Search

Resume La cystinose est une maladie multisystemique autosomique recessive, caracterisee par l’accumulation intra-lysosomale de cystine. Elle est due a un defaut de transport de cystine a travers la membrane lysosomale. La forme infantile classique se distingue par une tubulopathie proximale, des cristaux corneens de cystine et une insuffisance renale progressive, conduisant a l’insuffisance renale terminale dans 90 % des cas avant l’âge de 20 ans dans les cohortes historiques. Il s’agit de la premiere cause de syndrome de Fanconi chez l’enfant. Compte tenu des progres de la transplantation renale et du traitement specifique par cysteamine, la survie des patients s’est significativement amelioree au cours des dernieres annees, et le nephrologue adulte est desormais amene a prendre en charge de tels patients. Cependant, l’evolution de la maladie est caracterisee par la survenue d’autres complications : endocriniennes (hypothyroidie, diabete, hypogonadisme chez l’homme), neuromusculaires et neurologiques centrales. La cysteamine permet de retarder la survenue de ces complications. La prise en charge de tels patients devrait donc etre multidisciplinaire, meme si le nephrologue reste en premiere ligne. En plus de la forme infantile de cystinose, il existe une forme juvenile, d’apparition plus tardive, et une forme adulte, qui peut etre ophtalmologique pure, mais qui peut egalement etre associee a une atteinte renale. L’objet de cette revue est de faire part au nephrologue adulte des connaissances actuelles sur la maladie afin de le guider dans la prise en charge de ces patients.

International audience; BACKGROUND AND OBJECTIVES: Mutations in the MAGED2 gene, located on the X chromosome, have been recently detected in males with a transient form of antenatal Bartter syndrome or with idiopathic polyhydramnios. The aim of this study is to analyze the proportion of the population with mutations in this gene in a French cohort of patients with antenatal Bartter syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The French cohort of patients with antenatal Bartter syndrome encompasses 171 families. Mutations in genes responsible for types 1-4 have been detected in 75% of cases. In patients without identified genetic cause (n=42), transient antenatal Bartter syndrome was reported in 12 cases. We analyzed the MAGED2 gene in the entire cohort of negative cases by Sanger sequencing and retrospectively collected clinical data regarding pregnancy as well as the postnatal outcome for positive cases. RESULTS: We detected mutations in MAGED2 in 17 patients, including the 12 with transient antenatal Bartter syndrome, from 16 families. Fifteen different mutations were detected (one whole deletion, three frameshift, three splicing, three nonsense, two inframe deletions, and three missense); 13 of these mutations had not been previously described. Interestingly, two patients are females; in one of these patients our data are consistent with selective inactivation of chromosome X explaining the severity. The phenotypic presentation in our patients was variable and less severe than that of the originally described cases. CONCLUSIONS: MAGED2 mutations explained 9% of cases of antenatal Bartter syndrome in a French cohort, and accounted for 38% of patients without other characterized mutations and for 44% of male probands of negative cases. Our study confirmed previously published data and showed that females can be affected. As a result, this gene must be included in the screening of the most severe clinical form of Bartter syndrome.

Background Henoch-Schonlein purpura, more recently renamed immunoglobulin A vasculitis (IgAV), is a systemic vasculitis characterized by IgA deposits. The current markers used to assess IgAV inaccurately evaluate the risk of nephritis occurrence and its long-term outcomes. The current study assessed biomarkers of nephritis outcomes. Methods This French multicentre prospective study enrolled 85 adult patients at the time of disease onset. Patients were assessed for clinical and biological parameters and re-examined after 1 year. Immunoglobulins, cytokines, IgA glycosylation, IgA complexes and neutrophil gelatinase-associated lipocalin (NGAL) concentrations were assessed in blood and urine. Results We identified 60 patients with IgAV-related nephritis (IgAV-N) and 25 patients without nephritis (IgAV-woN). At the time of inclusion (Day 1), the serum levels of galactose-deficient IgA1 (Gd-IgA1) and urinary concentrations of IgA, IgG, IgM, NGAL, interleukin (IL)-1β, IL-6, IL-8, IL-10, IgA-IgG and IgA-sCD89 complexes were higher in the IgAV-N patients than in the IgAV-woN patients (P

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

International audience; HNF1B-related disease is an emerging condition characterized by an autosomal-dominant inheritance, a 50% rate of de novo mutations, and a highly variable phenotype (renal involvement, maturity-onset diabetes of the young type 5, pancreatic hypoplasia, and urogenital tract and liver test abnormalities). Given the current lack of pathognomonic characteristics and the wide overlap with other conditions, a genetic test is the diagnostic gold standard. However, pre-genetic screening is mandatory because genetic testing has substantial costs. Our aim was to develop a HNF1B score, based on clinical, imaging, and biological variables, as a pivotal tool for rational genetic testing. A score was created using a weighted combination of the most discriminative characteristics based on the frequency and specificity in published series. The HNF1B score is calculated upon 17 items including antenatal discovery, family history, and organ involvement (kidney, pancreas, liver, and genital tract). The performance of the score was assessed by a ROC curve analysis in a 433-individual cohort containing 56 HNF1B cases. The HNF1B score efficiently and significantly discriminated between mutated and nonmutated cases (AUC 0.78). The optimal cutoff threshold for the negative predictive value to rule out HNF1B mutations in a suspected individual was 8 (sensitivity 98.2%, specificity 41.1%, and negative predictive value over 99%). Thus, the HNF1B score is a simple and accurate tool to provide a more rational approach to select patients for HNF1B screening.

AIMS: The use of mycophenolate mofetil (MMF) in children with Systemic Lupus Erythematosus (SLE) is increasing. However, the clinical benefit of its monitoring has been scarcely studied, and little is known about its pharmacokinetics in this context. The objectives of the present study were: (i) to describe mycophenolic acid (MPA; the active moiety of MMF) pharmacokinetics; (ii) to develop a Bayesian estimator (BE) allowing the determination AUC (Area under the curve) from a limited number of blood samples; and (ii) to explore the relationships between exposure indices to MPA and the clinical status in children with SLE. METHODS: This was a retrospective study including 36 children with SLE, extracted from the expert system ISBA, for whom full- pharmacokinetic profiles of MPA were collected together with clinical data. A pharmacokinetic model and a BE were developed using an iterative two-stage Bayesian approach. ROC curve analyses and logistic regressions was used to investigate the association of exposure and active disease. RESULTS: A pharmacokinetic model and a BE were developed that allowed good AUC estimation performance (bias±SD=-0.02±0.15). ROC curve analyses showed that AUC/dose

Clinical proteomics has been applied to the identification of biomarkers of obstetric and neonatal disease. We will discuss a number of encouraging studies that have led to potentially valid biomarkers in the context of Down's syndrome, preterm birth, amniotic infections, preeclampsia, intrauterine growth restriction and obstructive uropathies. Obtaining noninvasive biomarkers (e.g., from the maternal circulation, urine or cervicovaginal fluid) may be more feasible for obstetric diseases than for diseases of the fetus, for which invasive methods are required (e.g., amniotic fluid, fetal urine). However, studies providing validated proteomics-identified biomarkers are limited. Efforts should be made to save well-characterized samples of these invasive body fluids so that many valid biomarkers of pregnancy-related diseases will be identified in the coming years using proteomics based analysis upon adoption of 'clinical proteomics guidelines'.

HNF1B encodes for a transcription factor involved in the early development of the kidney, pancreas, liver and genital tract. Mutations in HNF1B are dominantly inherited and consist of whole-gene deletion, or small mutation. De novo mutation occurs in half of tested kindreds. HNF1B-related disease combines renal and non-renal manifestations. Renal involvement is heterogeneous and may escape early recognition. During fetal life and childhood, it mostly consists of hyperechogenic kidneys or bilateral renal cystic hypodysplasia. The adult phenotype encompasses tubulointerstitial profile at presentation and slowly progressive renal decline (-2 ml/min/year). Renal involvement includes renal cysts (mostly few cortical cysts), a solitary kidney, pelvi-caliceal abnormalities, hypokalemia and hypomagnesemia related to tubular leak, and more rarely, Fanconi syndrome and chromophobe renal carcinoma. The latter warrants ultrasound screening. Extrarenal phenotype consists of diabetes mellitus (MODY-5), exocrine pancreas failure and pancreas atrophy; fluctuation liver tests abnormalities; diverse genital tract abnormalities in females or infertility in males; and mild mental retardation in rare individuals. Phenotype heterogeneity within families is striking. Individuals progressing to end-stage renal disease are eligible for kidney transplantation (or combined pancreas and kidney transplantation for diabetic individuals). While HNF1B disease was still unknown one decade ago, it has emerged as the second most prevalent dominantly inherited kidney disease. Data available pave the way for early recognition and improved specific management, including genetic counselling.

Background Hemolytic uremic syndrome related to pneumococcal infection (P+HUS) can be difficult to diagnose due to the lack of a specific test and the absence of a consensus for definite diagnostic criteria. Methods A retrospective study was conducted on the cases that have been considered as P+HUS in the participating centers during the past 10 years. Diagnostic strategy and criteria used for the diagnosis of P+HUS were evaluated and compared with a review of literature data. Results A total of 17 children were studied. Tests ruling out other causes of HUS were performed in 94% of cases. Direct confirmatory tests for P+HUS were done in a minority of cases as Thomsen-Friedenreich antigen testing using lectin assay were done in only 2 patients (11%). Retrospectively, the diagnosis of P+HUS was confirmed in 28% to 89% of cases depending on the already published criteria used. A literature review focused on the last 15 years confirmed these diagnostic difficulties due to variable definition criteria and bring a new light on the potential usefulness of tests used to reveal T activation in this setting. Conclusion To date, in a context of suspicion of P+HUS, no precise, practical and consensual strategy exists for T-antigen exposure diagnosis. The T-antigen activation test using peanut lectin might be the most appropriate test for a direct diagnosis of P+HUS. A large prospective study is required to confirm this hypothesis. However, before such data are available, its use could be of help when a suspicion of P+HUS is present given the therapeutic impact of such a diagnosis.

Rituximab (RTX) has recently showed promising results in the treatment of steroid-dependent idiopathic nephrotic syndrome (SDNS).This was a retrospective multicenter study of 18 children treated with RTX for SDNS, with a mean follow-up of 3.2 years. RTX was introduced because of side effects or relapses during therapy with immunosuppressive agents. The children received one to four infusions of RTX during the first course of treatment, and subsequent infusions were given due to CD19-cell recovery (CD19 1 %; 54 % of children) or relapse (41 %), as well as systematically (5 %).Treatment with RTX maintained sustained remission without relapse in 22 % of patients and increased the duration of remission in all other patients. The time between two successive relapses was 9 months in the absence of re-treatment and 24.5 months when infusions were performed at the time of CD19-cell recovery. At the last follow-up, 44.5 % of patients were free of oral drug therapy. Of those still receiving oral drugs, all doses had been decreased. No serious adverse events occurred.The results of this retrospective study confirm the efficacy and very good safety of RTX in the treatment of SDNS. The optimal therapeutic protocol seems to be a repeated single infusion at the time of CD19-cell recovery.

Objective Studies of early-onset systemic lupus erythematosus (SLE) have identified monogenic forms of the disease. The primary objective of this study was to compare the clinical and laboratory features of the first patients included in the GENIAL/LUMUGENE cohort to those reported in previous publications. The secondary objective was to determine whether subgroups with a distinctive pattern of clinical and biological features are seen in predominantly genetic forms of SLE. Methods GENIAL/LUMUGENE is a French nationwide study of the clinical, immunological, and genetic features of juvenile-onset SLE (clinicaltrials.gov # NCT01992666 ). Clinical and laboratory data from the first 64 patients younger than 18 years who were included in the first part of the study were collected retrospectively. Predefined criteria were used to divide the patients into three subgroups: syndromic SLE ( n = 10) and familial SLE ( n = 12) – both presumed to have a strong genetic component – and other forms of early-onset SLE ( n = 42). Results The predefined criteria for identifying subgroups based on knowledge of the clinical and epidemiological features of monogenic SLE showed a significantly younger age at onset in syndromic SLE ( P Conclusions In this study, clinical and epidemiological data alone failed to identify a specific patient subgroup characterized by the same disease presentation or progression. This result may be related to the small sample size or indicate marked heterogeneity of juvenile-onset SLE. Genetic studies using new sequencing techniques in these patients might identify genetic factors responsible for marked phenotypic variability.

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

Although capillary electrophoresis coupled to mass spectrometry (CE-MS) has potential application in the field of metabolite profiling, very few studies actually used CE-MS to identify clinically useful body fluid metabolites. Here we present an optimized CE-MS setup and analysis pipeline to reproducibly explore the metabolite content of urine. We show that the use of a beveled tip capillary improves the sensitivity of detection over a flat tip. We also present a novel normalization procedure based on the use of endogenous stable urinary metabolites identified in the combined metabolome of 75 different urine samples from healthy and diseased individuals. This method allows a highly reproducible comparison of the same sample analyzed nearly 130 times over a range of 4 years. To demonstrate the use of this pipeline in clinical research we compared the urinary metabolome of 34 newborns with ureteropelvic junction (UPJ) obstruction and 15 healthy newborns. We identified 32 features with differential urinary abundance. Combination of the 32 compounds in a SVM classifier predicted with 76% sensitivity and 86% specificity UPJ obstruction in a separate validation cohort of 24 individuals. Thus, this study demonstrates the feasibility to use CE-MS as a tool for the identification of clinically relevant urinary metabolites.

AKI is a frequent condition that involves renal microcirculation impairment, infiltration of inflammatory cells with local production of proinflammatory cytokines, and subsequent epithelial disorders and mitochondrial dysfunction. Peroxisome proliferator-activated receptor γ coactivator 1-α (PPARGC1A), a coactivator of the transcription factor PPAR-γ that controls mitochondrial biogenesis and function, has a pivotal role in the early dysfunction of the proximal tubule and the subsequent renal repair. Here, we evaluated the potential role of hepatocyte nuclear factor–1β (HNF-1β) in regulating PPARGC1A expression in AKI. In mice, endotoxin injection to induce AKI also induced early and transient inflammation and PPARGC1A inhibition, which overlapped with downregulation of the HNF-1β transcriptional network. In vitro, exposure of proximal tubule cells to the inflammatory cytokines IFN-γ and TNF-α led to inhibition of HNF-1β transcriptional activity. Moreover, inhibition of HNF-1β significantly reduced PPARGC1A expression and altered mitochondrial morphology and respiration in proximal tubule cells. Chromatin immunoprecipitation assays and PCR analysis confirmed HNF-1β binding to the Ppargc1a promoter in mouse kidneys. We also demonstrated downregulation of renal PPARGC1A expression in a patient with an HNF1B germinal mutation. Thus, we propose that HNF-1β links extracellular inflammatory signals to mitochondrial dysfunction during AKI partly via PPARGC1A signaling. Our findings further strengthen the view of HNF1B-related nephropathy as a mitochondrial disorder in adulthood.

HNF1B mutation is the leading cause of isolated hyperechogenic fetal kidneys with normal or moderately large size. Although most cases have normal amniotic fluid volume, some cases present with early oligohydramnios and renal failure associated with high perinatal mortality.Here we report on seven fetuses from six unrelated families, carrying an HNF1B mutation, and presenting with polyhydramnios during the second or third trimester of pregnancy. Polyhydramnios was transitory in two cases. None of the mothers was presenting gestational diabetes. Bilateral hyperechogenic kidneys with size between -2.5 and +2 SD was the most common renal phenotype at prenatal US. Two patients were born prematurely at 28 and 32 weeks of gestation, respectively. Both presented high urine output the first days of life with urinary salt and potassium loss requiring hydro-electrolytic compensation. All mutations were large deletions removing the whole HNF1B gene.In the absence of maternal diabetes, HNF1B mutation can be associated with polyhydramnios, probably due to fetal polyuria. Thus, HNF1B mutation represents a differential diagnosis of polyhydramnios associated with hyperechogenic (and sometimes enlarged) kidneys.

Protocol biopsies can detect subclinical rejection and early signs of calcineurin inhibitor-induced nephrotoxicity.In a prospective study, protocol biopsies 3 and 12 months after transplant in transplanted children from two centers were studied. One center used cyclosporine (CsA)-based immunosuppression and the other center used tacrolimus. Patients were on CsA (n = 26, group 1) or on tacrolimus (n = 10, group 2). Patients received basiliximab induction, mycophenolate mofetil, and prednisone.In patients on CsA, 26 kidney biopsies were performed during the 6 months after transplantation. Eighteen protocol biopsies were performed at 3 months post transplant; 13 were normal and five showed rejection (two borderline and three Banff II rejections). Eight biopsies were motivated by an increase of serum creatinine; four were normal and four revealed signs of acute rejection (two borderline and two Banff II). Twelve protocol biopsies were performed after 12 months; all were normal. For patients on tacrolimus (n = 10), ten protocol transplant biopsies were performed at 3 months post-transplant; none showed signs of rejection. No biopsy was performed for an increase of serum creatinine. There were no differences in patient age, number of human leukocyteantigen (HLA) incompatibilities, or other patient characteristics.Patients on tacrolimus had less acute rejection episodes detected on protocol biopsies 3 months after transplant. Protocol biopsies seem to play an important role in the detection of subclinical rejection in patients on CsA.

Resume Nous rapportons l’observation d’un patient âge de 13 ans atteint d’un syndrome de Churg et Strauss (SCS) revele par une atteinte cutanee predominante. Cet adolescent suivi pour un asthme modere depuis l’âge de 6 ans, avait brusquement presente des œdemes tendus et douloureux des membres inferieurs associes a une hypereosinophilie sanguine (9 000/mm 3 ) en l’absence de fievre. La constatation de nodules sous-cutanes violaces avec des lesions purpuriques peripheriques sur la face anterieure des tibias et du dos des pieds avaient justifie la realisation d’une biopsie cutanee. Cet examen montrait une necrose ischemique hypodermique massive en lien avec des lesions de vascularite necrosante a polynucleaires eosinophiles. Les autoanticorps antineutrophiles cytoplasmiques (ANCA) etaient negatifs. L’apparition secondaire de manifestations systemiques neurologiques (allodynie des membres inferieurs), pulmonaires (syndrome interstitiel et pleuresie), digestives (douleurs abdominales), articulaires (polyarthralgies) et genitales (inflammation scrotale) avait permis de poser le diagnostic de SCS. L’etat general etait conserve, aucune atteinte cardiaque ni renale n’avait ete mise en evidence. L’evolution avait ete favorable sous corticotherapie par voie orale. Le SCS, dont les formes pediatriques sont exceptionnelles, doit etre evoque devant l’association d’un asthme, de symptomes de vascularite systemique, atteignant au moins deux sites extrapulmonaires et d’une hypereosinophilie. L’atteinte cutanee est revelatrice dans moins de 25 % des cas chez l’adulte et l’atteinte genitale n’avait jamais ete decrite a notre connaissance auparavant. L’asthme et l’atteinte otorhinolaryngologique (ORL) etaient au second plan dans notre observation. Le pronostic reste reserve chez l’enfant en cas d’atteinte pleurale et cardiaque.

International audience; PURPOSE: Severe ureteropelvic junction obstruction is treated surgically. However, for milder cases most clinical teams adopt a watchful waiting approach and only operate in the presence of significant decline of renal function combined with severe hydronephrosis. Little is known about the long-term consequences of ureteropelvic junction obstruction. MATERIALS AND METHODS: Using capillary electrophoresis coupled with mass spectrometry, we analyzed the urinary proteome of 42 patients with ureteropelvic junction obstruction 5 years postoperatively or 5 years following spontaneous resolution. RESULTS: At 5-year followup urinary proteomes were similar between patients with early surgical correction of ureteropelvic junction obstruction and age matched controls. In contrast, urinary proteomes differed significantly between conservatively followed patients and controls. Analyses of the proteomic differences suggested ongoing renal or ureteral remodeling in the conservatively followed patients that was not visible clinically. CONCLUSIONS: Long-term followup studies are warranted in patients with ureteropelvic junction obstruction, especially those followed conservatively, to determine whether the observed changes in the urinary proteomes become clinically relevant at a later stage.

Background/Aims: HNF1B nephropathy is characterized by dominantly inherited renal hypodysplasia with few cysts, slow renal decline and hypomagnesemia. Mice with antenatal inactivation of HNF1B are characterized by polycystic kidneys, renal failure and a profound decrease in cystic gene (Pkhd1, Umod, Pkd2) expression. Mice with inactivation after postnatal day 10 have no renal phenotype. Methods: Quantification of mRNA expression of HNF1B, six of its potential target genes (PKHD1, PKD1, PKD2, IFT88, TMEM27 and UMOD) and three genes involved in the Mg2+ renal homeostasis (ATP1A1, FXYD2 and CLDN16) in the urinary sediment of 11 individuals with mutation of HNF1B and in 9 controls (non-invasive assessment of the renal transcriptome). Results: As compared to controls, no difference was observed in the urinary mRNA amount of HNF1B and the renal cystic genes. A significant increase in the expression of ATP1A1, which encodes the α1-subunit of the Na+/K+-ATPase, was identified in HNF1B patients consistent with its role in Mg2+ homeostasis. Conclusion:Assessment of mRNA expression in urinary sediment is a non-invasive method applicable to gain insights into the pathophysiology of inherited nephropathies in humans. HNF1B nephropathy is generally not associated with postnatal down-expression of renal cystic genes in human, a finding consistent with mouse models.

Renal coloboma syndrome, also known as papillorenal syndrome is an autosomal-dominant disorder characterized by ocular and renal malformations. Mutations in the paired-box gene, PAX2, have been identified in approximately half of individuals with classic findings of renal hypoplasia/dysplasia and abnormalities of the optic nerve. Prior to 2011, there was no actively maintained locus-specific database (LSDB) cataloguing the extent of genetic variation in the PAX2 gene and phenotypic variation in individuals with renal coloboma syndrome. Review of published cases and the collective diagnostic experience of three laboratories in the United States, France, and New Zealand identified 55 unique mutations in 173 individuals from 86 families. The three clinical laboratories participating in this collaboration contributed 28 novel variations in 68 individuals in 33 families, which represent a 50% increase in the number of variations, patients, and families published in the medical literature. An LSDB was created using the Leiden Open Variation Database platform: www.lovd.nl/PAX2. The most common findings reported in this series were abnormal renal structure or function (92% of individuals), ophthalmological abnormalities (77% of individuals), and hearing loss (7% of individuals). Additional clinical findings and genetic counseling implications are discussed.

Background MAGED2 was recently identified in an X-linked severe and transient form of antenatal Bartter's syndrome associated with polyhydramnios and prematurity but also in idiopathic polyhydramnios in the male offspring. An inappropriate expression of the sodium-chloride transporters NKCC2 and NCC is disclosed. Methods MAGED2 was screened by Sanger Sequencing in a series of 35 cases with transient or antenatal Bartter's syndrome and no pathogenic variant in SLC12A1, KCNJ1, CLCNKB and BSND genes. Results We found 15 cases from 14 families harboring MAGED2 variants including four nonsense, three miss sense, two frame shift and two splice-site variants; two small in frame deletions and one complete deletion of MAGED2 gene. Only one variant was previously reported, p.Arg446Cys. Severe polyhydramnios occurred in all pregnancies, at 18 to 25 weeks of gestation requiring serial amniocentesis (one to ten, when data available). In four cases, polyhydramnios was present in previous or later pregnancies. One pregnancy resulted in medical termination of pregnancy. All the infants (14) were born pre-term with gestational age at delivery between 26 and 36 weeks. All presented a Bartter's syndrome with severe polyuria (median diuresis was 13 mL/kg/h). Surprisingly, two cases were females. The severity of their phenotype and the course of the disease were comparable to those for male. The medical follow-up of 12 patients revealed that the salt and water losses resolved between 2 and 18 months with the end of indomethacin treatment or water and salts supplements. Two cases, with associated neurological disorders died at 1 and 12 months. Conclusion We confirmed with our French series of 15 MAGED2 cases the phenotypic presentation of this transient antenatal Bartter's syndrome. This new syndrome has to be considered in the differential diagnosis of Bartter's syndrome with the screening of MAGED2 as part of the molecular diagnosis.

Introduction Kidney transplantation (KT) is the treatment of choice for end-stage renal disease. Pre-emptive KT is considered to be the most optimal treatment of ESRD particularly in children but reports on the results of paediatric pre-emptive KT are scarce. The objective of this study was to evaluate the impact of pre-emptive KT on the risk of graft failure in children with ESRD. Methods We analyzed all first kidney transplants performed in children Results A total of 1920 paediatric patients were included, of whom 387 (20.2%) received a pre-emptive KT. Median time of follow-up was 7.0 years [IQR (3.0–11.7)]. At 10 years post-transplant, graft survival was 85.2% in pre-emptive KT and 67.1% in non-pre-emptive KT (P Conclusion In France, pre-emptive KT in children is associated with a lower risk of graft failure than KT performed after the initiation of dialysis, and should be encouraged when feasible.

Resume La survie des patients et des greffons en transplantation renale pediatrique s’est amelioree au cours des 20 dernieres annees. La mortalite est faible et principalement liee aux pathologies tumorales, infectieuses ou aux complications de la maladie initiale. La survie des greffons renaux est de 67 % a 10 ans. Les facteurs influencant cette survie sont le type de donneur (avec de meilleurs resultats avec un donneur vivant), l’âge du donneur, l’âge du receveur (avec 2 periodes a risque : les moins de 2 ans et l’adolescence), le nombre d’incompatibilites HLA et la recidive eventuelle de la maladie initiale. Le risque de perte du greffon a long terme est lie essentiellement a la nephropathie chronique d’allogreffe (CAN). La mauvaise observance, surtout observee chez les adolescents, peut etre responsable de rejets tardifs et de perte du greffon. La nephrotoxicite des anticalcineurines est egalement en cause dans le developpement de la CAN. Les traitements et la place des inhibiteurs de mTOR vont probablement evoluer. Les roles de ces differents facteurs sont discutes dans cet article.

Mycophenolate mofetil (MMF) has emerged as a new therapeutic option in steroid-dependent nephrotic syndrome (SDNS). We conducted a phase II Bayesian trial of MMF in children with SDNS. Phase II trials, usually single-arm studies, investigate the effect of new treatments. Standard Fleming's procedure relies on observed results (relapse rate during the trial), whereas Bayesian approach combines observed results with prior information (expected relapse rate according to prior studies and clinical experience). All patients were required to have received prior alkylating-agent treatment. Sixty-seven percent of them had also received levamisole. Patients received MMF (1,200 mg/m(2)/day) and prednisone according to a defined schedule [reduction of alternate-day (e.o.d) dose to 50% of pre-MMF dose at 3 months, 25% at 6 months]. Twenty-four children (median age 6.0 years, 2.8-14.4) entered the study and 23 completed it. Bayesian analysis showed that adding four patients would not change significance of results, allowing stopping inclusions. Four patients relapsed during the first 6 months (estimated probability 17.6%, 95% credibility interval: 5.4-35.0%) and two at months 8 and 11.5. In the 19 patients free of relapse during the first 6 months, median (Q1-Q3) prednisone maintenance dose decreased from 25 (10-44) to 9 (7.5-11.2) mg/m(2) e.o.d (p0.001) and cumulative dose from 459 (382-689) to 264 (196-306) mg/m(2)/month (p0.001) before and on MMF respectively. Pre-MMF patient characteristics and MMF pharmacokinetics did not differ between patients with or without relapse. MMF reduces relapse rate and steroid dose in children with SDNS and should be proposed before cyclosporine and cyclophosphamide.

Chromosomal imbalance of the 17q12 region (which includes the HNF1B transcription factor) has recently emerged as a frequent condition. 17q12 deletion was found in patients with various renal abnormalities, diabetes mellitus (MODY type 5), genital tract or liver test abnormalities, while 17q12 duplication was identified in a subset of patients with autism, mental retardation, epilepsy and/or schizophrenia but no renal disorder. We report here two first-degree relatives carrying a 17q12 duplication and harboring various renal abnormalities (bilateral hypoplastic kidneys with vesico-ureteric reflux or multicystic dysplatic kidney with contralateral hyperechogenic kidney). Esophageal atresia (EA) type C was identified at birth in one patient while none had neurological disorder. Because EA has already been identified in patients with 17q12 duplication or HNF1B point mutation, we screened HNF1B (QMPSF and direct sequencing) in nine additional patients with EA and renal abnormalities but failed to identify any pathogenic variant. This is the second report of HNF1B mutation associated with EA. Moreover, we showed herein, that renal malformations may be part of the 17q12 duplication syndrome.

Introduction Les malformations congenitales bilaterales des reins et des voies urinaires (CAKUT) representent la premiere cause d’insuffisance renale (IR) chez les enfants. La prise en charge des fœtus CAKUT est malheureusement extremement difficile du fait de notre incapacite a evaluer en periode prenatale la progression des atteintes renales. Le but de notre etude est donc de developper un outil pronostique, tire de l’exploration du peptidome amniotique, pour prevoir in utero le devenir fonctionnel des reins apres la naissance des patients CAKUT. Patients/Materiels et methodes Cent-soixante-dix-huit fœtus avec CAKUT ont ete inclus dans une etude prospective multicentrique (NCT02675686). Le critere de jugement etait la fonction renale a 2 ans de vie. Trente-huit fœtus ont finalement ete exclus pour des raisons cliniques ou techniques. Le groupe controle comprenait 69 fœtus avec un DFG postnatal normal ou moderement reduit (> 60 mL/min). Le groupe cas regroupait 35 fœtus atteints d’une IR postnatale severe, ou decedes d’une IR terminale ou sujets a une interruption medicale de grossesse (IMG) avec un phenotype renal severe confirme par fœtopathologie. Huit fœtus ont subi une IMG alors que la fœtopathologie montrait des lesions renales compatibles avec la vie. Vingt-huit autres IMG ont ete pratiquees sans que les anatomopathologistes ne puissent se prononcer sur la severite des anomalies. Le contenu peptidique du liquide amniotique a ete analyse par electrophorese capillaire couplee a la spectrometrie de masse. Observation/Resultats La comparaison du peptidome amniotique de 35 controles et 18 cas a permis d’identifier 98 peptides ayant une abondance significativement differente. Ces 98 marqueurs ont ete combines dans un modele mathematique pour generer l’outil pronostique nomme « bCAKUTPep ». Base sur l’attribution d’un score, bCAKUTPep a predit en aveugle la fonction renale postnatale de 51 nouveaux patients (34 controles, 17 cas) avec une sensibilite de 88 % [64 %–98 %], une specificite de 97 % [85 %–100 %] et une aire sous la courbe de ROC (AUC) egale a 0,96 [0,87–1,00]. Ces excellentes performances depassaient celles des parametres echographiques habituellement utilises en clinique comme le volume de liquide amniotique (AUC 0,84 [0,70–0,92], p = 0,03). De maniere tout a fait interessante, bCAKUTPep a egalement predit une bonne fonctionnalite renale pour 6/8 des grossesses interrompues cliniquement a tort, confirmant de ce fait l’analyse fœtopathologique. Discussion/Conclusion Ainsi, en permettant une evaluation objective et quantifiable de la severite des anomalies renales, l’outil predictif bCAKUTPep constituera un veritable soutien au clinicien, ameliorant de ce fait le conseil prenatal et la prise en charge des grossesses CAKUT.

Ureteropelvic junction (UPJ) obstruction is the most frequently observed cause of obstructive nephropathy in children. Neonatal and foetal animal models have been developed that mimic closely what is observed in human disease. The purpose of this review is to discuss how obstructive nephropathy alters kidney histology and function and describe the molecular mechanisms involved in the progression of the lesions, including inflammation, proliferation/apoptosis, renin-angiotensin system activation and fibrosis, based on both human and animal data. Also we propose that during obstructive nephropathy, hydrodynamic modifications are early inducers of the tubular lesions, which are potentially at the origin of the pathology. Finally, an important observation in animal models is that relief of obstruction during kidney development has important effects on renal function later in adult life. A major short-coming is the absence of data on the impact of UPJ obstruction on long-term adult renal function to elucidate whether these animal data are also valid in humans.

Because of its availability, ease of collection, and correlation with physiology and pathology, urine is an attractive source for clinical proteomics/peptidomics. However, the lack of comparable data sets from large cohorts has greatly hindered the development of clinical proteomics. Here, we report the establishment of a reproducible, high resolution method for peptidome analysis of naturally occurring human urinary peptides and proteins, ranging from 800 to 17,000 Da, using samples from 3,600 individuals analyzed by capillary electrophoresis coupled to MS. All processed data were deposited in an Structured Query Language (SQL) database. This database currently contains 5,010 relevant unique urinary peptides that serve as a pool of potential classifiers for diagnosis and monitoring of various diseases. As an example, by using this source of information, we were able to define urinary peptide biomarkers for chronic kidney diseases, allowing diagnosis of these diseases with high accuracy. Application of the chronic kidney disease-specific biomarker set to an independent test cohort in the subsequent replication phase resulted in 85.5% sensitivity and 100% specificity. These results indicate the potential usefulness of capillary electrophoresis coupled to MS for clinical applications in the analysis of naturally occurring urinary peptides.

Resume Grâce a l’echographie prenatale, les reins kystiques sont, avec les uropathies obstructives, les anomalies renales les plus frequemment identifiees au cours de la vie fœtale. Ils recouvrent des entites tres differentes qu’il faut savoir reconnaitre etant donne les implications cliniques et genetiques qui en decoulent. Les plus frequentes sont les polykystoses renales autosomique dominante et recessive, suivies des anomalies kystiques liees aux mutations du gene TCF2/HNF1β . Des kystes renaux sont egalement observes dans d’autres maladies hereditaires ou syndromes polymalformatifs (sclerose tubereuse de Bourneville, syndrome de Meckel-Grubber, syndrome oro-facio-digital, etc.). Le diagnostic repose sur une analyse echographique et morphologique precise des anomalies renales, sur la recherche d’antecedents familiaux et de signes extra-renaux. Une meilleure classification de ces patients permettra a l’avenir de proposer un « suivi sur mesure ».

International audience; Severe inflammation characterizes rapidly progressive glomerulonephritides, and expression of the kinin B1 receptor (B1R) associates with inflammation. Delayed B1R blockade reduces renal inflammation in a model of unilateral ureteral obstruction, but whether B1R modulates the pathophysiology of glomerulonephritides is unknown. Here, we observed an association of B1R protein expression and inflammation, in both glomeruli and the renal interstitium, in biopsies of patients with glomerulonephritides, Henoch-Schönlein purpura nephropathy, and ANCA-associated vasculitis. In the nephrotoxic serum-induced glomerulonephritis model, we observed upregulation of the B1R receptor; treatment with a B1R antagonist beginning 2 weeks after the onset of disease reduced both glomerular and tubular lesions and improved renal function. B1R blockade reduced renal chemokine expression and macrophage accumulation. Collectively, our data demonstrate that blockade of the kinin B1R has significant potential for the treatment of glomerulonephritis.

Background and objectives: Hepatocyte nuclear factor 1β (HNF1β) is a transcription factor that is critical for the development of kidney and pancreas. In humans, mutations in HNF1B lead to congenital anomalies of the kidney and urinary tract, pancreas atrophy, and maturity-onset diabetes of the young type 5 and genital malformations. Design, setting, participants, & measurements: We report HNF1B screening in a cohort of 377 unrelated cases with various kidney phenotypes (hyperechogenic kidneys with size not more than +3 SD, multicystic kidney disease, renal agenesis, renal hypoplasia, cystic dysplasia, or hyperuricemic tubulointerstitial nephropathy not associated with UMOD mutation). Results: We found a heterozygous mutation in 75 (19.9%) index cases, consisting of a deletion of the whole gene in 42, deletion of one exon in one, and small mutations in 32. Eighteen mutations were novel. De novo mutations accounted for 66% of deletions and 40% of small mutations. In patients who carried HNF1B mutation and for whom we were able to study prenatal ultrasonography (56 probands), isolated hyperechogenic kidneys with normal or slightly enhanced size were the more frequent (34 of 56) phenotype before birth. Various other prenatal renal phenotypes were associated with HNF1B mutations, at a lesser frequency. Diabetes developed in four probands. Hyperuricemia and hypomagnesemia, although not systematically investigated, were frequently associated. Conclusions: This large series showed that the severity of the renal disease associated with HNF1B mutations was extremely variable (from prenatal renal failure to normal renal function in adulthood) and was not correlated with the genotype.

International audience; Aging induces morphological changes of the kidney and reduces renal function. We analyzed the low molecular weight urinary proteome of 324 healthy individuals from 2-73 years of age to gain insight on human renal aging. We observed age-related modification of secretion of 325 out of over 5000 urinary peptides. The majority of these changes were associated with renal development before and during puberty, while 49 peptides were related to aging in adults. We therefore focussed the remainder of the study on these 49 peptides. The majority of these 49 peptides were also markers of chronic kidney disease, suggesting high similarity between aging and chronic kidney disease. Blinded evaluation of samples from healthy volunteers and diabetic nephropathy patients confirmed both the correlation of biomarkers with aging and with renal disease. Identification of a number of these aging-related peptides led us to hypothesize that reduced proteolytic activity is involved in human renal aging. Finally, among the 324 supposedly healthy individuals, some had urinary aging-related peptide excretion patterns typical of an individual significantly older than their actual age. In conclusion, these aging-related biomarkers may allow noninvasive detection of renal lesions in healthy persons and show high resemblance between human aging and chronic kidney disease. This similarity has to be taken into account when searching for biomarkers of renal disease.

International audience; Non-invasive prognosis of the clinical progression of disease is of high interest, especially in newborn and children. Neonatal ureteropelvic (UPJ) junction obstruction needs close and invasive surveillance to determine the necessity of pyeloplasty. A number of groups have initiated research with the aim to find non-invasive biomarkers for UPJ obstruction. Two different strategies have been followed. One strategy, based on the knowledge obtained in animal models of UPJ obstruction, has identified a number of individual urinary markers of severe UPJ obstruction. Combining these markers might allow prediction of which patients will require surgery and in which patients UPJ obstruction will spontaneously resolve. The other strategy is based on urinary proteomics. In this strategy the entire urinary proteome is probed for a set of biomarkers that correlates with the degree of UPJ obstruction. In subsequent steps, these sets of urinary biomarkers are used for prediction of the clinical evolution of UPJ obstruction patients. This proteomic-based strategy allowed prediction, several months in advance, of the clinical evolution of neonates with UPJ-obstruction. Both strategies will be complementary and will hopefully replace in the near future the invasive follow-up of newborns with UPJ obstruction.

International audience; Prenatal discovery of fetal bilateral hyperechogenic kidneys is very stressful for pregnant women and their family, and accurate diagnosis of the cause of the moderate forms of this pathology is very difficult. Hepatocyte nuclear factor-1beta that is encoded by the TCF2 gene is involved in the embryonic development of the kidneys. Sixty-two pregnancies with fetal bilateral hyperechogenic kidneys including 25 fetuses with inaccurate diagnosis were studied. TCF2 gene anomalies were detected in 18 (29%) of these 62 patients, and 15 of these 18 patients presented a complete heterozygous deletion of the TCF2 gene. Family screening revealed de novo TCF2 anomalies in more than half of the patients. TCF2 anomalies were associated with normal amniotic fluid volume and normal-sized kidneys between -2 and +2 SD in all patients except for two sisters. Antenatal cysts were detected in 11 of 18 patients, unilaterally in eight of 11. After birth, cysts appeared during the first year (17 of 18), and in patients with antenatal cysts, the number increased and developed bilaterally with decreased renal growth. In these 18 patients, the GFR decreased with longer follow-up and was lower in patients with solitary functioning dysplastic kidney. Heterozygous deletion of the TCF2 gene is an important cause of fetal hyperechogenic kidneys in this study and showed to be linked with early disease expression. The renal phenotype and the postnatal evolution were extremely variable and need a prospective long-term follow-up. Extrarenal manifestations are frequent in TCF2-linked pathologies. Therefore, prenatal counseling and follow-up should be multidisciplinary.

Sir, Mutations in several genes have been identified in congenital abnormalities of kidneys and urinary tract (CAKUT): heterozygous mutations in HNF1β account for 8%, while other genes (PAX2, EYA1, SALL1, SIX1) have been identified as causing isolated renal hypo/dysplasia to a lesser extent in humans [1]. Despite extensive HNF1β molecular analysis, including direct sequencing of the minimal promoter and of the nine exons associated with screening for exonic rearrangement, HNF1β genetic testing failed to identify mutations in a majority of patients with CAKUT, even in individuals with very evocative renal phenotype [2,3]. Recently, specifically conserved cis-acting RARE (retinoic acid responsive element) and T-MARE (MafB responsive element) regulatory sequences have been identified [4]. RA signalling cascade and MafB bind RARE and T-MARE regulatory DNA sequences, respectively, and promote the expression of Hnf1β in both the caudal hindbrain (r4/r5 boundary) and pancreas. These sequences are both located in intron 4 of HNF1β and are not actually studied for the purpose of diagnosis. Finally, the roles of RA and MAFB in kidney development suggest that the RA-MAFB-HNF1β pathway may also be functional in human kidney. In this study, we hypothesized that mutations in the highly conserved (see Figure ​Figure1)1) RARE and T-MARE regulatory sequences could disturb the early embryologic process of intermediate mesoderm, from which kidneys and urinary tract both derived, and consequently lead to renal phenotype mimicking HNF1β-related nephropathy. Fig. 1 Alignment of human, mouse and chick nucleotide sequences from the enhancer of HNF1β (within intron 4): RARE and T-MARE regulatory sequences (boxes). Dashes indicate conserved residues. Among the 63 individuals we tested for HNF1β, a mutation was identified in 12 (19%). We therefore performed molecular analysis of these regulatory sequences in the 51 remaining patients with isolated or syndromic CAKUT of unknown origin for whom previous molecular analysis of HNF1β (QMPSF and direct sequencing) had failed to identify any causative mutation. All patients gave informed consent according to French law. Renal and extra-renal features of the 51 tested patients [31 males, 20 females, median age 9 years (0–53)] are summarized in Tables ​Tables11 and ​and2,2, respectively. RARE and T-MARE regulatory sequences were amplified by PCR using a set of primers deduced from the genomic sequence (forward: TC CCCAGAACCCTCTTCCTA, reverse: TGGTTCAAAGC CCCAACTTA), corresponding to amplification of a 344 bp fragment (G1266–17138 to G1266–16794). Among the 51 tested patients, no sequence variation of the RARE and T-MARE regulatory sequences of HNF1β was evidenced. Table 1 Renal characteristics of 51 patients with CAKUT tested for RARE and T-MARE regulatory sequences of HNF1β Table 2 Extra-renal characteristics of 51 patients with CAKUT tested for RARE and T-MARE regulatory sequences of HNF1β In conclusion, although mutations in RARE and T-MARE regulatory sequences of HNF1β may nevertheless be implicated in some renal congenital disorders, we show here that mutations in these sequences are not a frequent cause of CAKUT. More experiments are required to assess the role of the RA-MAFB-HNF1β pathway in kidney development. Moreover, the molecular basis of these renal malformations is still poorly understood, and further works remain to be done to identify new CAKUT genes. Delineation of transcriptional networks involved in early human metanephros development may be a way to identify these new genes. Conflict of interest statement. None declared.

Varicella Zoster Virus (VZV) is a well-known virus that belongs to the Herpesviridae family which induces a self-limited disease except in specific cases in particular among stem cell transplant patients. This virus is not known however to trigger atypical Hemolytic Uremic Syndrome (aHUS). Here we report the case of a six-year-old boy who was hospitalized with fever and abdominal pains associated to pruritic and vesicular rash, thrombocytopenia and acute renal failure. He was diagnosed with aHUS precipitated by varicella virus. He was treated by an association of antimicrobials against potential superinfections, plasmapheresis and eculizumab for curative aHUS treatment. This was effective but after 6 months the kidney function remained poor. The current case describes an aHUS associated to varicella infection as demonstrated by the simultaneous occurrence of the viral infection and aHUS manifestations. Apart from typical Hemolytic Uremic Syndrome which is triggered by bacteria mostly Shiga toxin producing Echerichia coli and Streptococcus pneumoniae or Shigella, aHUS may be linked to viral infections such as HIV, EBV and enteroviruses, but very rarely by varicella. This case highlights a possible even rare complication of varicella infection a very common childhood disease. This complication could be avoided by to anti-VZV vaccination.

Resume Les E. coli restent de loin l‘espece bacterienne dominante dans les bacteriuries lors des infections urinaires et des pyelonephrites aigues (PNA) en pediatrie. La sensibilite aux antibiotiques des 506 souches d’ E. coli urinaires isolees lors d’un premier episode infectieux a l’admission a l’hopital des Enfants de Toulouse entre le 1 juin 2002 et le 1 juin 2003 a ete analysee. Alors que 53 % des souches etaient resistantes a l’amoxicilline, pour l’association amoxicilline–acide clavulanique trois populations se distinguaient : souches resistantes 7 %, intermediaires 40 % et sensibles 53 %. La resistance au cotrimoxazole n’interessait que 22 % des souches et aux nitrofuranes que 7 %. En ce qui concerne les cephalosporines de troisieme generation (CIIIG), seulement cinq souches (1 %) presentaient une resistance a la ceftazidime et a la cefotaxime tout en restant sensibles a la ceftriaxone et au cefepime. La decouverte preoccupante de cinq souches de « resistance superieure », productrices plus ou moins abondamment de penicillinases et cephalosporinases, est restee rare. Quel que soit le type de resistance suggere, les resultats ont conforte le choix de l’association ceftriaxone + gentamicine comme strategie d’antibiotherapie dans les PNA, adaptee a l’ecologie bacterienne locale.

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

Introduction La dysplasie fibromusculaire arterielle (DFM) est la principale cause d’HTA d’origine renovasculaire chez l’enfant. Les troncs supra-aortiques (TSA) sont parfois concernes. Objectifs et methodes Evaluer la prevalence et decrire l’atteinte des TSA chez des enfants ayant une stenose de l’artere renale (SAR). Un questionnaire a ete envoye aux centres pediatriques. L’evaluation de la prevalence de l’atteinte des TSA n’a ete faite qu’a l’hopital Necker sur la periode 1985–2015. Resultats Dix-neuf patients ont ete suivis dans 7 centres pour une HTA en rapport avec une SAR associee a une stenose des TSA. L’âge moyen au diagnostic etait de 3,4 ans (10 jours-11 ans). L’HTA etait le mode de revelation dans 7 cas (63 %). Chez 2 patients (37 %) la maladie est revelee par un accident vasculaire cerebral. La stenose est situee sur l’artere renale principale dans 15 cas (80 %) (10/15 unilaterale et 5/15 bilaterale). Quinze patients sur 19 (79 %) avaient une atteinte de l’artere carotide interne (7/15 atteinte isolee). Douze patients sur 19 (63 %) avaient une atteinte du polygone de Willis. Un aspect Moyamoya est associe dans 8 cas (42 %). Cinq patients sur 19 sont decedes, 4 fois par ischemie cerebrale (1/4 pendant une procedure anesthesique, 3/4 par instabilite hemodynamique durant la periode postoperatoire) et un patient est decede d’infarctus du myocarde. A l’hopital Necker parmi les 35 patients ayant une SAR, 14 (40 %) avaient une atteinte des TSA. Dix patients sur 14 (71 %) avaient une DFM isolee, 3/14 (22 %) une maladie de Takayasu et 1/14 (7 %) une neurofibromatose NF-1. Conclusions Le pronostique est defavorable chez les patients avec atteinte diffuse des arteres intracrânienes. La pression arterielle doit etre maintenue a un niveau relativement eleve specialement au cours des procedures anesthesiques et en periode post-operatoire.

Introduction Le rituximab (RTX) a prouve son efficacite dans la prise en charge des syndromes nephrotiques idiopathiques cortico-dependants (SNCD) mais ces modalites d’administration ne sont pas clairement definies. Notre travail consiste a comparer l’efficacite et la tolerance du RTX chez des patients ayant recu 1 versus 2 injections lors de la cure initiale. Materiels et methodes Nous avons realise une etude retrospective multicentrique francaise incluant 38 enfants (18 filles et 20 garcons) traites par RTX pour un SNCD. Vingt et un enfants ont recu une seule injection de RTX a 375 mg/m2 (groupe 1) et 17 enfants ont recu 2 injections de RTX a 375 mg/m2 a 1 semaine d’intervalle (groupe 2) lors de la cure initiale. Nous avons etudie la duree de la depletion en cellules CD19+, le delai de survenue d’une rechute et la tolerance du traitement. Resultats Au moment de la premiere injection de RTX la duree moyenne d’evolution du SNCD etait de 6,3 ± 3,6 annees et l’âge moyen des enfants de 11,7 ± 2,5 ans. Il n’y avait aucune difference significative entre les 2 groupes au niveau de la duree moyenne de depletion en cellules CD19+ (154,3 ± 41 jours dans le groupe 1, 152,2 ± 33 jours dans le groupe 2, p = 0,889), du delai de survenue d’une rechute (119 ± 36 jours dans le groupe 1, 143 ± 31,1 jours dans le groupe 2, p = 0,489) et de la tolerance du traitement. Conclusion Notre etude montre qu’il n’y a pas de difference significative sur la duree de depletion en CD19+, le delai de survenue d’une rechute et la tolerance du traitement entre 1 versus 2 injections de RTX lors de la cure initiale dans le cadre du traitement du SNCD.

Two hundred E. coli strains isolated from children with pyelonephritis were investigated for the presence of six virulence factors. The used primers amplified adhesin pap and sfa, toxin haemolysin (hly) and cytotoxic necrotizing factor 1 (cnf1) and aerobactin (aer). For afimbrial adhesin, the previously used set of primers could not allow to detect the newly reported afa operons (Le Bouguenec et al., 2001). With a new set of primers specific for the afa operon family the prevalence of afa+ strains increased from 3.5% to 13.5%. Combinations of three or more factors in a same strain were found in 48.5%. Thirty two different urovirulent genotypes were observed; two strains contained the six studied factors.

Background Data on anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis are scarce in children. The current study is aimed at describing the clinical features and outcomes of childhood-onset ANCA-associated vasculitis (AAV). Methods We conducted a retrospective French multicentre study involving patients in whom AAV was diagnosed before the age of 18 years. Inclusion criteria were (i) granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) according to classification criteria of the European League Against Rheumatism/Paediatric Rheumatology European Society, and (ii) ANCA positivity. Patient and renal survival were analysed. Results Among 66 children included, 80% were female, 42% had GPA and 58% MPA including renal-limited vasculitis, 67% were pANCA+ and 33% cANCA+. The mean incidence of reported cases increased to 0.45 per million children/year in the period 2006-10. Median age at diagnosis was 11.5 years, and median time to diagnosis was 1 month. Initial symptoms included fever and fatigue (79%), skin lesions (41%), arthritis (42%), pulmonary (45%) and renal involvement (88%). Clinical features were similar between GPA and MPA with the exception of upper airway impairment (28%) specific of GPA. Ninety percent of the patients achieved remission after induction treatment. After a median follow-up of 5.2 years, 4 patients (6%) died, corresponding to a mortality rate of 1.2 per 100 person-years, and 22 patients (34%) developed end-stage renal disease (ESRD). Renal survival was 74, 70 and 59% at 1, 5 and 10 years, respectively. In a multivariable Cox regression model, baseline glomerular filtration rate, ethnic origin, histopathological classification and era of treatment were associated with the occurrence of ESRD. Relapse-free survival was 57% at 5 years and 34% at 10 years of follow-up. Patient and renal outcome did not significantly differ between GPA and MPA. Conclusion Childhood-onset AAV is a rare disease characterized by female predominance, delayed diagnosis, frequent renal impairment and a high remission rate. Baseline GFR and new histopathological classification system are strong predictors of ESRD. Renal survival in childhood AAV has improved over time.

Joint Bone Spine - In Press.Proof corrected by the author Available online since mercredi 9 decembre 2015

BACKGROUND AND OBJECTIVES: Cystinuria is an autosomal recessive disorder affecting renal cystine reabsorption; it causes 1% and 8% of stones in adults and children, respectively. This study aimed to determine epidemiologic and clinical characteristics as well as comorbidities among cystinuric patients, focusing on CKD and high BP. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective study was conducted in France, and involved 47 adult and pediatric nephrology and urology centers from April 2010 to January 2012. Data were collected from 442 cystinuric patients. RESULTS: Median age at onset of symptoms was 16.7 (minimum to maximum, 0.3-72.1) years and median diagnosis delay was 1.3 (0-45.7) years. Urinary alkalinization and cystine-binding thiol were prescribed for 88.8% and 52.2% of patients, respectively, and 81.8% had at least one urological procedure. Five patients (1.1%, n=4 men) had to be treated by dialysis at a median age of 35.0 years (11.8-70.7). Among the 314 patients aged ≥16 years, using the last available plasma creatinine, 22.5% had an eGFR≥90 ml/min per 1.73 m(2) (calculated by the Modification of Diet in Renal Disease equation), whereas 50.6%, 15.6%, 7.6%, 2.9%, and 0.6% had an eGFR of 60-89, 45-59, 30-44, 15-29, and

Introduction Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), is an effective treatment in lupus nephritis. Therapeutic drug monitoring studies of MMF suggest that area under the concentration-time curve (AUC) values of MPA of 30–45 mg.h/L may be associated with better outcome in adults with lupus but data in children is scarce. Methods In this retrospective study, 27 children were treated with MMF for biopsy proven class III–IV–V lupus nephritis between 2009 and 2016. AUC of MPA was determined on the basis of sampling times at 20, 60, and 180 minutes post-dose using a Bayesian estimator. In 25 children, AUC was performed within 6 months after kidney biopsy and MMF initiation. Treatment response at 6 months of MMF treatment was defined as follows: normal or improved GFR by 25% compared to baseline, 50% reduction of proteinuria resulting in a level Results In total, 62 AUC of MPA were analyzed [median 44 mg.h/L (IQR 33–54)] in 27 patients. The findings indicate individual dose adaptation in 32 cases (52%) to achieve an AUC target of 30–60 mg.h/L. At 6 months, 14/25 patients were defined as responders (56%) with a median AUC value of 49 [40–59] and 11/25 as non-responders (44%) with a median AUC value of 29 [24–38]. Patients with MPA AUC levels of > 45, 30–45, and 45 was significantly associated with therapeutic response (OR 3.9, 95% CI 2.4–10.5, P Conclusion Therapeutic drug monitoring leading to individualize dosing may improve the efficacy of MMF. An AUC of MPA > 45 mg.h/L is associated with a better response rate and may be considered as a target value in paediatric lupus nephritis.

Introduction Les frontieres nosologiques des dermatoses neutrophiliques (DN) de l’adulte ont evolue vers un chevauchement avec les syndromes auto-inflammatoires (SAI) monogeniques. Notre objectif etait de decrire les aspects anatomocliniques, systemiques et therapeutiques des DN pediatriques de type pyoderma gangrenosum (PG) et syndrome de Sweet (SS). Materiel et methodes Etude retrospective multicentrique francaise incluant les PG et SS pediatriques definis en formes typiques ou atypiques selon des criteres anatomocliniques preetablis a partir des donnees de la litterature. La maladie neutrophilique extracutanee (MN) et les maladies generales (MG) associees ont ete decrites. Resultats Au total, 17 PG et 10 SS ont ete inclus (âge median 6,2 ans). La DN evoluait par poussees dans 59 % des cas, etait multiple (> 5 lesions dans 52 % des cas) et disseminee (≥ 3 sites dans 71 % des cas). Une DN atypique etait retrouvee chez 59 % des enfants avec une proportion diminuant avec l’âge : 90 % chez les 0–2 ans, 60 % chez les 3–6 ans et 30 % chez les plus de 10 ans. Les SS typiques etaient plus frequents chez les moins de 6 ans par rapport aux plus âges, les PG typiques etant retrouves seulement chez les plus de 10 ans. 63 % des enfants avaient une MN (80 % chez les SS et 53 % chez les PG, p = 0,1). Tous les organes pouvaient etre atteints, 2 exclusivement dans la tranche d’âge 0–2 ans : laryngotracheale severe (n = 3) et cardiaque (n = 3) dont une perforation mitrale. 70 % des enfants avaient une MG : 2 SAI monogeniques de type syndrome Pyogenic Arthritis Pyoderma Acne (PAPA) atypique, 2 deficits immunitaires et 2 syndromes non encore identifies chez les 0–2 ans ; 1 polyangeite microscopique, 1 maladie de Basedow et 1 leucemie myelomonocytaire chronique juvenile (gene CBL mute) chez les 3–6 ans ; 9 MICI et 1 maladie de Behcet chez les plus de 10 ans. Le traitement de la DN etait instaure entre 2 et 322 jours apres l’apparition des lesions cutanees. La corticotherapie generale en monotherapie n’a pas permis la remission cutanee dans 85 % des cas. Une biotherapie avec ou sans corticoides a permis une remission a chaque fois (11 poussees cutanees). Discussion SS et PG de l’enfant appartiennent au meme spectre anatomoclinique, epidemiologique et physiopathologique avec d’autant moins de formes typiques que la dermatose debute tot dans la vie. Les specificites pediatriques sont : le polymorphisme de la MN dont l’atteinte laryngotracheale du petit enfant ; un etat predisposant frontiere entre auto-inflammation, auto-immunite et deficit immunitaire ; une corticosensibilite inconstante. Il s’agit d’une des series les plus importantes existantes, proposant d’analyser la MN dans sa globalite et confirmant la frequence des MG mono ou polygeniques chez ces enfants. Conclusion Il faut evoquer une DN pediatrique devant une clinique polymorphe, depister MN et MG par un bilan adapte, un suivi prolonge et traquer un terrain genetiquement determine surtout chez les moins de 2 ans.

Over the last few decades, the number of pregnant women under immunosuppressive (IS) therapy following transplantation or autoimmune diseases has increased. At first, IS drugs, including prednisone, azathioprine, and cyclosporine A were used, but now new molecules such as tacrolimus and mycophenolate mofetil have appeared. These IS drugs cross the placental barrier and enter into the fetal circulation, which poses a risk for fetal development. Experimental data have shown that IS drugs often have deleterious effects on fetuses, while human data have reported an increased rate of abortion, prematurity, intrauterine growth retardation (IUGR), and low birth weight, without significant increases in malformation rates. However, only limited information is available about the newly used molecules. Although fetal and neonatal data are reassuring, long-term effects of IS drugs on fertility, immune response and renal function, as well as the consequences of prematurity and IUGR, should be monitored.

Obstructive nephropathy is a frequently encountered situation in newborns. In previous studies, the urinary peptidome has been analyzed for the identification of clinically useful biomarkers of obstructive nephropathy. However, the urinary proteome has not been explored yet and should allow additional insight into the pathophysiology of the disease. We have analyzed the urinary proteome of newborns (n = 5/group) with obstructive nephropathy using label free quantitative nanoLC-MS/MS allowing the identification and quantification of 970 urinary proteins. We next focused on proteins exclusively regulated in severe obstructive nephropathy and identified Arginase 1 as a potential candidate molecule involved in the development of obstructive nephropathy, located at the crossroad of pro- and antifibrotic pathways. The reduced urinary abundance of Arginase 1 in obstructive nephropathy was verified in independent clinical samples using both Western blot and MRM analysis. These data were confirmed in situ in kidneys obtained from a mouse obstructive nephropathy model. In addition, we also observed increased expression of Arginase 2 and increased total arginase activity in obstructed mouse kidneys. mRNA expression analysis of the related arginase pathways indicated that the pro-fibrotic arginase-related pathway is activated during obstructive nephropathy. Taken together we have identified a new actor in the development of obstructive nephropathy in newborns using quantitative urinary proteomics and shown its involvement in an in vivo model of disease. The present study demonstrates the relevance of such a quantitative urinary proteomics approach with clinical samples for a better understanding of the pathophysiology and for the discovery of potential therapeutic targets.