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1. Efficacy and safety of intravenous immunoglobulin with rituximab versus rituximab alone in childhood-onset steroid-dependent and frequently relapsing nephrotic syndrome: protocol for a multicentre randomised controlled trial

Author

Djamal Djeddi, Julien Hogan, Aubriana Perez, Anne-Laure Sellier-Leclerc, Isabelle Vrillon, Francoise Broux, Francois Nobili, Jerome Harambat, Lucie Bessenay, V Audard, Camille Faudeux, Denis Morin, Christine Pietrement, Stephanie Tellier, Philippe Eckart, Annie Lahoche, G Roussey-Kesler, Tim Ulinski, Olivia Boyer, Emmanuelle Plaisier, Sylvie Cloarec, Anne Jolivot, Vincent Guigonis, Sophie Guilmin-Crepon, Veronique Baudouin, Claire Dossier, and Georges Deschênes

Subjects
Medicine
Abstract

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.

Published
2020
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2. The genetic landscape and clinical spectrum of nephronophthisis and related ciliopathies

Author

Friederike Petzold, Katy Billot, Xiaoyi Chen, Charline Henry, Emilie Filhol, Yoann Martin, Marina Avramescu, Maxime Douillet, Vincent Morinière, Pauline Krug, Cécile Jeanpierre, Kalman Tory, Olivia Boyer, Anita Burgun, Aude Servais, Remi Salomon, Alexandre Benmerah, Laurence Heidet, Nicolas Garcelon, Corinne Antignac, Mohamad Zaidan, Sophie Saunier, Tania Attié-Bitach, Valerie Comier-Daire, Jean-Michel Rozet, Yaacov Frishberg, Brigitte Llanas, Michel Broyer, Nabil Mohsin, Marie-Alice Macher, Nicole Philip, Véronique Baudouin, Damian Brackman, Chantal Loirat, Marina Charbit, Maud Dehennault, Claude Guyot, Pierre Bataille, Mariet Elting, Georges Deschenes, Andrea Gropman, Geneviève Guest, Marie-France Gagnadoux, Philippe Nicoud, Pierre Cochat, Bruno Ranchin, Albert Bensman, Anne-Marie Guerrot, Bertrand Knebelmann, Ilmay Bilge, Danièle Bruno, Stéphane Burtey, Caroline Rousset Rouvière, Valérie Caudwell, Denis Morin, Hélène Dollfus, Anne Maisin, Christian Hamel, Eric Bieth, Sophie Gie, Judith Goodship, Gwenaelle Roussey, Hermine La Selve, Hubert Nivet, Lucie Bessenay, Mathilde Caillez, Jean Bernard Palcoux, Stéphane Benoît, Philippe Dubot, Marc Fila, Fabienne Giuliano, Daouya Iftene, Michele Kessler, Theresa Kwon, Anine Lahoche, Audrey Laurent, Anne-Laure Leclerc, David Milford, Thomas Neuhaus, Sylvie Odent, Philippe Eckart, Dominique Chauveau, Patrick Niaudet, Horacio Repetto, Sophie Taque, Alexandra Bruel, Alexandra Noel-Botte, Emma Allain Launay, Lisa Allard, Dany Anlicheau, Anne-Laure Adra, Arnaud Garnier, Arvind Nagra, Remy Baatard, Justine Bacchetta, Banu Sadikoglu, Christine Barnerias, Anne Barthelemy, Lina Basel, Nader Bassilios, Hedi Ben Maiz, Fatma Ben Moussa, Faïza Benmati, Romain Berthaud, Aurélia Bertholet, Dominique Blanchier, Jean Jacques Boffa, Karim Bouchireb, Ihab Bouhabel, Zakaria Boukerroucha, Guylhène Bourdat-Michel, Odile Boute, Karine Brochard, Roseline Caumes, Siham Chafai Elalaoui, Bernard Chamontin, Marie Caroline Chastang, Christine Pietrement, Christine Richer, Christophe Legendre, Karin Dahan, Fabienne Dalla-Vale, Damien Thibaudin, Maxime Dauvergne, Salandre Davourie, Martin Debeukelaer, Jean Daniel Delbet, Constantinos Deltas, Denis Graber, Nadège Devillars, Boucar Diouf, Martine Doco Fenzy, Jean-Luc André, Dominique Joly, Alan Fryer, Laetitia Albano, Elisabeth Cassuto, Aline Pincon, Ana Medeira, Annabelle Chaussenot, Anne Mensire-Marinier, Francois Bouissou, Stephane Decramer, Armand Bottani, Aurélie Hummel, Alexandre Karras, Avi Katz, Christine Azema, Bénédicte Janbon, Bernard Roussel, Claude Bonniol, Christiophe Mariat, Gérard Champion, Deborah Chantreuil, Nicolas Chassaing, Christiane Mousson, Christine Baudeau, Delphine Hafdar Cuntz, Cyril Mignot, Laurene Dehoux, Didier Lacombe, Thierry Hannedouche, Elodie Mérieau, Emmanuelle Charlin, Eric Gauthier, Florent Plasse, Stanislas Faguer, Fanny Lebas, Florence Demurger, Francesco Emma, François Cartault, Geneviève Dumont, Nathalie Godefroid, Vincent Guigonis, Sophie Hillaire, Jaap Groothoff, Jan Dudley, Noémie Jourde-Chiche, Khalil El Karoui, Saoussen Krid, Krier Coudert, Larbi Bencheick, Laurent Yver, Marie-Pierre Lavocat, Le Monies De Sagazan, Valerie Leroy, Lise Thibaudin, Liz Ingulli, Lorraine Gwanmesia, Lydie Burglen, Marie-Hélène Saïd-Menthon, Marta Carrera, Mathilde Nizon, Catherine Melander, Michel Foulard, Monique Blayo, Jacques Prinseau, Nadine Jay, Nathalie Brun, Nicolas Camille, François Nobili, Olivier Devuyst, Ouafa Ben Brahim, Paloma Parvex, Laurence Perrin Sabourin, Philippe Blanc, Philippe Vanhille, Pierre Galichon, Sophie Pierrepont, Vincent Planquois, Gwenaelle Poussard, Claire Pouteil Noble, Radia Allal, Raphaelle Bernard, Raynaud Mounet, Rémi Cahen, Renaud Touraine, Claire Rigothier, Amélie Ryckewaert, Mathieu Sacquepee, Salima El Chehadeh, Charlotte Samaille, Shuman Haq, Ari Simckes, Stéphanie Lanoiselée, Stephanie Tellier, Jean-François Subra, Sylvie Cloarec, Julie Tenenbam, Thomas Lamy, Valérie Drouin Garraud, Huguette Valette, Vanina Meyssonnier, Rosa Vargas-Poussou, Yves Snajer, Sandrine Durault, Emmanuelle Plaisier, Etienne Berard, Fadi Fakhouri, Ferielle Louillet, Paul Finielz, Michel Fischbach, Bernard Foliguet, Hélène Francois-Pradier, Florentine Garaix, Marion Gerard, Gianfranco Rizzoni, Brigitte Gilbert, Denis Glotz, Astrid Godron Dubrasquet, Jean-Pierre Grünfeld, Guillaume Bollee, Michelle Hall, Sverker Hansson, Damien Haye, Hélène Taffin, Friedhelm Hildebrandt, Maryvonne Hourmand, Hümya Kayserili, Ivan Tack, Marie Line Jacquemont, Jennifer Fabre-Teste, Cliff Kashtan, Kkoen Van Hoeck, Alexandre Klein, Yannick Knefati, Nine Knoers, Martin Konrad, Alain Lachaux, Isabelle Landru, Gilbert Landthaler, Philippe Lang, Patrick Le Pogamp, Tristan Legris, Catherine Didailler, Thierry Lobbedez, Loïc de Parscau, Lucile Pinson, Hervé Maheut, Marc Duval-Arnould, Marlène Rio, Marie-Claire Gubler, Pierre Merville, Guillaume Mestrallet, Maite Meunier, Karine Moreau, Jérôme Harambat, Graeme Morgan, Georges Mourad, Niksic Stuber, Odile Boespflug-Tanguy, Olivier Dunand, Olivier Niel, Nacera Ouali, Paolo Malvezzi, Pauline Abou Jaoude, Solenne Pelletier, Julie Peltier, M.B. Petersen, Philippe Michel, Philippe Rémy, Jean-Baptiste Philit, Valérie Pichault, Thierry Billette de Villemeur, Bernard Boudailliez, Bruno Leheup, Claire Dossier, Djamal-Dine Djeddi, Yves Berland, Bruno Hurault de Ligny, Susan Rigden, Christophe Robino, Annick Rossi, Sabine Sarnacki, Messaoud Saidani, Albane Brodin Sartorius, Elise Schäfer, Sztriha Laszlo, Marie-Christine Thouret, Angélique Thuillier-Lecouf, Howard Trachtman, Claire Trivin, Michel Tsimaratos, Rita Van Damme-Lombaerts, Marjolaine Willems, Michel Youssef, Ariane Zaloszyc, Alexis Zawodnik, and Marie-Julia Ziliotis

Subjects
Nephrology
Abstract

Nephronophthisis (NPH) is an autosomal-recessive ciliopathy representing one of the most frequent causes of kidney failure in childhood characterized by a broad clinical and genetic heterogeneity. Applied to one of the worldwide largest cohorts of patients with NPH, genetic analysis encompassing targeted and whole exome sequencing identified disease-causing variants in 600 patients from 496 families with a detection rate of 71%. Of 788 pathogenic variants, 40 known ciliopathy genes were identified. However, the majority of patients (53%) bore biallelic pathogenic variants in NPHP1. NPH-causing gene alterations affected all ciliary modules defined by structural and/or functional subdomains. Seventy six percent of these patients had progressed to kidney failure, of which 18% had an infantile form (under five years) and harbored variants affecting the Inversin compartment or intraflagellar transport complex A. Forty eight percent of patients showed a juvenile (5-15 years) and 34% a late-onset disease (over 15 years), the latter mostly carrying variants belonging to the Transition Zone module. Furthermore, while more than 85% of patients with an infantile form presented with extra-kidney manifestations, it only concerned half of juvenile and late onset cases. Eye involvement represented a predominant feature, followed by cerebellar hypoplasia and other brain abnormalities, liver and skeletal defects. The phenotypic variability was in a large part associated with mutation types, genes and corresponding ciliary modules with hypomorphic variants in ciliary genes playing a role in early steps of ciliogenesis associated with juvenile-to-late onset NPH forms. Thus, our data confirm a considerable proportion of late-onset NPH suggesting an underdiagnosis in adult chronic kidney disease.

Published
2023

3. Bi-allelic mutations in renin-angiotensin system genes, associated with renal tubular dysgenesis, can also present as a progressive chronic kidney disease

Author

Marc Fila, Joelle Terzic, Philippe Eckart, Laurence Heidet, Vincent Morinière, Marie-Claire Gubler, and Corinne Antignac

Subjects
Male, Nephrology, medicine.medical_specialty, Pathology, Adolescent, Anemia, 030232 urology & nephrology, Disease, 030204 cardiovascular system & hematology, urologic and male genital diseases, Kidney Tubules, Proximal, Renin-Angiotensin System, 03 medical and health sciences, 0302 clinical medicine, Nephronophthisis, Internal medicine, medicine, Humans, Renal Insufficiency, Chronic, Allele, Loss function, biology, business.industry, Infant, Newborn, Angiotensin-converting enzyme, medicine.disease, Child, Preschool, Urogenital Abnormalities, Mutation, Pediatrics, Perinatology and Child Health, biology.protein, Female, business, Kidney disease
Abstract

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. 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. 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.

Published
2020

4. Amniotic fluid peptides predict postnatal kidney survival in developmental kidney disease

Author

Romain Favre, Marie-Pierre Lavocat, Bernard Boudailliez, Charlotte Lucas, Camille Fédou, Jean-Sebastien Saulnier Blache, Anne-Sophie Weingertner, Blandine Hougas, Joost P. Schanstra, Pascal Gaucherand, Sylvie Cloarec, Julie Batut, Catherine Noel, J. Gondry, Philippe Eckart, Norbert Winer, Benjamin Breuil, Gérard Champion, Jean-Baptiste Benevent, Franck Perrotin, Christophe Vayssière, Florence Biquard, Harald Mischak, Gwenaelle Le Bouar, Jérôme Massardier, Françoise Conte Auriol, Pedro Magalhães, Sophie Martin, Jean-Paul Bory, Sophie Collardeau-Frachon, Eve Mousty, Lucie Bessenay, Corinne Floch, Julie Klein, Amelie Ryckewaert, Elisabeth Simon, Alain Martin, Guylène Bourdat-Michel, Marie-Françoise Froute, Franz Schaefer, Pascale Marcorelles, Stéphane Decramer, Nabila Moussaoui, Franck Boizard, Marie-Christine Manca-Pellissier, Mariannick Maupin-Hyvonnet, Marion Groussolles, Jean-Marie Delbosc, Guylène Feuillet, Anke Raaijmakers, François Nobili, Sophie Taque, Petra Zürbig, Vincent Guigonis, Audrey Casemayou, Patrick Blader, An Hindryckx, Luc Decatte, Karel Allegaert, Ophélie Lescat, Eric Neau, Odile Basmaison, Emma Allain-Launay, Agnes Sartor, Jean-Loup Bascands, Claudine Le Vaillant, Hélène Laurichesse Delmas, Bénédicte Buffin-Meyer, Nadia Lounis, Anne-Hélène Saliou, Véronique Baudouin, Elena Levtchenko, Maryse Fiorenza, Christine Pietrement, Valérie Goua, Marina Merveille, Laurent Bidat, Yves Aubard, Alexandra Benachi, Sylvie Kessler, Loic De Parscau, Jean-François Oury, Fabienne Prieur, Centre de biologie du développement (CBD), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Equipe 7 Inserm U1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées, University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Laboratoire de Gérontechnologie [Hôpital La Grave-CHU de Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Gérontopôle, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Gatien de Clocheville [Tours] (CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Clermont-Ferrand, Centre hospitalier universitaire de Nantes (CHU Nantes), Groupe de Recherche sur l'Analyse Multimodale de la Fonction Cérébrale - UMR INSERM_S 1105 (GRAMFC), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Amiens-Picardie, Centre Hospitalier Universitaire de Nice (CHU Nice), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Centre Hospitalier René Dubos [Pontoise], Hôpital Louis Mourier - AP-HP [Colombes], Centre Hospitalier Universitaire [Grenoble] (CHU), Les Hôpitaux Universitaires de Strasbourg (HUS), AP-HP Hôpital universitaire Robert-Debré [Paris], Centre Hospitalier Universitaire de Reims (CHU Reims), Hospices Civils de Lyon (HCL), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Centre de dépistage des Carmes [Toulouse] (CDC), Hôpital des Enfants, CHU Toulouse [Toulouse], Laboratoire sur les interactions Epithéliums Neurones (LIEN), Université de Brest (UBO), Département de Pathologie [CHU Lyon-Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Mosaiques Diagnostics & Therapeutics AG [Hannover, Germany], University of Glasgow, Hannover Medical School [Hannover] (MHH), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Heidelberg University, Centre De Référence des Maladies Rénales Rares du Sud Ouest (SORARE), Centre De Référence des Maladies Rénales Rares du Sud Ouest, BIOMAN consortium: Karel Allegaert, Yves Aubard, Odile Basmaison, Jean-Baptiste Benevent, Florence Biquard, Gérard Champion, Jean-Marie Delbosc, Philippe Eckart, Marie-Françoise Froute, Pascal Gaucherand, Marion Groussolles, Vincent Guigonis, Blandine Hougas, Gwenaelle Le Bouar, Alain Martin, Sophie Martin, Mariannick Maupin-Hyvonnet, Marina Merveille, Eve Mousty, François Nobili, Amelie Ryckewaert, Agnes Sartor, Sophie Taque, Norbert Winer, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Development and Regeneration, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Gérontopôle-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse], Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clocheville, Department of Pediatric and Prenatal Radiology, Timone's Children-Hospital (APHM), Hôpital Dupuytren [CHU Limoges], CHU Toulouse, Hôpital des Enfants, Unité de Gastroentérologie, Hépatologie et Nutrition, Département de Pédiatrie, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Groupement Hospitalier Est [Bron], University Medical Center Heidelberg, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Saulnier-Blache, Jean Sébastien, Pôle Gériatrie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), and Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Amniotic fluid, Urinary system, [SDV]Life Sciences [q-bio], congenital anomalies of the kidney and the urinary tract, 030232 urology & nephrology, Kidney, Fetal Kidney, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, medicine, Animals, Humans, termination of pregnancy, Prospective Studies, Child, Urinary Tract, Zebrafish, ComputingMilieux_MISCELLANEOUS, Fetus, business.industry, infants, Area under the curve, amniotic fluid, prediction, medicine.disease, 3. Good health, Pronephros, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Nephrology, Urogenital Abnormalities, peptides, Female, Kidney Diseases, business, management, Kidney disease
Abstract

Although a rare disease, bilateral congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of end stage kidney disease in children. Ultrasound-based prenatal prediction of postnatal kidney survival in CAKUT pregnancies is far from accurate. To improve prediction, we conducted a prospective multicenter peptidome analysis of amniotic fluid spanning 140 evaluable fetuses with CAKUT. We identified a signature of 98 endogenous amniotic fluid peptides, mainly composed of fragments from extracellular matrix proteins and from the actin binding protein thymosin-β4. The peptide signature predicted postnatal kidney outcome with an area under the curve of 0.96 in the holdout validation set of patients with CAKUT with definite endpoint data. Additionally, this peptide signature was validated in a geographically independent sub-cohort of 12 patients (area under the curve 1.00) and displayed high specificity in non-CAKUT pregnancies (82 and 94% in 22 healthy fetuses and in 47 fetuses with congenital cytomegalovirus infection respectively). Change in amniotic fluid thymosin-β4 abundance was confirmed with ELISA. Knockout of thymosin-β4 in zebrafish altered proximal and distal tubule pronephros growth suggesting a possible role of thymosin β4 in fetal kidney development. Thus, recognition of the 98-peptide signature in amniotic fluid during diagnostic workup of prenatally detected fetuses with CAKUT can provide a long-sought evidence base for accurate management of the CAKUT disorder that is currently unavailable. ispartof: KIDNEY INTERNATIONAL vol:99 issue:3 pages:737-749 ispartof: location:United States status: published

Published
2020

5. School level of children carrying a HNF1B variant or a deletion

Author

Annie Lahoche, Pierre Cochat, Cécile Saint-Martin, Isabelle Vrillon, Sylvie Cloarec, Philippe Eckart, Marie-Pierre Lavocat, Gwenaelle Roussey, Olivier Dunand, Brigitte Llanas, J. Tenenbaum, Vincent Guigonis, François Nobili, Nicolas Chassaing, Véronique Baudouin, Christine Bellanné-Chantelot, Laurence Heidet, Loïc De Parscau, Laurence Michel-Calemard, Christine Pietrement, Valérie Bonneville, Stéphane Decramer, Michel Tsimaratos, Fanny Lalieve, Claire Bahans, Nicolas Rodier, Françoise Broux, Vincent Morinière, and Lucie Bessenay

Subjects
Male, Pediatrics, medicine.medical_specialty, Adolescent, Prenatal counseling, Population, Kidney, Article, Academic Performance, Genetics, medicine, Humans, In patient, School level, Child, education, Prospective cohort study, Genetics (clinical), Hepatocyte Nuclear Factor 1-beta, education.field_of_study, business.industry, Neuropsychology, Syndrome, HNF1B, Neurodevelopmental Disorders, Female, business, Gene Deletion, Neuropsychiatric disease
Abstract

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.

Published
2019

6. Efficacy and safety of intravenous immunoglobulin with rituximab versus rituximab alone in childhood-onset steroid-dependent and frequently relapsing nephrotic syndrome: protocol for a multicentre randomised controlled trial

Author

Julien Hogan, Lucie Bessenay, Sylvie Cloarec, Stéphanie Tellier, Annie Lahoche, Camille Faudeux, Françoise Broux, Aubriana Perez, Djamal Djeddi, Claire Dossier, Isabelle Vrillon, Christine Pietrement, François Nobili, Jérôme Harambat, Anne Jolivot, Emmanuelle Plaisier, Georges Deschênes, S. Guilmin-Crépon, Olivia Boyer, Vincent Audard, Tim Ulinski, Véronique Baudouin, Philippe Eckart, Denis Morin, Anne-Laure Sellier-Leclerc, Gwenaëlle Roussey-Kesler, Vincent Guigonis, Hôpital Robert Debré, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Henri Mondor, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), and Université Sorbonne Paris Cité (USPC)

Subjects
Nephrology, Pediatrics, Nephrotic Syndrome, 030204 cardiovascular system & hematology, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, LEHA, law.invention, 0302 clinical medicine, Superiority Trial, Randomized controlled trial, Quality of life, law, Recurrence, hemic and lymphatic diseases, Multicenter Studies as Topic, media_common, Randomized Controlled Trials as Topic, Renal Medicine, Immunoglobulins, Intravenous, Glomerulonephritis, General Medicine, 3. Good health, Treatment Outcome, Medicine, Rituximab, Steroids, medicine.drug, Drug, medicine.medical_specialty, media_common.quotation_subject, nephrology, 03 medical and health sciences, Internal medicine, medicine, Humans, 030203 arthritis & rheumatology, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, business.industry, paediatric nephrology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Quality of Life, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neoplasm Recurrence, Local, business, Nephrotic syndrome, glomerulonephritis
Abstract

IntroductionGuidelines 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 analysisWe 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 disseminationThe 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 numberNCT03560011.

Published
2020

7. Eculizumab treatment in severe pediatric STEC-HUS: a multicenter retrospective study

Author

Hassid Chehade, Chloé Dimeglio, Lucas Percheron, Valérie Leroy, Guylhène Bourdat-Michel, Marc Fila, A.-L. Adra, Jérôme Harambat, Etienne Bérard, Elodie Merieau, Raluca Gramada, Christine Pietrement, Brigitte Llanas, Arnaud Garnier, Anne-Laure Sellier-Leclerc, Anne-Laure Lapeyraque, Véronique Frémeaux-Bacchi, Emma Allain-Launay, Stéphanie Tellier, Philippe Eckart, Rémi Salomon, Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Nephrology, Male, medicine.medical_specialty, 030232 urology & nephrology, Antibodies, Monoclonal, Humanized, Severity of Illness Index, LEHA, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Severity of illness, medicine, Humans, 030212 general & internal medicine, Adverse effect, Child, Complement Activation, Escherichia coli Infections, Retrospective Studies, Shiga-Toxigenic Escherichia coli, business.industry, Acute kidney injury, Complement C5, Infant, Retrospective cohort study, Eculizumab, Acute Kidney Injury, medicine.disease, Pathophysiology, 3. Good health, Blockade, Complement Inactivating Agents, Treatment Outcome, Child, Preschool, Pediatrics, Perinatology and Child Health, Hemolytic-Uremic Syndrome, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, business, medicine.drug, Follow-Up Studies
Abstract

BACKGROUND: 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. METHODS: On behalf of the French Society of Pediatric Nephrology, we retrospectively studied 33 children from 15 centers treated with EC for severe STEC-HUS. Indication for EC was neurologic involvement in 20 patients, cardiac and neurologic involvement in 8, cardiac involvement in 2, and digestive involvement in 3. Based on medical status at last follow-up, patients were divided into two groups: favorable (n = 15) and unfavorable outcomes (n = 18). RESULTS: Among patients with favorable outcome, 11/14 patients (79%) displayed persistent blockade of complement activity before each EC reinjection. Conversely, in patients with unfavorable outcome, only 9/15 (53%) had persistent blockade (p = n.s.). Among 28 patients presenting neurological symptoms, 19 had favorable neurological outcome including 17 with prompt recovery following first EC injection. Only two adverse effects potentially related to EC treatment were reported. CONCLUSIONS: Taken together, these results may support EC use in severe STEC-HUS patients, especially those presenting severe neurological symptoms. The study, however, is limited by absence of a control group and use of multiple therapeutic interventions in treatment groups. Thus, prospective, controlled trials should be undertaken.

Published
2017

8. Molecular characterization of a recurrent 10.9 kb CYP24A1 deletion in Idiopathic Infantile Hypercalcemia

Author

Nadia Coudray, Genevieve Abeguile, Mireille Castanet, Marie-Laure Kottler, Philippe Eckart, Arnaud Molin, Hervé Mittre, Nicolas Richard, Marie Nowoczyn, Celine Ballandone, Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Service de biochimie [CHU Caen], Œstrogènes, reproduction, cancer (OeReCa), Service de Pédiatrie Médicale [Caen], Service de pédiatrie médicale et médecine de l'adolescent [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CCSD, Accord Elsevier, CHU Caen, and Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN)

Subjects
Male, Adolescent, DNA Copy Number Variations, Genetic counseling, 030232 urology & nephrology, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Bioinformatics, Genetic analysis, Infant, Newborn, Diseases, 03 medical and health sciences, 0302 clinical medicine, CYP24A1, Loss of Function Mutation, Genetics, medicine, Vitamin D and neurology, Humans, Hypercalciuria, Renal Insufficiency, Copy-number variation, Pathology, Molecular, Vitamin D, Child, Vitamin D3 24-Hydroxylase, Genetics (clinical), Sequence Deletion, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, Massive parallel sequencing, business.industry, Infant, General Medicine, medicine.disease, 3. Good health, Nephrocalcinosis, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, Hypercalcemia, Female, business, Metabolism, Inborn Errors
Abstract

International audience; 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.

Published
2019

9. NPHS2Mutations in Steroid-Resistant Nephrotic Syndrome: A Mutation Update and the Associated Phenotypic Spectrum

Author

Aurélia Liutkus, Elisabet Ars, Géraldine Mollet, Raphaëlle Campait, Kenza Soulami, Olivier Gribouval, Olivia Boyer, André Mégarbané, N. Mohsin, Beata S. Lipska, Maddalena Gigante, Fatih Ozaltin, Nicolas Garcelon, Jacques Dantal, Corinne Antignac, Philippe Eckart, Vincent Morinière, Moin A. Saleem, Franz Schaefer, Karin Dahan, Fabien Nevo, Karim Bouchireb, Evelyne Huynh-Cong, Damien Brackman, and Roser Torra

Subjects
Adult, Nephrotic Syndrome, NPHS2, Genotype, Biology, Bioinformatics, Compound heterozygosity, Polymorphism, Single Nucleotide, steroid-resistant nephrotic syndrome, Genetic variation, Genetics, Animals, Humans, Missense mutation, Age of Onset, Indel, Genetics (clinical), Intracellular Signaling Peptides and Proteins, Genetic Variation, Membrane Proteins, Stop codon, Steroid-resistant nephrotic syndrome, Transplantation, Disease Models, Animal, FSGS, Phenotype, Child, Preschool, Mutation, Leiden Open Variation Database, Software, podocin
Abstract

Mutations in the NPHS2 gene encoding podocin are implicated in an autosomal-recessive form of nonsyndromic steroid-resistant nephrotic syndrome in both pediatric and adult patients. Patients with homozygous or compound heterozygous mutations commonly present with steroid-resistant nephrotic syndrome before the age of 6years and rapidly progress to end-stage kidney disease with a very low prevalence of recurrence after renal transplantation. Here, we reviewed all the NPHS2 mutations published between October 1999 and September 2013, and also all novel mutations identified in our personal cohort and in international genetic laboratories. We identified 25 novel pathogenic mutations in addition to the 101 already described. The mutations are distributed along the entire coding region and lead to all kinds of alterations including 53 missense, 17 nonsense, 11 small insertions, 26 small deletions, 16 splicing, two indel mutations, and one mutation in the stop codon. In addition, 43 variants were classified as variants of unknown significance, as these missense changes were exclusively described in the heterozygous state and/or considered benign by prediction software. Genotype-phenotype analyses established correlations between specific variants and age at onset, ethnicity, or clinical evolution. We created a Web database using the Leiden Open Variation Database (www.lovd.nl/NPHS2) software that will allow the inclusion of future reports. (C) 2013 Wiley Periodicals, Inc.

Published
2013

11. An audit analysis of a guideline for the investigation and initial therapy of diarrhea negative (atypical) hemolytic uremic syndrome

Author

Johnson S, Stojanovic J, Ariceta G, Bitzan M, Besbas N, Frieling M, Karpman D, Landau D, Langman C, Licht C, Pecoraro C, Riedl M, Siomou E, van de Kar N Walle JV, Loirat C, Taylor CM, Anne-Laure Adra, Klaus Arbeiter, Yelda Bilginer, Heiko Billing, Maria Bitsori, Bernard Boudailliez, Francisco de la Cerda – Ojeda, Gérard Champion, Amit Dagan, Bradley Dixon, Philippe Eckart, Israel Eisenstein, Arnaud Garnier, Clara Gomes, Karsten Häffner, Jerome Harambat, Carol Inward, Rafael Krmar, Theresa Kwon, Anne-Laure Lapeyraque, Sebastian Loos, Meeta Malik, Mignon McCulloch, David Milford, Danko Milosevic, Carla Nester, François Nobili, Pedro J Ortega, Fotios Papachristou, Antonia Peña - Carrión, Ludmila Podracká, Nikoleta Printza, Bruno Ranchin, Christopher Reid, Caroline Rousset-Rouvière, Rémi Salomon, Anne-Laure Sellier-Leclerc, James Springate, Sophie Taque, Despoina Tramma, Sibylle Tschumi, Ulrike Walden, Kay Tyerman, Aoife Waters, and Donald J Weaver Jr

Subjects
Male, Nephrology, Clinical audit, medicine.medical_specialty, Pediatrics, Thrombotic microangiopathy, Adolescent, medicine.medical_treatment, atypical hemolytic-uremic syndrome, alternative complement pathway, plasmapheresis, complement disregulation, chronic kidney disease, thrombotic microangiopathy, urologic and male genital diseases, Surveys and Questionnaires, hemic and lymphatic diseases, Internal medicine, Atypical hemolytic uremic syndrome, medicine, Humans, Child, Atypical Hemolytic Uremic Syndrome, Clinical Audit, business.industry, Infant, Newborn, Infant, Guideline, Eculizumab, medicine.disease, female genital diseases and pregnancy complications, Diarrhea, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Child, Preschool, Practice Guidelines as Topic, Pediatrics, Perinatology and Child Health, Immunology, Female, Plasmapheresis, Guideline Adherence, medicine.symptom, business, medicine.drug
Abstract

Item does not contain fulltext BACKGROUND: In 2009, the European Paediatric Study Group for Haemolytic Uraemic Syndrome (HUS) published a clinical practice guideline for the investigation and initial therapy of diarrhea-negative HUS (now more widely referred to as atypical HUS, aHUS). The therapeutic component of the guideline (comprising early, high-volume plasmapheresis) was derived from anecdotal evidence and expert consensus, and the authors committed to auditing outcome. METHODS: Questionnaires were distributed to pediatric nephrologists across Europe, North America, and the Middle East, who were asked to complete one questionnaire per patient episode of aHUS between July 1, 2009 and December 31, 2010. Comprehensive, anonymous demographic and clinical data were collected. RESULTS: Seventy-one children were reported with an episode of aHUS during the audit period. Six cases occurred on a background of influenza A H1N1 infection. Of 71 patients, 59 (83 %) received plasma therapy within the first 33 days, of whom ten received plasma infusion only. Complications of central venous catheters occurred in 16 out of 51 patients with a catheter in-situ (31 %). Median time to enter hematological remission was 11.5 days, and eight of 71 (11 %) patients did not enter hematological remission by day 33. Twelve patients (17 %) remained dialysis dependent at day 33. CONCLUSIONS: This audit provides a snapshot of the early outcome of a group of children with aHUS in the months prior to more widespread use of eculizumab. 01 oktober 2014

Published
2014

13. Comparison of multiplex PCR assays and conventional techniques for the diagnostic of respiratory virus infections in children admitted to hospital with an acute respiratory illness

Author

Jacques Brouard, Astrid Vabret, Joëlle Petitjean, Loïc Legrand, Delphine Cuvillon-Nimal, Sandrine Simon, François Freymuth, Philippe Eckart, Stéphanie Gouarin, and Julia Dina

Subjects
Male, viruses, Orthomyxoviridae, coronavirus, medicine.disease_cause, Polymerase Chain Reaction, Virus, Article, influenza virus, Cell Line, Human metapneumovirus, stomatognathic system, Nidovirales, multiplex‐PCR, Virology, medicine, Humans, Respiratory Tract Infections, Coronavirus, biology, virus diseases, Infant, RSV, biology.organism_classification, respiratory virus, Hospitalization, Infectious Diseases, rhinovirus, Virus Diseases, Immunology, hMPV, Respiratory virus, Enterovirus, Female, Rhinovirus, Research Article
Abstract

The performances of four multiplex PCR (m‐PCR) were compared to direct immunofluorescence assay (DFA) and HuH7 cell culture for the detection of viruses in 263 children admitted to hospital with an acute respiratory illness. One hundred fifty (57.6%) nasal aspirates were found DFA‐positive; 188 (72.3%) were found positive by both DFA and HuH7 cell culture, and 242 (92%) were PCR‐positive. The m‐PCR detected 124 viruses which were not found by conventional methods: 68 rhinovirus, 17 human metapneumovirus, 15 respiratory syncytial virus (RSV), 8 parainfluenza virus (PIV), 5 coronavirus 229E, 3 OC43 and 3 NL63, 4 enterovirus, 2 influenza virus B and C virus. The m‐PCR were more sensitive, had the advantages of a shorter delay in specific diagnosis, and a lower cost than DFA and culture. Using these m‐PCR, the prevalence of each virus was compared between in‐patient and out‐patient groups of children attending the emergency unit of the hospital. Nasal aspirates from 411 (91.5%) children were found positive by the PCRs. RSV, rhinovirus, and influenza virus were the most frequent viruses detected in this population, representing 43.6%, 31.8%, and 8.8% of the virus found, respectively, followed by human metapneumovirus (4.4%), coronavirus (3.4%), parainfluenza virus (3.2%), adenovirus (2.3%), and enterovirus (2.1%). RSVs were detected more significantly in the in‐patient group than in the out‐patient group, and influenza viruses were detected more frequently in the out‐patient group than in the in‐patient group. Moreover, the use of m‐PCR pointed out the frequency of rhinovirus and mixed viral detections in these patients. In conclusion, according to the requirements of speed and low cost of the methods, and to achieve the highest rate of detection of respiratory viruses, the combined use of DFA and m‐PCR is today likely to be the best way to improve diagnosis of respiratory illnesses in children. J. Med. Virol. 78:1498–1504, 2006. © 2006 Wiley‐Liss, Inc.

Published
2006

15. Genetic investigation of autosomal recessive distal renal tubular acidosis: evidence for early sensorineural hearing loss associated with mutations in the ATP6V0A4 gene

Author

Pierre Cochat, Gwenaelle Roussey Kesler, François Nobili, Laurence Strompf, Philippe Eckart, Mathilde Cailliez, Marie-Alice Macher, Robert Novo, Gilles Morin, Valérie Layet, Anne Fargeot, Anne Blanchard, Nathalie Godefroid, Michèle Dechaux, Rémi Salomon, Stéphanie Lorotte, Ivan Tack, Véronique Baudouin, Pascal Houillier, Tim Ulinski, Rosa Vargas-Poussou, Hubert Nivet, Chantal Loirat, Xavier Jeunemaitre, François Bouissou, and Nelly Le Pottier

Subjects
Adult, Male, Heterozygote, Adolescent, Hearing loss, Hearing Loss, Sensorineural, DNA Mutational Analysis, Chromosome Disorders, Genes, Recessive, Comorbidity, Gene mutation, medicine.disease_cause, Polymorphism, Single Nucleotide, Risk Assessment, Linkage Disequilibrium, Distal renal tubular acidosis, Risk Factors, Genotype, otorhinolaryngologic diseases, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Child, Phylogeny, Genetic testing, Genetics, Mutation, Evidence-Based Medicine, medicine.diagnostic_test, business.industry, Genetic heterogeneity, Incidence, Chromosome Mapping, Infant, General Medicine, Acidosis, Renal Tubular, Mitochondrial Proton-Translocating ATPases, medicine.disease, Nephrology, Child, Preschool, Sensorineural hearing loss, Female, France, medicine.symptom, business
Abstract

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.

Published
2006

16. Multicentric Kaposi's sarcoma in a 5-year-old human immunodeficiency virus-negative renal allograft recipient

Author

Jean-Louis Stephan, Nicole Brousse, Jean-Christophe Fournet, Michel Peuchmaur, Hubert Philippe, Marie-France Gagnadoux, Philippe Eckart, and Patrick Niaudet

Subjects
Male, Pathology, medicine.medical_specialty, medicine.medical_treatment, Autopsy, HIV Antibodies, Pathology and Forensic Medicine, HIV Seropositivity, Medicine, Humans, Transplantation, Homologous, Lymph node, Kaposi's sarcoma, Sarcoma, Kaposi, Kidney, business.industry, Immunosuppression, medicine.disease, Kidney Transplantation, Transplantation, surgical procedures, operative, medicine.anatomical_structure, Child, Preschool, Sarcoma, Differential diagnosis, business
Abstract

We describe the clinical and pathologic features of a case of pediatric multicentric Kaposi's sarcoma (KS) associated with allograft transplantation in a human immunodeficiency virus (HIV)-negative child. A lethal polyadenopathic and visceral KS occurred in a 5-year-old Caribbean boy who had undergone an allogenic renal transplantation for diffuse mesangial sclerosis with end-stage renal failure 4 months previously. The HIV-1 and HIV-2 serologies were negative. Despite its rarity, KS must be considered as a differential diagnosis in posttransplantation polyadenopathic or multisystemic syndromes in children.

Published
1992

18. Paediatric haemolytic uraemic syndrome related to Shiga toxin-producing Escherichia coli, an overview of 10 years of surveillance in France, 2007 to 2016

Author

Simon Le Hello, Alexandra Mailles, Lisa-A King, François-Xavier Weill, Delphine Sergentet-Thevenot, Réseau français hospitalier de surveillance du Shu pédiatrique, Nathalie Jourdan-Da Silva, Malika Gouali, Estelle Loukiadis, Stéphane Bonacorsi, Patricia Mariani-Kurkdjian, Dieter Van Cauteren, Chantal Loirat, Marie-Pierre Donguy, Mathias Bruyand, Henriette de Valk, Sophie Lefèvre, Département des maladies infectieuses, Institut de Veille Sanitaire (INVS), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de Référence - National Reference Center Escherichia coli, Shigella et Salmonella (CNR-ESS), Institut Pasteur [Paris], Santé publique France - French National Public Health Agency [Saint-Maurice, France], Direction Générale de l'Alimentation (DGAL), Ministère de l'agriculture, de l'agroalimentaire et de la forêt, Laboratoire d'Ecologie Microbienne - UMR 5557 (LEM), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Ecole Nationale Vétérinaire de Lyon (ENVL), Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Members of the Réseau français hospitalier de surveillance du SHU pédiatrique Djamal-Dine Djeddi: Paediatric and Adolescent Medicine Departement, Centre Hospitalier Universitaire d’Amiens, Amiens, France. Lise Allard: Paediatric Departement, Centre Hospitalier Universitaire d’Angers, Angers, France. Sylvie Roullaud: Paediatric Departement, Centre Hospitalier d’Angoulême, Angoulême, France. François Nobili: Paediatric Nephrology Departement, Centre Hospitalier Universitaire de Besançon, Besançon, France. Brigitte Llanas: Paediatric Nephrology Departement, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France. Loïc de Parscau: Paediatric Departement, Centre Hospitalier Régional Universitaire Morvan, Brest, France. Anne-Laure Sellier-Leclerc: Paediatric Nephrology Departement, hôpital Femme-Mère-Enfant, Bron, France. Philippe Eckart: Paediatric Departement, Centre Hospitalier Universitaire de Caen, Caen, France. Lucie Bessenay: Paediatric Departement, Centre Hospitalier Universitaire Estaing, Clermont Ferrand, France. Frédéric Huet: Paediatric Departement, Hôpital d’Enfants, Dijon, France. Guylhene Bourdat-Michel: Paediatric Departement, Centre Hospitalier Universitaire de Grenoble, Grenoble, France. Corinne Guitton: Paediatric Departement, AP-HP Centre Hospitalier Universitaire Bicêtre, Le Kremlin-Bicêtre, France. Robert Novo: Paediatric Nephrology Departement, Hôpital Jeanne de Flandre, Centre Hospitalier Universitaire de Lille, Lille, France. Vincent Guigonis: Paediatric Departement, Centre Hospitalier Universitaire Limoges, Limoges, France. Marcel Guillot: Peadiatric Departement, Centre Hospitalier Robert Bisson, Lisieux, France. Michel Tsimaratos: Paediatric Nephrology Departement, Hôpital de la Timone, Marseille, France. Marc Fila: Paediatric Departement, Centre Hospitalier Universitaire de Montpellier, Montpellier, France. Gwenaelle Roussey-Kessler: Paediatric Nephrology Departement, Centre Hospitalier Universitaire de Nantes, Nantes, France. Etienne Berard: Paediatric Nephrology Departement, Centre Hospitalier Universitaire de Nice, Archet 2, Nice, France. Tim Ulinski: Paediatric Nephrology Departement, Hôpital Armand Trousseau, APHP, Paris, France. Chantal Loirat: Paediatric Nephrology Departement, Hôpital Robert Debré, APHP, Paris, France. Pauline Krug: Nephrology Departement, Hôpital Necker Enfants Malades, APHP, Paris, France. Violaine Lefranc: Paediatric Emergencies Departement, Centre Hospitalier Universitaire La Miletrie, Poitiers, France. Catherine Didier-Wright: Paediatric Department, Centre Hospitalier de la Région Annecienne, Pringy, France. Christine Pietremont: Nephrology Department, American Mémorial Hospital, Reims, France. Amélie Ryckewaert: Paediatric Nephrology Departement, Centre Hospitalier Universitaire Rennes, Rennes, France. Françoise Broux: Paediatric Nephrology Departement, Centre Hospitalier Universitaire Charles Nicolle, Rouen, France. Marie-Pierre Lavocat: Paediatric Departement, Hôpital Nord, Centre Hospitalier Universitaire de Saint Etienne, Saint Etienne, France. Joelle Terzic: Paediatric Departement, Centre Hospitalier Universitaire de Strasbourg, Strasbourg, France. Stéphane Decramer: Pediatric Nephrology Department, Centre Hospitalier Universitaire de Toulouse, Toulouse, France. Hubert Nivet: Pediatric Nephrology Department, Centre Hospitalier Universitaire de Tours, Tours, France. Isabelle Vrillon: Paediatric Nephrology Departement, Hôpitaux de Brabois, Centre Hospitalier Universitaire de Nancy, Vandoeuvre Les Nancy, France., Institut Pasteur [Paris] (IP), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence des Escherichia coli, Shigella et Salmonella - Bactéries pathogènes entériques (CNR-ESS), Santé publique France, Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Lyon (ENVL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Infectious Disease Department [Saint Maurice], Agence Nationale de la Santé Publique [Saint-Maurice] (ANSP), and Mzembaba, Sandy

Subjects
Male, food-borne infections, Epidemiology, Shiga Toxins, medicine.disease_cause, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Disease Outbreaks, Feces, 0302 clinical medicine, fluids and secretions, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, haemolytic uraemic syndrome, Medicine, 030212 general & internal medicine, Child, Escherichia coli Infections, 0303 health sciences, Shiga-Toxigenic Escherichia coli, Transmission (medicine), Escherichia coli Proteins, Incidence, E coli, 3. Good health, Population Surveillance, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, surveillance, France, medicine.medical_specialty, Shiga toxin producing Escherichia coli, Microbiology, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, children, Virology, Humans, Serologic Tests, HUS, Sex Distribution, Escherichia coli, Shiga toxin-producing Escherichia coli, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, 030306 microbiology, business.industry, Public Health, Environmental and Occupational Health, Infant, Outbreak, bacterial infections and mycoses, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Hemolytic-Uremic Syndrome, bacteria, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Haemolytic-uraemic syndrome, business
Abstract

Introduction Haemolytic uraemic syndrome (HUS) related to Shiga toxin-producing Escherichia coli (STEC) is the leading cause of acute renal failure in young children. In France, HUS surveillance in children aged Aim We present the results of this surveillance between 2007 and 2016. Methods A voluntary nationwide network of 32 paediatric departments notifies cases. Two national reference centres perform microbiological STEC confirmation. Results Over the study period, the paediatric HUS incidence rate (IR) was 1.0 per 100,000 children-years, with a median of 116 cases/year. In 2011, IR peaked at 1.3 per 100,000 children-years, and decreased to 1.0 per 100,000 children-years in 2016. STEC O157 associated HUS peaked at 37 cases in 2011 and decreased to seven cases in 2016. Cases of STEC O26-associated HUS have increased since 2010 and STEC O80 associated HUS has emerged since 2012, with 28 and 18 cases respectively reported in 2016. Four STEC-HUS food-borne outbreaks were detected (three STEC O157 linked to ground beef and raw-milk cheese and one STEC O104 linked to fenugreek sprouts). In addition, two outbreaks related to person-to-person transmission occurred in distinct kindergartens (STEC O111 and O26). Conclusions No major changes in HUS IRs were observed over the study period of 10 years. However, changes in the STEC serogroups over time and the outbreaks detected argue for continuing epidemiological and microbiological surveillance.

Published
2019

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