paediatric patients, undetectable RTX concentrations were found in ADA-positive patients, indicative that these ADA have a PK impact. RTX-ADA also seem to affect the PD, as in the majority of these patients, B cell depletion failed. ADA were most present in SLE-patients and anaphylactic reactions occurred only in ADA-positive patients. With this knowledge, a change of drug might be considered in the presence of RTX-ADA.

Background: Parental donor kidney transplantation is the most common treatment option for children and adolescents with kidney failure. Emerging data from observational studies have reported improved short- and medium-term allograft outcomes in recipients of paternal compared to maternal donors. The INCEPTION study aims to identify potential differences in immunological compatibility between maternal and paternal donor kidneys and ascertain how this affects kidney allograft outcomes in children and adolescents with kidney failure., Methods: This longitudinal observational study will recruit kidney transplant recipients aged ≤18 years who have received a parental donor kidney transplant across 4 countries (Australia, New Zealand, United Kingdom and the Netherlands) between 1990 and 2020. High resolution human leukocyte antigen (HLA) typing of both recipients and corresponding parental donors will be undertaken, to provide an in-depth assessment of immunological compatibility. The primary outcome is a composite of de novo donor-specific anti-HLA antibody (DSA), biopsy-proven acute rejection or allograft loss up to 60-months post-transplantation. Secondary outcomes are de novo DSA, biopsy-proven acute rejection, acute or chronic antibody mediated rejection or Chronic Allograft Damage Index (CADI) score of > 1 on allograft biopsy post-transplant, allograft function, proteinuria and allograft loss. Using principal component analysis and Cox proportional hazards regression modelling, we will determine the associations between defined sets of immunological and clinical parameters that may identify risk stratification for the primary and secondary outcome measures among young people accepting a parental donor kidney for transplantation. This study design will allow us to specifically investigate the relative importance of accepting a maternal compared to paternal donor, for families deciding on the best option for donation., Discussion: The INCEPTION study findings will explore potentially differential immunological risks of maternal and paternal donor kidneys for transplantation among children and adolescents. Our study will provide the evidence base underpinning the selection of parental donor in order to achieve the best projected long-term kidney transplant and overall health outcomes for children and adolescents, a recognized vulnerable population., Trial Registration: The INCEPTION study has been registered with the Australian New Zealand Clinical Trials Registry, with the trial registration number of ACTRN12620000911998 (14th September 2020)., (© 2021. The Author(s).)

Context: Idiopathic nephrotic syndrome (INS) in children is a disease with considerable morbidity, yet the incidence and risk for relapse have not been systematically reviewed., Objective: To estimate the overall pooled weighted incidence and risk for relapse of INS in children., Data Sources: Medline and Embase (until December 2020)., Study Selection: All studies reporting incidence (per 100 000 children per year) and/or risk for relapse (the proportion of patients who experience ≥1 relapse) of INS in children (age: <18 years) were eligible., Data Extraction: After quality assessment, data were extracted: study (design, localization, and sample size) and patient (age, sex, steroid response, and ethnicity) characteristics, incidence, and risk for relapse., Results: After screening, 73 studies were included for analysis (27 incidence, 54 relapse). The overall pooled weighted estimate and corresponding prediction interval (PI) of the incidence was 2.92 (95% PI: 0.00-6.51) per 100 000 children per year. Higher incidences were found in non-Western countries ( P < .001). Incidence tended to be lower in white children, but this was not significant. The overall pooled weighted estimate of the risk for relapse was 71.9% (95% PI: 38.8-95.5). Between 1945 and 2011, incidence did not change ( P = .39), yet the risk for relapse decreased significantly ( P = .024), from 87.4% to 66.2%., Limitations: There was no full-text availability ( n = 33), considerable heterogeneity, and limited studies from Africa, Latin America, and Asia., Conclusions: INS has a low incidence with ethnic variation but high risk for relapse. Although corticosteroids have significantly reduced the risk for relapse, it remains unacceptably high, underscoring the need for alternative treatment strategies., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Nephrotic syndrome in childhood is a common entity in the field of pediatric nephrology. The optimal treatment of children with nephrotic syndrome is often debated. Previously conducted studies have shown significant variability in nephrotic syndrome management, especially in the choice of steroid-sparing drugs. In the Netherlands, a practice guideline on the management of childhood nephrotic syndrome has been available since 2010. The aim of this study was to identify practice variations and opportunities to improve clinical practice of childhood nephrotic syndrome in the Netherlands. A digital structured survey among Dutch pediatricians and pediatric nephrologists was performed, including questions regarding the initial treatment, relapse treatment, kidney biopsy, additional immunosuppressive treatment, and supportive care. Among the 51 responses, uniformity was seen in the management of a first presentation and first relapse. Wide variation was found in the tapering of steroids after alternate day dosing. Most pediatricians and pediatric nephrologists (83%) would perform a kidney biopsy in case of steroid-resistant nephrotic syndrome, whereas for frequent relapsing and steroid-dependent nephrotic syndrome this was 22% and 41%, respectively. Variation was reported in the steroid-sparing treatment. Finally, significant differences were present in the supportive treatment of nephrotic syndrome.Conclusion: Substantial variation was present in the management of nephrotic syndrome in the Netherlands. Differences were identified in steroid tapering, use of steroid coverage during stress, choice of steroid-sparing agents, and biopsy practice. To promote guideline adherence and reduce practice variation, factors driving this variation should be assessed and resolved. What is Known: • National and international guidelines are available to guide the management of childhood nephrotic syndrome. • Several aspects of the management of childhood nephrotic syndrome, including the choice of steroid-sparing drugs and biopsy practice, are controversial and often debated among physicians. What is New: • Significant practice variation is present in the management of childhood nephrotic syndrome in the Netherlands, especially in the treatment of FRNS, SDNS, and SRNS. • The recommendation on the steroid treatment of a first episode of nephrotic syndrome in the KDIGO guideline leaves room for interpretation and is likely the cause of substantial differences in steroid-tapering practices among Dutch pediatricians and pediatric nephrologists.

Background: Levamisole is used as a steroid-sparing drug for the treatment of frequently relapsing or steroid-dependent idiopathic nephrotic syndrome in children. As part of a large multicentre randomized controlled trial with levamisole, pharmacokinetic and pharmacodynamic parameters of levamisole in children with idiopathic nephrotic syndrome were investigated, as well as the feasibility of using saliva as an alternative and patient-friendly matrix for determining levamisole concentrations. In this study, the authors presented the development and validation of a highly sensitive method for determining levamisole in plasma and saliva using liquid chromatography-tandem mass spectrometry (LC-MS/MS)., Methods: In 100 μL samples, proteins were precipitated with 750 μL acetonitrile/methanol 420:80 (v/v) with levamisole-D5 as an internal standard. Calibration standards were prepared over a range of 0.1 ng/mL-50 ng/mL. To determine ultrafiltration efficiency, the ultrafiltrate was obtained by centrifuging blank plasma samples over the filter. Both filtered and nonfiltered samples were analyzed., Results: For plasma, accuracy and within-run and between-run imprecision were between 95.0% and 100% and <14.5%, respectively, and for saliva, between 100.9% and 107.5%, and <13.3%. No significant matrix effects were observed. Samples were stable at benchtop for 24 hours and -80°C, for at least 14 months (stability experiments ongoing). The ultrafiltration efficiency of unbound concentrations in plasma was lower than 85% (58.9%) but stable, and, therefore, the observed concentration should be corrected., Conclusions: Based on observations, the developed measure can determine levamisole concentrations in participant saliva samples., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Idiopathic nephrotic syndrome (INS) is characterised by a high relapse rate up to 80% after initial response to standard therapy with corticosteroids. Steroid toxicity is common and causes a great burden of disease that negatively influences the health-related quality of life (HRQoL). Recently, studies have shown that levamisole, an anthelminthic drug, significantly improves relapse-free survival in children with frequent relapses or steroid dependency. Compared with other steroid-sparing drugs, levamisole has relatively few side effects. We hypothesise that adding levamisole to standard therapy with corticosteroids in children with a first episode of INS will prevent relapses, decrease cumulative dosage of steroids used and improve HRQoL. This paper presents the study protocol for the LEARNS study (LEvamisole as Adjuvant therapy to Reduce relapses of Nephrotic Syndrome)., Methods and Analysis: An international, double-blind, placebo-controlled randomised trial will be conducted in 20 participating hospitals in the Netherlands and Belgium. Participants (n=92) with a first episode of INS, aged 2-16 years, who achieve remission after 4 weeks of oral prednisolone will be randomly assigned (1:1) to receive either levamisole 2.5 mg/kg alternate day or placebo added to prednisolone (18-week tapering schedule) for a total of 24 weeks. Follow-up will be until 2 years after first presentation. Additionally, parents and/or children will fill out five HRQoL questionnaires. Primary outcome of the LEARNS study is occurrence of relapses within 12 months after first presentation. Secondary outcomes include time to first relapse, cumulative steroid dose after 2 years, safety parameters and quality of life scores., Ethics and Dissemination: The trial was approved by the Medical Ethical Committee. Results of the study will be published in a peer-reviewed journal., Trial Registration Number: NL6826, 2017-001025-41., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Isolated antenatal hydronephrosis (ANH), defined as a dilation of the renal pelvis (≥5 mm), is one of the most common abnormalities detected on prenatal ultrasound. However, established cut-off values for postnatal follow-up differ between countries and are based on little evidence. The current protocol in the Netherlands for follow-up might be too conservative., Objective: To assess the applicability of a higher threshold for follow-up of isolated antenatal hydronephrosis (ANH) than the current practice, without the risk of missing significant postnatal urinary tract obstruction., Study Design: Retrospective case series on all fetuses with isolated ANH (anteroposterior pelvic diameter (APPD) ≥5 mm) at the second trimester anomaly scan, and diagnosed between 2000 and 2009, in relationship to renal outcome., Results: A total of 279 infants with second trimester isolated ANH were included. In 201/279 (72%) fetuses, ANH had normalized (APPD <10 mm) before the third trimester scans. Hydronephrosis persisted postnatally in a minority of 56/279 (20.1%). Postnatal assessment showed signs of obstruction in 41/279 (14.7%) infants, duplicated collecting system or vesicoureteral reflux (VUR). Surgery was performed in 18/279 (6.5%) infants. A non-functioning kidney was shown in 6/279 (2.2%) infants with ANH. Mild ANH (APPD <7 mm) during the second trimester (172/279 (61.6%)) never resulted in surgery for renal anomalies or non-functioning kidney. Infants with an APPD ≥10 mm in the second trimester were far more likely to develop renal anomalies or undergo surgery compared with infants with an APPD 7-10 mm. The number of non-functioning kidneys was too low to be conclusive., Conclusions: Follow-up ultrasounds for isolated ANH ≥7 mm instead of ≥5 mm at the second trimester scan would have saved 62% of third trimester scans, without missing any infant with a non-functioning kidney, significant obstruction or symptomatic VUR. In view of the results, it is reasonable that referral for follow-up of second trimester ANH is not strictly indicated in cases with an APPD <7 mm., (Copyright © 2017 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Introduction: Oral corticosteroids are the first-line treatment for idiopathic childhood nephrotic syndrome. Most children experience several relapses, needing repeated courses of corticosteroid therapy. This exposes them to side effects and long-term complications. For most patients, long-term prognosis is for complete resolution of the disease over time and maintenance of normal kidney function. Therefore, it is vital to focus on minimising adverse events of the disease and its therapy. Unfortunately, no randomised controlled trials are available to determine the optimal corticosteroid treatment of an infrequent relapse of nephrotic syndrome. Recent studies show that treatment schedules for the first episode can safely be shortened to 2 months. The hypothesis of the REducing STEroids in Relapsing Nephrotic syndrome (RESTERN) study is that a 4-week reduction of alternate-day steroids after inducing remission is effective and safe, reduces steroid exposure by 35% on average and is therefore preferable., Methods and Analysis: The RESTERN study is a nationwide, double-blind, randomised, placebo-controlled, non-inferiority intervention study. Children aged 1-18 years with a relapse of steroid-sensitive nephrotic syndrome are eligible for this study. Study subjects (n=144) will be randomly assigned to either current standard therapy in the Netherlands or a reduced prednisolone schedule. The primary outcome of the RESTERN study is the time to first relapse after the final prednisolone dose. The secondary outcomes are the number or relapses, progression to frequent relapsing or steroid dependent nephrotic syndrome and the cumulative dosage of prednisolone during the study period., Ethics and Dissemination: This non-inferiority trial will be performed in accordance with the Declaration of Helsinki and has been approved by the medical ethical committee of Arnhem-Nijmegen and the Dutch Competent Authority (Central Committee on Research Involving Human Subjects, CCMO). After completion of this study, results will be published in national and international peer-reviewed scientific journals. Papers will be published according to CCMO guidelines. The final report will be made available to trial participants., Trial Registration Number: NTR5670, EudraCT no 2016-002430-76., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Peritoneal transport characteristics in children on peritoneal dialysis (PD) has been reported to be different compared to adults. However, various test methods can influence this difference. Thirty-one standard peritoneal permeability analyses (SPA) were performed in 18 PD children with a median (range) age of 9.8 yr (2 to 19) and a median duration of PD of 2.6 yr (0.19 to 6.8). The median mass transfer area coefficient (MTAC) for creatinine was 9.6 ml/min per 1.73 m(2) (4.4 to 18.0), and for urea 17.3 ml/min per 1. 73 m(2) (12.2 to 22.8). The median dialysate to plasma creatinine ratio (D/P(Cr)) was 0.69 (0.44 to 0.92), the glucose absorption 59% (23 to 75), and the D/D(0) for glucose 0.38 (0.23 to 0.62). The median clearance of beta(2)-microglobulin was 923 microl/min per 1. 73 m(2) (366 to 1828), of albumin 103 microl/min per 1.73 m(2) (55 to 211), of IgG 48 microl/min per 1.73 m(2) (20 to 105), and of alpha(2)-macroglobulin 12 microl/min per 1.73 m(2) (5 to 49). No correlation was found between these results and age or PD time. The restriction coefficient for macromolecules indeed increased with duration of PD treatment (r = 0.38, P = 0.03). The median transcapillary ultrafiltration rate was 1.2 ml/min per 1.73 m(2) (-0. 01 to 2.8), the net ultrafiltration rate 0.2 ml/min per 1.73 m(2) (-1.97 to 1.82), and the effective lymphatic absorption rate 1.04 ml/min per 1.73 m(2) (-0.06 to 2.91). When corrected for body surface area, no differences were found in peritoneal fluid and solute transport characteristics between children and adults. No effect of time on PD on the transport parameters was found in a cross-sectional analysis, except for an increase of the restriction coefficient to macromolecules. This finding is similar to observations in adults. Therefore, the present study showed no evidence for the common belief that the peritoneal membrane in children is different from that in adult patients.