BACKGROUND:Distal renal tubular acidosis (dRTA) is characterized by metabolic acidosis, growth failure nephrocalcinosis, nephrolithiasis and chronic kidney disease (CKD). Previous retrospective data suggested improved outcome with adequate metabolic control, but confirmation from prospective data is lacking. Since 2019, the European dRTA registry has collected prospective data on patients with dRTA. Herein we present results of the first data analysis. METHODS:The registry is hosted as a subregistry of the European Rare Kidney Disease Network (www.ERKnet.org). In addition to the standard items of growth and plasma creatinine, additional data on plasma and urine biochemistries, genetics, treatment and clinical manifestations were collected from February 2019 through May 2024. Logistic regression analysis was used to identify predictors of CKD and impairedgrowth. RESULTS:Of the 214 patients enrolled in the registry, only 22% were >18 years at the last visit. A genetic cause was documented in 69% of patients.On average, low blood bicarbonate levels (<22 mmol/L) and hypercalciuria were observed in 42% and 25% of patients, respectively, independently from age. Multivariable analysis showed that height standard deviation score (SDS) was positively associated with serum bicarbonate levels (p=0.008) and with early diagnosis (p=0.005). Further modelling based on odds ratios indicated that height SDS increased progressively with serum bicarbonate levels until they reached 22-24 mmol/L. Patients aged >30 years had significantly lower eGFR (p<0.001) and the overall prevalence of CKD ≥stage 2 was 36%. Patients with SLC4A1 variants were at higher risk of CKD>1 (p=0.013). CONCLUSION:Our results in this primarily paediatric cohort highlight the importance of metabolic control and support increasing the blood bicarbonate level for therapy to 24 mmol/L to improve growth. Compared to the overall population, patients with dRTA are at higher risk of CKD from childhood, particularly if they have underlying SLC4A1 variants.

Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of chronic kidney disease in children. Although prenatal ultrasound enables early detection, its ability to predict postnatal renal outcome, particularly in bilateral cases, remains limited due to substantial phenotypic variability and the inability of imaging to capture ongoing disease processes. Genetic testing improves etiological classification but shows weak genotype–phenotype correlations and limited prognostic value, reflecting the multifactorial nature of CAKUT and prompting investigation of molecular biomarkers in prenatal body fluids. This review summarizes current prenatal prognostic strategies in CAKUT, including imaging, genetics, and downstream molecular approaches such as transcriptomics, metabolomics, and proteomics, with particular emphasis on peptide-based profiling. Among these, prenatal peptide signatures derived from fetal urine or amniotic fluid have demonstrated strong prognostic performance for predicting postnatal renal outcome and may capture early molecular processes related to tissue remodeling and inflammation. However, translation into clinical practice remains challenging. Validation requires large prospective multicenter studies that are difficult to conduct in rare diseases and often lack sustained funding. In addition, implementation will likely rely on mass spectrometry-based assays in clinical laboratories. Despite these hurdles, integrating molecular peptide profiling with improved and standardized imaging approaches may enhance prenatal counselling and clinical decision-making in CAKUT.

Introduction: Although anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is rare in children, kidney involvement is both common and potentially severe. Data on the clinico-pathological presentation and progression of kidney involvement in pediatric AAV are limited. Methods: This multicentric, retrospective, observational study aims to characterize kidney involvement in pediatric AAV, through a centralized pathology review of kidney biopsies and comparisons with an adult AAV cohort. Results: Eighty-one pediatric patients (median age 12.7 years, 23% male) were included over 20 years. Compared with adults (median age 66 years, 52% male), children presented with more frequent nephrotic-range proteinuria (42% vs. 18%, P < 0.001), lower hemoglobin levels (8.7 vs. 9.7 g/dl, P < 0.001), and more common cutaneous (24% vs. 9%, P = 0.001) and gastrointestinal involvement (18% vs. 3%, P < 0.001); histologically, more crescentic (P < 0.001) and fewer focal forms (P < 0.001), less interstitial fibrosis and tubular atrophy (IF/TA 0: 41% vs. 19%, P = 0.001) and more interstitial inflammation (ti1-2-3 per Banff classification: 66% vs. 47%, P = 0.025). For induction treatment children had a more frequent use of rituximab (65% vs. 43%, P = 0.001) and plasma exchange (31% vs. 15%, P = 0.004). Kidney outcomes were comparable to adults. The Berden classification, ANCA Renal Risk Score (ARRS), and ANCA Kidney Risk Score (AKRiS) showed good predictive accuracy for pediatric patients. Repeat biopsies demonstrated reduced activity and progression towards fibrosis. Conclusion: Pediatric patients present a more active kidney histology than adults, a more frequent nephrotic-range proteinuria and more severe anemia at presentation. Despite this, outcomes are comparable to adults. Berden, ARRS, and AKRiS can be used for predicting kidney prognosis in the pediatric population.

OBJECTIVES:Juvenile-onset systemic lupus erythematosus (jSLE) is a rare autoimmune disease. Belimumab, a monoclonal antibody targeting soluble B-lymphocyte stimulator, has been approved for paediatric use in France since 2020. This retrospective, multicentre study aimed to descriptively evaluate the real-world use, efficacy and safety of belimumab after 6 months of treatment in jSLE patients. METHODS:Patients were diagnosed with SLE according to the 2019 EULAR/ACR criteria, and belimumab therapy (intravenous or subcutaneous) was initiated before age 18. Efficacy was assessed using clinical (SLEDAI, low disease activity status, corticosteroid dose) and biological parameters (anti-dsDNA, complement, proteinuria), along with qualitative and semi-quantitative symptom analysis. RESULTS:Twenty-one patients were included. The majority received intravenous belimumab (90.5%) for articular (66.7%) or cutaneous (23.8%) manifestations. At 6 months, SLEDAI scores showed no significant reduction, although there was a trend towards lower corticosteroid use (0.53 vs 0.15 mg/kg/day) and an increase in the proportion of patients achieving low disease activity status (6.3% vs 37.5%). Marked improvement was observed in articular manifestations with 77.8% achieving complete resolution. Cutaneous, renal and haematological responses were limited. Overall, treatment was well tolerated, though psychiatric symptoms led to treatment discontinuation in one patient. CONCLUSION:This retrospective, multicentre study found that belimumab, primarily administered intravenously, was effective for articular involvement and had a corticosteroid-sparing effect in jSLE, with a favourable safety profile. Its efficacy was limited for cutaneous, renal and haematological manifestations. These findings support the potential benefit of belimumab in this population while highlighting the need for prospective, multicentre and long-term studies to confirm these observations.

BACKGROUND:Febrile urinary tract infection (FUTI) is one of the most common bacterial infections in children. Extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBLE) involved in these infections are increasing worldwide. The aim of this study is to establish risk factors (RFs) for developing community-acquired FUTI due to ESBLE in children. The secondary objectives are to analyze therapeutic options used in probabilistic and definitive treatments and their efficacy. METHODS:In this single-center, retrospective, case-control study conducted at Toulouse Children's Hospital between 1st January 2016 and 31 December 2020, we identified all children hospitalized for FUTI. ESBLE-mediated FUTI was the case group. The control group comprising non-ESBLE-mediated FUTIs was randomly selected and matched according to age and year of diagnosis with a ratio of 1 case for 3 controls. RESULTS:264 children were enrolled, 66 in the ESBLE-mediated FUTIs group and 198 in the non-ESBLE-mediated FUTIs group. RFs found to be significant were antibiotic therapy in the previous 3 months (p 0.0018); hospitalization in the previous 3 months (p<0.001); hospitalization in an intensive care unit in the previous 3 months (p<0.016); recurrence of FUTI whatever the delay (p 0.042); travel to a highly endemic area in the previous 3 months (p 0.003); a history of infection due to resistant bacteria (p<0.001); CAKUT (p 0.018); antibiotic prophylaxis (p 0.045); the number of days presenting fever prior to diagnosis (p 0.03). In multivariate analysis, the independent RFs were: hospitalization in the previous 3 months (ORa 3.6 [1.9-6.9]), history of infection due to resistant bacteria (ORa 20.9 [5-311]) and the number of days presenting fever prior to diagnosis (ORa 1.3 [1.1-1.6]). CONCLUSION:Identifying risk factors for developing community-acquired FUTI due to ESBLE may allow for better management of patients.

Acute kidney injury (AKI) affects 30

Background:The diagnosis of autosomal recessive polycystic kidney disease (ARPKD) can be hampered by its pronounced phenotypic variability and ARPKD-mimicking phenocopies. Here, for the first time we specifically studied the urinary peptidome of patients with ARPKD with the aim of distinguishing ARPKD from other causes of chronic kidney disease (CKD). Methods:Fifty-eight urine samples from patients with ARPKD, 662 urine samples from paediatric patients with CKD with various other CKD aetiologies and 45 samples from healthy children were included. The urinary peptidome was analysed by capillary electrophoresis/mass spectrometry. Results:A 77-peptide signature specific for ARPKD was identified. Application of this signature in a matched random validation set of 19 samples of patients with ARPKD, 23 samples from patients with other CKD and 21 samples from healthy individuals led to a sensitivity of 84.2% [95% confidence interval (CI) 60.4-96.6], a specificity of 100% (95% CI 92.0-100%) and an area under the receiver operating characteristics curve (AUC) of 0.994 (95% CI 0.93-1.00). The 77-peptide signature displayed a specificity of 76.1% (95% CI 72.4-79.5) and an AUC of 0.88 (95% CI 0.85-0.90) in 591 samples from non-matched children with various CKD aetiologies. The signature was primarily (83%) composed of collagen fragments indicating structural damage. Of the remaining peptides, five originated from proteins known to bind to calcium potentially linking the current work to defaults in calcium signalling in polycystic disease. Conclusions:We determined a urinary peptide signature that identifies paediatric patients with ARPKD with high precision among a population of children with CKD. Knowledge of the identity of the underlying peptides offers a novel starting point for discussion of possible pathophysiological processes involved in ARPKD.

AIMS:Prednisone is a widely used glucocorticoid in the treatment of lupus, although its dosing is often determined empirically. Prednisolone, the active metabolite of prednisone, is found in its free form in the serum. The goal of this study was to develop a population pharmacokinetic model in patients with systemic lupus erythematosus (SLE) to forecast free prednisolone concentrations and its association with disease activity. METHODS:A total of 66 active SLE patients (adults and children) were included, and followed up prospectively (242 observations available). Plasma prednisolone concentrations were assessed using liquid chromatography-mass spectrometry, and the data were analysed using Monolix software. The pharmacokinetic model was a one-compartment open model with absorption lag time representing the delay for both absorption and metabolism from inactive (prednisone) to active form (prednisolone). This model predicted free concentrations, which were then used to calculate total concentrations based on established binding constants. RESULTS:Free prednisolone clearance (CLu/F) and volume of distribution (Vu/F) were scaled allometrically to body weight. The typical population estimates (95% confidence interval) were 54 (48-62) L/h/70 kg and 235 (203-274) L/70 kg, respectively. Additionally, the bioavailability parameter was found to decrease non-linearly with the dose. Prednisolone cumulative exposure was not different between patients who responded at 3 months and those who did not. CONCLUSIONS:Robust pharmacokinetic targets are not yet clearly defined regarding toxicity or efficacy and are warranted in order to make a valuable contribution to prednisolone therapeutic drug monitoring in the context of SLE.

BACKGROUND AND HYPOTHESIS:Podocytopathy associated with likely pathogenic/pathogenic variants of Transient receptor potential cation channel subfamily C member 6 (TRPC6) (TRPC6-AP) has been recognized for about 20 years. As a result of its rarity however, the spectrum of clinical phenotypes and genotype-phenotype correlation of TRPC6-AP remains poorly understood. Here, we characterized clinical, histological and genetic correlates of familial and sporadic patients with TRPC6-AP. METHODS:In this multicentre observational study, an online questionnaire followed by a systematic literature review was performed to create a cohort with comprehensive data on genetic and clinical outcomes [age of onset, clinical presentation, treatment response, kidney biopsy findings and progression to kidney failure (KF)]. Logistic regression, Cox proportional hazards model and Kaplan-Meier analyses investigated the associations between genetic variants and disease progression. RESULTS:Among 87 families (96 familial and 45 sporadic cases), 31 distinct missense TRPC6 variants (including 2 novel) were identified, with c.2683C>T p.(Arg895Cys) and c.523C>T p.(Arg175Trp) the commonest variants. Proteinuric kidney disease/nephrotic syndrome was the most common clinical presentation (83.7%), while focal segmental glomerulosclerosis was the most common histological finding (89.4%). By 33 (interquartile range 17-40) years, 48.9% (69/141) of patients had progressed to KF. Sporadic TRPC6-AP demonstrated an earlier progression to KF than familial cases (P = .001) and were more likely to present with nephrotic syndrome [odds ratio 4.34 (1.85-10.15); P = .001]. Gain-of-function TRPC6 variants were more frequent in familial than sporadic TRPC6-AP (70.8% vs 44.4%; P = .004). Compared with patients with other TRPC6 variants, patients with TRPC6 p.R175W and p.R895C variants progressed to KF earlier [median kidney survival of 21 years, hazard ratio 2.985 (95% confidence interval 1.40-5.79); and 38 years, hazard ratio 1.65 (95% confidence interval 1.01-2.81), respectively, log-rank P = .005]. CONCLUSION:Our study shows unique clinical and genetic correlations of TRPC6-AP, which may enable personalized care and promising novel therapies.

Background:Although terminal complement inhibitors transformed the prognosis of atypical haemolytic uraemic syndrome (aHUS) from dismal to favourable, treatment approaches vary due to the intermittent disease nature and high costs. Occasionally, complement inhibition is applied in infectious (i)HUS. We aimed to examine real-world C5 inhibitor use and its impact on patient outcomes. Methods:This retrospective cohort study used longitudinal data from the European Rare Kidney Disease Registry, collected from 76 nephrology centres across 24 European countries between January 1, 2019 and January 31, 2024. Eligible patients had aHUS or iHUS with onset after January 1, 2011, and/or documented C5 inhibitor use. Exclusions included complement-unrelated HUS, post-transplant HUS, and prophylactic C5 inhibitor use around kidney transplantation. Data, derived from medical records and focused queries, were used to assess C5 inhibitor duration, via time-to-event analysis, and kidney function based on annual creatinine levels. Findings:A total of 238 aHUS and 472 patients with iHUS were included in the analysis. C5 inhibition was applied in 76.5% of aHUS and 18.4% of iHUS, with major utilisation differences between countries (p < 0.0001) and less common use in female patients with aHUS (p = 0.0022). Median (interquartile range) treatment duration was 16.1 (3.6-41.2) months in aHUS and 9 (7-32) days in iHUS. After five years, 56% of genetic, 28% of anti-complement factor H (anti-CFH) antibody-mediated, and 23% of aHUS cases with no identified cause remained on treatment. The long-term (>7 years) risk of treatment resumption was 35% in genetic, 15% in aHUS of no identified cause, and 0% in anti-CFH antibody-mediated aHUS. Post-withdrawal aHUS relapses were mostly mild and did not lead to permanent kidney function impairment, ultimately leading to long-term treatment withdrawal in 92.5% of discontinued cases. Interpretation:Currently, C5 inhibitors are administered in three-quarters of newly diagnosed patients with aHUS in Europe, with varied utilisation and discontinuation practices. Treatment withdrawal is common and safe, although relapses may occur, particularly in genetic aHUS. However, baseline disease severity, selective use in expert centres, and indication bias affect outcome comparability. Findings must be considered in the context of patient-specific factors and disease severity at the time of treatment decisions. Funding:This research was supported by the European Reference Network for Rare Kidney Diseases, funded by the European Union within the framework of the "EU4Health Programme 2021-2027".

ABSTRACT Background Immunoglobulin A vasculitis with nephritis (IgAVN) is the most common vasculitis in children. Due to a lack of evidence, treatment recommendations are based on expert opinion, resulting in variation. The aim of this study was to describe the clinical presentation, treatment and outcome of an extremely large cohort of children with biopsy-proven IgAVN in order to identify prognostic risk factors and signals of treatment efficacy. Methods Retrospective data were collected on 1148 children with biopsy-proven IgAVN between 2005 and 2019 from 41 international paediatric nephrology centres across 25 countries and analysed using multivariate analysis. The primary outcome was estimated glomerular filtration rate (eGFR) and persistent proteinuria at last follow-up. Results The median follow-up was 3.7 years (interquartile range 2–6.2). At last follow-up, 29% of patients had an eGFR <90 mL/min/1.73 m2, 36% had proteinuria and 3% had chronic kidney disease stage 4–5. Older age, lower eGFR at onset, hypertension and histological features of tubular atrophy and segmental sclerosis were predictors of poor outcome. There was no evidence to support any specific second-line immunosuppressive regimen being superior to others, even when further analysing subgroups of children with reduced kidney function, nephrotic syndrome or hypoalbuminemia at onset. Delayed start of immunosuppressive treatment was associated with a lower eGFR at last follow-up. Conclusion In this large retrospective cohort, key features associated with disease outcome are highlighted. Importantly, there was no evidence to support that any specific immunosuppressive treatments were superior to others. Further discovery science and well-conducted clinical trials are needed to define accurate treatment and improve outcomes of IgAVN.

Today, prenatal diagnosis of congenital urogenital malformations is mostly dependent on anatomical variations found on imaging. However, these findings can mislead us in telling us when to intervene, and about post-natal prognosis. Since many findings are dependent on multiple assessments, delayed diagnosis can occur, leading to less optimal outcomes compared to early intervention. Analyses of fetal urinary biomarkers have been proposed as a method of finding biological changes that are predictive for diagnosis and prognosis in fetuses at risk of kidney disease. We interviewed a group of researchers that have demonstrated that by combining multiple omics traits extracted from fetal urine, the biological variability found in single omics data can be circumvented. By analyzing multiple fetal urine peptides and metabolites at single time point, the prognostic power of postnatal renal outcome in fetuses with lower urinary tract obstruction is significantly increased. In this interview, we inquired about the technical aspects of the tests, challenges, and limitations the research group have come across, and how they envision the future for multi-omics fetal analysis in the clinic.

Introduction: Unlike idiopathic nephrotic syndrome (NS), hereditary podocytopathies are not expected to recur after kidney transplantation. However, some reports of posttransplant recurrence of NS in patients carrying variants in the NPHS2 gene have been described, notably with the p.Arg138Gln variant, which is more prevalent in Europe. The objective of this study was to assess the risk of recurrence after kidney transplantation in a large cohort of patients with biallelic NPHS2 pathogenic variants. Methods: Since January 2010, 61 patients identified at Necker-Enfants Malades Hospital and 56 enrolled in the PodoNet Registry with biallelic variants in the NPHS2 gene were transplanted and were compared with 44 transplanted children with steroid-resistant NS (SRNS) without any identified pathogenic variant. Results: Of the 117 patients, 23 carried the p.Arg138Gln variant in the homozygous state and 16 in the compound heterozygous state. The other 78 patients carried different variants in the homozygous (n = 44) or compound heterozygous state. Only 1 patient with NPHS2-related SRNS experienced posttransplant recurrence (median follow-up of cohort 8.5 years [2.5–15]). Conversely, 7 of 44 patients (16%) without any identified pathogenic variant recurred within a maximum of 7 days after transplantation (median follow-up 8.9 years [0.6–13.9]). Conclusion: In this large cohort, the risk of patients with causative variants in the NPHS2 gene to develop NS recurrence after kidney transplantation was extremely low. This is coherent with the pathophysiology of intrinsic slit-diaphragm disease. These data are reassuring and should be considered when counselling patients, making living kidney donation, whether related or not, a safe choice.

BACKGROUND:Schistosomiasis affects approximately 230 million people worldwide. There is an increased incidence of schistosomiasis cases in France acquired from outside the country. This increases the risk of schistosomiasis outbreaks as observed in Corsica. Clinicians from non-endemic regions are not accustomed to diagnosing and managing this pathology. The objective of this study is to provide a better description of the clinical and paraclinical characteristics and disease evolution of affected children.METHODS:Through the French Pediatric Nephrology Society and the Pediatric Infectious Pathology Group, we contacted all French pediatric centers that may have treated children with urinary schistosomiasis between 2013 and 2019. Age, sex, comorbidities, and clinical, biological, and radiological data (at discovery and follow-up) were collected retrospectively.RESULTS:A total of 122 patients from 10 different centers were included. The median age was 14 years and the sex ratio M/F was 4:1. Hematuria was present in 82% of the patients while urinary tract abnormality was found in 36% of them. Fourteen patients (11%) displayed complicated forms of urinary schistosomiasis including 10 patients with chronic kidney disease. A total of 110 patients received treatment with praziquantel, which was well-tolerated and led to clinical resolution of symptoms in 98% of cases.CONCLUSION:Patients with schistosomiasis present frequent kidney, urinary, or genital involvement. Systematic screening of patients returning from endemic areas is therefore recommended, especially since treatment with antiparasitic drugs is effective and well-tolerated. Enhancing medical knowledge of this pathology among all practitioners is essential to improve care and outcomes.

Background. Congenital anomalies of the kidney and urinary tract (CAKUT), often discovered in utero, cover a wide spectrum of outcomes ranging from normal postnatal kidney function to foetal death. The current ultrasound workup does not allow for an accurate assessment of the outcome. The present study aimed to significantly improve the ultrasound-based prediction of postnatal kidney survival in CAKUT. Methods. Histological analysis of kidneys of 15 CAKUT foetuses was performed to better standardize the ultrasound interpretation of dysplasia and cysts. Ultrasound images of 140 CAKUT foetuses with 2-year postnatal follow-up were annotated for amniotic fluid volume and kidney number, size, dysplasia and/or cysts using a standardized ultrasound readout. Association of ultrasound features and clinical data (sex and age at diagnosis) with postnatal kidney function was studied using logistic regression. Amniotic fluid proteome related to kidney dysplasia or cysts was characterized by mass spectrometry. Results. Histologically, poor ultrasound corticomedullary differentiation was associated with dysplastic lesions and ultrasound hyperechogenicity was associated with the presence of microcysts. Of all ultrasound and clinical parameters, reduced amniotic volume, dysplasia and cysts were the best predictors of poor outcome (odds ratio 57 [95% confidence interval (CI) 11-481], 20 [3-225] and 7 [1-100], respectively). Their combination into an algorithm improved prediction of postnatal kidney function compared with amniotic volume alone (area under the receiver operating characteristics curve 0.92 [95% CI 0.86-0.98] in a 10-fold cross-validation). Dysplasia and cysts were correlated (Cramer's V coefficient = 0.44, P < .0001), but amniotic fluid proteome analysis revealed that they had a distinct molecular origin (extracellular matrix and cell contacts versus cellular death, respectively), probably explaining the additivity of their predictive performances. Conclusion. Antenatal clinical advice for CAKUT pregnancies can be improved by a more standardized and combined interpretation of ultrasound data.