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

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

BACKGROUND:Bi-allelic loss of function variations in genes encoding proteins of the renin-angiotensin system (AGT, ACE, REN, AGTR1) are associated with autosomal recessive renal tubular dysgenesis, a severe disease characterized by the absence of differentiated proximal tubules leading to fetal anuria and neonatal end-stage renal disease.CASE-DIAGNOSIS/TREATMENT:We identified bi-allelic loss of function mutations in ACE, the gene encoding angiotensin-converting enzyme, in 3 unrelated cases displaying progressive chronic renal failure, whose DNAs had been sent for suspicion of juvenile hyperuricemic nephropathy, nephronophthisis, and cystic renal disease, respectively. In all cases, patients were affected with anemia whose severity was unexpected regarding the level of renal failure and with important polyuro-polydipsia.CONCLUSIONS:Bi-allelic loss of function mutation of ACE can have atypical and sometimes late presentation with chronic renal failure, anemia (out of proportion with the level of renal failure), and polyuro-polydipsia. These data illustrate the usefulness of next generation sequencing and "agnostic" approaches to elucidate cases with chronic kidney disease of unknown etiology and to broaden the spectrum of phenotypes of monogenic renal diseases. It also raises the question of genetic modifiers involved in the variation of the phenotypes associated with these mutations.

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

Loss-of-function mutations in CYP24A1 (MIM 126065 20q13.2), the gene encoding the 24-hydroxylase responsible for 25-OH-D and 1,25-(OH)2D degradation, are identified in about 20% of patients presenting Idiopathic Infantile Hypercalcemia (IIH) (MIM 143880). Common features of this autosomal recessive condition included hypercalcemia with hypercalciuria, suppressed PTH and a high 25-OH-D3:24,25-(OH)2D3 ratio. Medical care mainly relies on sun protection and life-long contraindication of vitamin D to avoid complications such as early nephrocalcinosis and renal failure. Molecular diagnosis therefore keeps a crucial place in the diagnosis of IIH, and genetic counseling should be systematically recommended to prevent vitamin D administration in affected siblings. In this report is described the molecular characterization of a CYP24A1 deletion identified in two unrelated families. This highlights the potential role of CYP24A1 copy number variations (CNV) in IIH. Considering the presence of CNV affecting CYP24A1 in public databases, CNV analysis should be systematically added to the sequencing studies in IIH. Targeted Massively Parallel Sequencing (MPS) study coupled with a CNV detection tool called CovCop is a powerful method to detect genic rearrangement and improve genetic analysis.

Hemolytic uremic syndrome related to Shiga-toxin-secreting Escherichia coli infection (STEC-HUS) remains a common cause of acute kidney injury in young children. No specific treatment has been validated for this severe disease. Recently, experimental studies highlight the potential role of complement in STEC-HUS pathophysiology. Eculizumab (EC), a monoclonal antibody against terminal complement complex, has been used in severe STEC-HUS patients, mostly during the 2011 German outbreak, with conflicting results.

BACKGROUND AND OBJECTIVES:Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a rare autosomal recessive renal tubular disease. It is caused by mutations in CLDN16 and CLDN19, encoding claudin-16 and -19, respectively. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is usually complicated by progressive CKD. The objectives of this study were to describe the clinical and genetic features of familial hypomagnesemia with hypercalciuria and nephrocalcinosis and analyze phenotype-genotype associations in patients with CLDN16 or CLDN19 mutations. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Data from 32 genetically confirmed patients (9 patients with CLDN16 and 23 patients with CLDN19 mutations) from 26 unrelated families were retrospectively reviewed. RESULTS:Diagnosis was based on clinical criteria at a median age of 9.5 years and confirmed by genetic testing at a median age of 15.5 years. In total, 13 CLDN16 or CLDN19 mutations were identified, including 8 novel mutations. A founder effect was detected for the recurrent CLDN16 p.Ala139Val mutation in North African families and the CLDN19 p.Gly20Asp mutation in Spanish and French families. CKD was more frequently observed in patients with CLDN19 mutations: survival without CKD or ESRD was 56% at 20 years of age in CLDN19 versus 100% in CLDN16 mutations (log rank P<0.01). Ocular abnormalities were observed in 91% of patients with CLDN19 mutations and none of the patients with CLDN16 mutations (P<0.01). Treatments seem to have no effect on hypercalciuria and CKD progression. CONCLUSIONS:Patients with CLDN19 mutations may display more severe renal impairment than patients with CLDN16 mutations. Ocular abnormalities were observed only in patients with CLDN19 mutations.

Mutations in the ATP6V1B1 and ATP6V0A4 genes, encoding subunits B1 and 4 of apical H(+) ATPase, cause recessive forms of distal renal tubular acidosis (dRTA). ATP6V1B mutations have been associated with early sensorineural hearing loss (SNHL), whereas ATP6V0A4 mutations are classically associated with either late-onset SNHL or normal hearing. The phenotype and genotype of 39 new kindreds with recessive dRTA, 18 of whom were consanguineous, were assessed. Novel and known loss-of-function mutations were identified in 31 kindreds. Fourteen new and five recurrent mutations of the ATP6V0A4 gene were identified in 21 families. For the ATP6V1B1 gene, two new and two previously described mutations were identified in 10 families. Surprisingly, seven probands with ATP6V0A4 gene mutations developed severe early SNHL between the ages of 2 mo and 10 yr. No mutation was detected in eight families. These data extend the spectrum of disease-causing mutations and provide evidence for genetic heterogeneity in SNHL. The data also demonstrate that mutations in either of these genes may cause early deafness, and they highlight the importance of genetic screening for recessive forms of dRTA independent of hearing status.

La glomérulonéphrite aiguë (GNA) post-streptococcique est une cause fréquente de glomérulonéphrite aiguë chez l’enfant. L’objectif de ce travail était de décrire les particularités cliniques et évolutives et de chercher des facteurs prédictifs de sévérité.Il s’agissait d’une étude rétrospective descriptive des patients atteints de GNA hospitalisés dans le service de pédiatrie, urgences et réanimation pédiatrique du CHU Hédi Chaker de Sfax sur une période de 12 ans (2005–2016).Ont été inclus 178 patients. L’âge moyen des patients était de 7,6 ans ± 3,43 ans. Cent quarante deux patients (80 %) avaient des antécédents d’infection récente des voies respiratoires supérieures ou d’infection cutanée. L’angine représentait la cause la plus fréquente, retrouvée chez 113 malades (67,6 %). À l’examen initial, 135 enfants (75,8 %) avaient une hématurie macroscopique. Les oedèmes étaient présents chez 114 enfants (64 %). L’HTA était notée chez 55 patients (31 %). L’oligurie était notée chez 30 enfants (16,8 %). Soixante-six patients (37 %) ont développé une insuffisance rénale aiguë (créatinine sanguine ≥ 70 micromoles/L). Il n’y avait pas de corrélation entre la survenue d’une insuffisance rénale aiguë et l’âge, le sexe, l’infection déclenchante, l’anémie, ni avec l’hyperleucocytose. Une créatininémie supérieure à 56,35 micromoles/L était associée à un haut risque d’apparition d’une hypertension artérielle. La durée moyenne d’hospitalisation était de 5,8 jours ± 4,44. Un seul malade a évolué vers une insuffisance rénale chronique.La GNA post-streptococcique demeure une néphropathie fréquente dans notre région. La détection et le traitement efficace de toute infection susceptible d’être en cause permettraient de réduire l’incidence de cette pathologie.Post-streptococcal glomerulonephritis (PSGN) is a frequent cause of acute nephritis in children. This study aimed to describe the epidemiology, clinical characteristics and outcomes of PSGN and look for predictor's factors of severity.A 12-year retrospective review of case notes and laboratory data was conducted at a department of pediatrics, pediatric emergency and intensive care, Hedi Chaker Hospital.One hundred seventy eight children were treated for PSGN with a mean age of 7.6 ans ± 3.43 ans. One hundred and forty-two patients (80%) had a history of a recent upper respiratory tract or skin infection. Streptococcal pharyngitis was the most common cause, identified in 113 patients (67.6%). Macroscopic hematuria and edema were noted in 135 (75.8%) and 114 cases (64%) respectively. Hypertension was present in 55 patients (31%). Oliguria was noted in 30 children (16.8%). Sixty-six subjects (37%) developed acute renal impairment (creatinine ≥ 70 micromoles/L). No correlation was demonstrated between acute renal impairment and age, sex, triggering infection, anemia and white blood cell count. Creatinine greater than 56.35 micromoles/L was associated with a high risk of developing high blood pressure. The mean length of admission was 5.8 days ± 4.44. Only one subject has ongoing renal dysfunction.PSGN remains a common nephropathy in our region. The detection and effective treatment of any infection that may be involved can reduce the incidence of this disease.