ABSTRACT:Congenital thrombotic thrombocytopenic purpura (cTTP) is caused by a severe inherited ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) deficiency. Although acute episodes are life-threatening, long-term burden of ischemic complications, and effectiveness of prophylactic strategies remain underexplored. We conducted a 25-year national, multicenter study of 88 patients with cTTP enrolled in the French Thrombotic Microangiopathy registry. Patients were stratified by age and clinical context at disease onset: pediatric (n = 42), pregnancy (n = 33), and adult onset (n = 13). Clinical features, genotypes, treatment regimens, and long-term ischemic outcomes were analyzed. Pediatric patients exhibited early-onset disease (median age at diagnosis, 2 years [interquartile range, 0-13]) with recurrent episodes and a high burden of neurological complications. In patients with pregnancy-onset disease, no relapses were observed outside pregnancy. Adult-onset patients, typically diagnosed aged >50 years, showed prevalent cardiovascular disease, stroke, and kidney injury. Mental health disorders were common across all groups. Despite long-term plasma prophylaxis, organ dysfunction persisted, particularly in pediatric- and adult-onset groups. In pregnancy-onset cTTP, tailored midterm prophylaxis during pregnancy reduced maternal and fetal complications. Thirty-nine patients received recombinant human ADAMTS13 (rhADAMTS13) prophylaxis (median follow-up, 5 months [interquartile range, 6-17]). Prophylactic treatment significantly improved relapse-free survival, with a comparable outcome using intensive plasma-derived products and rhADAMTS13 in pediatric-onset cases, although adverse events were more prevalent using plasma therapy. Our findings highlight the clinical and genetic heterogeneity of cTTP and the burden of organ dysfunction. Intensive prophylaxis improves relapse-free survival. rhADAMTS13 represents a safe and promising first-line option that should help reduce long-term organ damage and improve quality of life.

Lupus nephritis (LN) is a severe manifestation of pediatric systemic lupus erythematosus (pSLE). This study aims to describe the epidemiology, clinical, biological, histological features and prognosis of pediatric LN in the Afro-descendant (AD) population of the French Overseas Departments of America. We conducted a retrospective and longitudinal multicenter study of pediatric LN patients from January 2000 to June 2024. Patients were identified from multiple sources including pediatricians’ registries, pathologist’s registries for kidney biopsies, national registry for rare diseases and referral centers. Data were collected from medical records. Diagnostic criteria for pSLE kidney impairment were based on international classifications. Twenty-seven patients with pediatric LN were included. The mean age at diagnosis was 11.3 years (range: 6–17) and mean follow-up duration was 7.5 years (range: 0.3–27). Kidney involvement (75

Contexte Dans le syndrome néphrotique corticorésistant (SNCR), l’absence de réponse au traitement de seconde ligne par anticalcineurine expose au risque d’évolution vers l’insuffisance rénale terminale. L’ajout d’une déplétion B par rituximab a été proposée avec une efficacité variable. L’obinutuzumab est un anti-CD20 de seconde génération, dont l’efficacité a été montrée supérieure au rituximab. Objectif Évaluer l’effet de l’obinituzumab dans le SNCR. Matériel et méthodes Étude rétrospective monocentrique à l’hôpital Robert-Debré, incluant les patients avec SNCR traités par obinutuzumab entre mai 2018 et mai 2025, excluant les injections associées à des immunoadsorptions. Résultats Nous avons inclus 12 patients. L’âge moyen au diagnostic et à l’obinutuzumab était de 10,3 et 13 ans. Dix patients étaient d’origine afro-caribéenne, dont 6 avaient un génotype à risque de APOL1. La biopsie rénale montrait des lésions d’HSF (n=9) ou LGM (n=2). Pour 4 patients répondeurs au tacrolimus, la déplétion B par obinutuzumab a permis le sevrage du tacrolimus en 4,3 mois et une rémission prolongée (2/4 rechuteurs à 20 et 30 mois). Pour les 8 patients partiellement répondeurs, la moyenne d’albuminémie, protéinurie (RPC) à l’injection était de 32g/l, 1,5g/l (0,19g/mmol), à M6 : 33g/l, 3,8g/l (0,45g/mmol) et M12 : 35g/l, 2,2g/l (0,24g/mmol). Aucun cas de neutropénie ou infection sévère n’a été rapporté sous déplétion B. Conclusion La déplétion B par obinutuzumab peut être une aide au sevrage du tacrolimus dans le SNCR-tacrosensible. En revanche, chez les 8 SNCR avec réponse partielle au tacrolimus, aucune amélioration de la protéinurie n’a été observée après obinutuzumab.

Cancer and its treatment may lead to kidney injury and the need for kidney replacement therapy (KRT). We identified 287 pediatric KRT patients with a history of malignancy from the European Society for Paediatric Nephrology/European Renal Association Registry. Of these, 197 had cancer as a primary cause of KRT (group 1) and 90 had a malignancy diagnosis before KRT (group 2). Two matched controls without malignancy were randomly selected for each patient. Data were complemented with a questionnaire. Median time to kidney transplantation (KT) from KRT initiation was 2.4 (IQR: 1.5-4.7), 1.5 (IQR: 0.4-3.3), 3.6 (IQR: 1.3 to Q3 not reached), and 1.1 (IQR: 0.3-3.6) years for group 1, their controls, group 2, and their controls, respectively. Overall 10-year mortality for those on KRT was higher among cancer patients vs controls in group 1: 16% vs 9% (adjusted hazard ratio 2.02, 95% CI: 1.21-3.37) and in group 2: 23% vs 14% (adjusted hazard ratio 2.32, 95% CI: 1.11-4.85). In contrast, 10-year patient survival after the first KT was comparable to controls (93% vs 96%; 100% vs 94%, in groups 1 and 2, respectively). In summary, childhood cancer survivors' KT was delayed, and their overall mortality when on KRT was increased, but once transplanted, their long-term outcome was similar to other KT recipients.

Thrombotic Thrombocytopenic Purpura (TTP) is a rare disease characterized by a severe deficiency of ADAMTS13, the specific protease that cleaves von Willebrand factor. The congenital form of TTP (cTTP) results from pathogenic variants oftheADAMTS13 gene. cTTP has two peaks of incidence: one in childhood and the other in adulthood, mainly in an obstetric context. The treatment of cTTP relies on ADAMTS13 replacement therapy for prophylaxis or on-demand, depending on the evolving nature of the disease, along with the management of cardiovascular risk factors. The historical treatment for cTTP has been substitution plasma therapy. Since 2017, a recombinant human ADAMTS13 protein (rhADAMTS13) has been evaluated in cTTP in international clinical trials. The rhADAMTS13 protein, intravenous infusion used for prophylaxis or on-demand, has been granted early access or compassionate use in cTTP in France in 2024. The objective of this document is to establish academic recommendations for the use of rhADAMTS13 in cTTP. (c) 2024 The Author(s). Published by Elsevier Masson SAS on behalf of Societe Nationale Franc,aise de Medecine Interne (SNFMI). This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Introduction: Gitelman syndrome (GS) is a rare inherited salt-losing tubulopathy with limited clinical data. Methods: Surveys were conducted with GS physicians in Europe and patients with GS in the Netherlands to compare findings with the general population. Results: Data from 587 patients (25% pediatric) across 13 countries showed 93% were genotyped, with 94% having variants in SLC12A3. Children with GS were shorter and lighter than the general population, with lower bodyweight persisting into adulthood. The sex distribution was uneven, with more males in childhood and more females in adulthood. Patients with GS had the expected electrolyte disorders as well as significantly lower blood phosphate levels. Positive correlations were found between blood magnesium and potassium, and potassium and aldosterone. Physicians reported muscle cramps, salt craving, and muscle weakness as most common GS symptoms. Patients with GS scored worse than the general population in fatigue, physical, and cognitive function; and ranked salt craving and polydipsia-polyuria as the most severe symptoms. Symptom burden was higher in adult females and patients with lower blood magnesium. Treatment mainly consisted of potassium (94%) and magnesium (50%) supplementation. Potassium-sparing medication (used in 33%) slightly increased blood potassium levels (3.2 vs. 3.1 mmol/l). Adult patients with GS had a high prevalence of chondrocalcinosis (15%) and elevated blood cell counts (26%). Compared with the general population, adult patients with GS had lower rates of chronic kidney disease (CKD) and hypertension, a similar rate of diabetes, but a higher rate of albuminuria or proteinuria (28%). Conclusions: These findings provide new insights into GS, highlight disease burden, and suggest areas for future research.

OBJECTIVE:Juvenile systemic lupus erythematosus (j-SLE) is a rare chronic auto-immune disease involving several organs. Neuropsychiatric (NP) SLE (NPSLE) is frequent in j-SLE and associated with increased morbidity/mortality. Although NPSLE classification criteria exist, attributing NP features to j-SLE remains a major challenge. The study objective is to thoroughly describe j-NPSLE patients and assist in their diagnosis.METHODS:This is a 4-year retrospective monocentric study of j-SLE patients. NP events were attributed to j-SLE using standardised diagnostic criteria and multidisciplinary paediatric clinical expertise. Clinical features, brain magnetic resonance imaging (MRI)s and samples analysis including cerebrospinal fluid were assessed. A risk of j-NPSLE score was developed based on multivariable logistic regression analysis.RESULTS:Of 39 patients included, 44% were identified as having j-NPSLE. J-NPSLE diagnosis was established at the onset of j-SLE in 59% of patients. In addition to frequent kidney involvement (76%) and chilblains (65%), all j-NPSLE patients displayed psychiatric features: cognitive symptoms (82%), hallucinations (76%), depressed mood (35%), acute confused state (18%) and catatonia (12%). Neurological involvement was often mild and nonspecific, with headache (53%) in about half of the patients. The main features reported on brain MRI were nonspecific T2/FLAIR white matter hyperintensities (65%), and cerebral atrophy (88%). Upon immunosuppressive treatment, clinical improvement of NP features was observed in all j-NPSLE patients. The score developed to attribute j-NPSLE probability, guide further investigations and appropriate treatments is based on hallucinations, memory, sleep and renal involvement (Sensitivity: 0.95 Specificity: 0.85). Cerebrospinal fluid (CSF) neopterin assessment increases the score sensitivity and specificity.CONCLUSION:Physicians should carefully and systematically assess the presence of NP features at diagnosis and early stages of j-SLE. For j-NPSLE patients with predominant psychiatric features, a multidisciplinary collaboration, including psychiatrists, is essential for the diagnosis, management and follow-up.

Le purpura thrombotique thrombocytopénique (PTT) est une maladie rare définie par un déficit sévère en ADAMTS13, la protéase spécifique de clivage du facteur Willebrand. La forme congénitale de PTT (PTTc) résulte de variants pathogènes du gène ADAMTS13. Le PTTc a deux pics de fréquence, l’un dans l’enfance, l’autre chez l’adulte et principalement dans un contexte obstétrical. Le traitement du PTTc repose sur un traitement substitutif en ADAMTS13 en prophylaxie ou à la demande selon les modalités évolutives de la maladie, et la prise en charge des facteurs de risque cardiovasculaires. Le traitement historique du PTTc repose sur la plasmathérapie substitutive. Depuis 2017, une protéine ADAMTS13 recombinante humaine (rhADAMTS13) a été évaluée dans le PTTc dans des essais cliniques internationaux. La protéine rhADAMTS13, administrée par voie intraveineuse en prophylaxie ou à la demande, a été autorisée en accès précoce ou compassionnel dans le PTTc en France en 2024. L’objectif de ce document est d’établir des recommandations académiques pour l’utilisation de rhADAMTS13 dans le PTTc.

BackgroundEarly-onset isolated systemic hypertension is a rare condition of unknown genetic origin. Renovascular, renal parenchymal diseases or aortic coarctation are the most common causes of secondary systemic hypertension in younger children and neonates. We investigated the genetic bases of early-onset isolated systemic hypertension. MethodsWhole-exome sequencing (WES) was followed by variant filtering and Sanger sequencing for validation and familial segregation of selected variants in a large consanguineous family. mRNA expression was performed to evaluate the impact of the predicted pathogenic variant on gene expression. WES or Sanger sequencing was performed in additional unrelated affected individuals. ResultsIn one consanguineous family with four children presenting with isolated neonatal-onset systemic hypertension, we identified homozygous stop-gain variant in the NPR1 gene (NM_000906.4:c.1159C>T (p.Arg387Ter)) in the affected individuals. This variant leads to a dramatic reduction of NPR1 RNA levels. NPR1 gene analysis of additional families allowed the identification of another family with two affected children carrying homozygous frameshift variant in NPR1 (NM_000906.4:c.175del (p.Val59TrpfsTer8)). ConclusionWe show for the first time that biallelic loss of function of NPR1 is responsible for isolated neonatal-onset systemic hypertension in humans, which represents a new autosomal recessive genetic cause of infantile systemic hypertension or cardiogenic shock. This is consistent with studies reporting early-onset systemic hypertension and sudden death in Npr1-deficient mice. NPR1 gene analysis should be therefore investigated in infants with early-onset systemic hypertension with or without cardiogenic shock of unknown origin.

Neurological complications pose a significant threat in pediatric hemolytic and uremic syndrome (HUS) resulting from infections with Shiga toxin-producing Escherichia coli (STEC), with no established treatment. The involvement of complement activation in the pathogenesis of STEC-HUS is acknowledged, and eculizumab (ECZ), a terminal complement blocker, has been documented in several pediatric series with inconsistent results. Antibody-mediated mechanisms have also been suggested, with IgG-immunoadsorption (IgIA) showing promise in adults with neurological complications. We aimed to assess the benefit of combining IgIA with ECZ in pediatric patients with neurological STEC-HUS compared to patients treated with ECZ alone or supportive care. Multicenter retrospective study conducted on pediatric patients (< 18 years) with neurological STEC-HUS treated with IgIA + ECZ or ECZ alone from 2010 to 2020 in France. A historical cohort treated with supportive care served as controls. Primary outcome included survival and neurological evaluation at 1-year follow-up (dichotomized as normal vs. abnormal). A total of 42 children were included: 18 treated with IgIA + ECZ, 24 with ECZ alone, and 27 with supportive care. Although there was no significant difference in survival between groups, three deaths occurred in the control group in the acute phase, while none was reported in both the IgIA + ECZ and ECZ alone groups, despite presenting with more severe neurological symptoms for IgIA + ECZ patients. No significant association was found between treatment group and 1-year neurological evaluation after adjustment for age, sex, and initial neurological presentation. Systematic association of IgIA + ECZ is not supported for all neurological STEC-HUS pediatric patients; potential rescue therapy for severe cases warrants consideration.

BackgroundBetween 5 and 50% of atypical hemolytic uremic syndrome (aHUS) cases in children are caused by autoantibodies against complement factor H (CFH). Given the acquired autoimmune nature of the disease, plasma exchange (PE) and various immunosuppressive treatments have been used. More recently, eculizumab has been proposed.MethodsIn this multicenter, retrospective study, we report outcomes of 12 children with anti-FH antibody-associated HUS treated with eculizumab associated with various immunosuppressive regimens.ResultsPatients were treated with eculizumab for 15.5 [9.5;23.0] months and 3 received PE or IgG adsorption. Three patients received mycophenolate mofetil (MMF) alone, 1 patient received MMF and steroids, 1 patient received MMF and rituximab, 3 patients received MMF/steroids and rituximab, and 4 patients did not receive any immunosuppression. Anti-FH antibody levels significantly decreased but no difference was observed based on the immunosuppressive regimen. Eculizumab was discontinued in 7/10 patients after 11 [7.5;15.5] months and MMF in 6/8 patients after 36 [35;40] months. Anti-FH titers at MMF discontinuation ranged from 257 to 3425 UI/L. None of these patients relapsed and eGFR at last follow-up was above 70 mL/min/1.73 m2 in all patients.ConclusionsEculizumab is effective and safe in inducing and maintaining remission in aHUS secondary to anti-FH antibodies and renders reduction of anti-FH titers less urgent. Anti-FH antibody titers decreased in most patients irrespective of the immunosuppressive treatment chosen, so that a strategy consisting of combining eculizumab with MMF monotherapy seems sufficient at least in non-Indian or less severe forms of anti-FH antibody-associated HUS.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Purpose Transient Bartter syndrome related to pathogenic variants of MAGED2 is the most recently described antenatal Bartter syndrome. Despite its transient nature, it is the most severe form of Bartter syndrome in the perinatal period. Our aim was to describe 14 new cases and to try to explain the incomplete penetrance in women. Methods We report on 14 new cases, including 3 females, and review the 40 cases described to date. We tested the hypothesis that MAGED2 is transcriptionally regulated by differential methylation of its CpG-rich promotor by pyrosequencing of DNA samples extracted from fetal and adult leukocytes and kidney samples. Results Analysis of the data from 54 symptomatic patients showed spontaneous resolution of symptoms in 27% of cases, persistent complications in 41% of cases and fatality in 32% of cases. Clinical anomalies were reported in 76% of patients, mostly renal anomalies (52%), cardiovascular anomalies (29%) and dysmorphic features (13%). A developmental delay was reported in 24% of patients. Variants were found in all regions of the gene. Methylation analysis of the MAGED2 CpG-rich promotor showed a correlation with gender, independent of age, tissue or presence of symptoms, excluding a role for this mechanism in the incomplete penetrance in women. Conclusion This work enriches the phenotypic and genetic description of this recently described disease, and deepens our understanding of the pathophysiological role and regulation of MAGED2. Finally, by describing the wide range of outcomes in patients, this work opens the discussion on genetic counseling offered to families.

BACKGROUND:B-cell depletion with rituximab induces sustained remission in children with steroid-dependent or frequently relapsing nephrotic syndrome. However, most patients relapse after B-cell recovery, and some patients do not achieve B-cell depletion. Obinutuzumab is a second-generation anti-CD20 antibody designed to overcome such situations in B-cell malignancies and was recently reported to be safe and effective in other autoimmune diseases affecting the kidneys. METHODS:We retrospectively report 41 children with steroid-dependent or frequently relapsing nephrotic syndrome treated with a single low-dose infusion of obinutuzumab at Robert-Debre Hospital between April 2018 and December 2020. Participants were treated because of rituximab resistance or relapse after rituximab and received a single infusion of 300 mg/1.73 m 2 obinutuzumab with cessation of oral immunosuppressors within 2 months. RESULTS:B-cell depletion was achieved in all participants and lasted a median of 8.3 months (interquartile range, 6.4-11.1), a duration exceeding that for last rituximab treatment. At 12 and 24 months, 92% (38/41) and 68% (28/41) of patients, respectively, were in sustained remission. Mild infusion reactions occurred in five participants (12%) and neutropenia in nine (21%). No significant decrease in IgG level was reported during treatment, and whereas IgM levels decreased in 34 patients (83%), they were normal at last follow-up in 32 (78%). CONCLUSIONS:These results identified low-dose obinituzumab as a promising treatment option in children with steroid-dependent or frequently relapsing nephrotic syndrome, including those resistant to rituximab. The tolerance profile of obinutuzumab was similar to that of rituximab, but hemogram and immunoglobulin levels should be monitored.