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1. Generation of induced pluripotent stem cells-derived hepatocyte-like cells for ex vivo gene therapy of primary hyperoxaluria type 1

Author: Julie Estève, Jean-Marc Blouin, Magalie Lalanne, Lamia Azzi-Martin, Pierre Dubus, Audrey Bidet, Jérôme Harambat, Brigitte Llanas, Isabelle Moranvillier, Aurélie Bedel, François Moreau-Gaudry, and Emmanuel Richard
Subjects: Biology (General), QH301-705.5
Abstract: Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder of the liver metabolism due to functional deficiency of the peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). AGT deficiency results in overproduction of oxalate which complexes with calcium to form insoluble calcium-oxalate salts in urinary tracts, ultimately leading to end-stage renal disease. Currently, the only curative treatment for PH1 is combined liver-kidney transplantation, which is limited by donor organ shortage and lifelong requirement for immunosuppression. Transplantation of genetically modified autologous hepatocytes is an attractive therapeutic option for PH1. However, the use of fresh primary hepatocytes suffers from limitations such as organ availability, insufficient cell proliferation, loss of function, and the risk of immune rejection. We developed patient-specific induced pluripotent stem cells (PH1-iPSCs) free of reprogramming factors as a source of renewable and genetically defined autologous PH1-hepatocytes. We then investigated additive gene therapy using a lentiviral vector encoding wild-type AGT under the control of the liver-specific transthyretin promoter. Genetically modified PH1-iPSCs successfully provided hepatocyte-like cells (HLCs) that exhibited significant AGT expression at both RNA and protein levels after liver-specific differentiation process. These results pave the way for cell-based therapy of PH1 by transplantation of genetically modified autologous HLCs derived from patient-specific iPSCs. Keywords: Hyperoxaluria, Induced pluripotent stem cell, Gene therapy, Hepatic differentiation, Lentiviral vector
Published: 2019
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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
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3. Atteinte rénale chez les enfants infectés par la leptospirose en France

Author: Sarah De Thomasis, Hugues Flodrops, Brigitte Llanas, Édouard Martinez Casado, Sylvie Cloarec, Christine Pietrement, and Ariane Zaloszyc
Subjects: Nephrology
Published: 2022
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4. Targeted gene therapy in human-induced pluripotent stem cells from a patient with primary hyperoxaluria type 1 using CRISPR/Cas9 technology

Author: Jean-Marc Blouin, Pierre Dubus, J.P. Esteve, Audrey Bidet, Lamia Azzi-Martin, Aurélie Bedel, Brigitte Llanas, Emmanuel Richard, François Moreau-Gaudry, Jérôme Harambat, Magalie Lalanne, Isabelle Moranvillier, Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), and Physiopathologie du cancer du foie
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Genetic enhancement, Genetic Vectors, Induced Pluripotent Stem Cells, Biophysics, Biochemistry, Primary hyperoxaluria, Mice, 03 medical and health sciences, 0302 clinical medicine, CRISPR-Associated Protein 9, Animals, Humans, CRISPR, Medicine, Induced pluripotent stem cell, Molecular Biology, Base Sequence, business.industry, Cas9, Gene targeting, Genetic Therapy, Cell Biology, medicine.disease, 3. Good health, Transplantation, 030104 developmental biology, Genetic Loci, 030220 oncology & carcinogenesis, Hyperoxaluria, Primary, Hepatocytes, Cancer research, CRISPR-Cas Systems, business, Minigene
Abstract: Primary hyperoxaluria type 1 (PH1) is an inherited metabolic disorder caused by a deficiency of the peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT), which leads to overproduction of oxalate by the liver and results in urolithiasis, nephrocalcinosis and renal failure. The only curative treatment for PH1 is combined liver and kidney transplantation, which is limited by the lack of suitable organs, significant complications, and the life-long requirement for immunosuppressive agents to maintain organ tolerance. Hepatocyte-like cells (HLCs) generated from CRISPR/Cas9 genome-edited human-induced pluripotent stem cells would offer an attractive unlimited source of autologous gene-corrected liver cells as an alternative to orthotopic liver transplantation (OLT). Here we report the CRISPR/Cas9 nuclease-mediated gene targeting of a single-copy AGXT therapeutic minigene into the safe harbour AAVS1 locus in PH1-induced pluripotent stem cells (PH1-iPSCs) without off-target inserts. We obtained a robust expression of a codon-optimized AGT in HLCs derived from AAVS1 locus-edited PH1-iPSCs. Our study provides the proof of concept that CRISPR/Cas9-mediated integration of an AGXT minigene into the AAVS1 safe harbour locus in patient-specific iPSCs is an efficient strategy to generate functionally corrected hepatocytes, which in the future may serve as a source for an autologous cell-based gene therapy for the treatment of PH1.
Published: 2019
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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
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6. Complement Gene Variants and Shiga Toxin-Producing Escherichia coli-Associated Hemolytic Uremic Syndrome

Author: Corinne Alberti, Paula Vieira-Martins, Véronique Frémeaux-Bacchi, Anne-Laure Sellier-Leclerc, Patricia Mariani, Tim Ulinski, Georges Deschênes, Sophie Limou, Annie Lahoche, Gwenaelle Roussey, François Nobili, Mathilde Cailliez, Brigitte Llanas, Theresa Kwon, Robert Novo, François-Xavier Weill, Chantal Loirat, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Translational ImmunoGenetic in AutoImmunity and Transplantation (Team 5 - U1064 Inserm - CRTI), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de Néphrologie pédiatrique [Hôpital Robert Debré, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Bordeaux [Bordeaux], Service de pédiatrie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Marseille, Service de néphrologie et pédiatrie générale [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques Hopital Robert Debre, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Référence - National Reference Center Escherichia coli, Shigella et Salmonella (CNR-ESS), Institut Pasteur [Paris], Service de Microbiologie [Hôpital Robert Debré - APHP], Centre National de Référence associé Escherichia coli [Hôpital Robert Debré - APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by grants from the Programme Hospitalier de Recherche Clinique (AOR 09 077 and AOM08198, to V.F.-B., A.-L.S.-L., and C.L.), by the European Union FP7 grant 2012-305608 (to V.F.-B., EURenOmics), the Fondation du rein (FRM Prix 2012 FDR, to V.F.-B.), and the Association pour l’Information et la Recherche dans les maladies Rénales génétiques (AIRG France)., European Project: 305608,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,EURENOMICS(2012), École Pratique des Hautes Études (EPHE), CHU Trousseau [APHP], Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris] (IP), AP-HP Hôpital universitaire Robert-Debré [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de Référence associé Escherichia coli [Hôpital Robert Debré - APHP]
Subjects: Genotype, Epidemiology, Complement, 030232 urology & nephrology, Critical Care and Intensive Care Medicine, Shiga Toxin, Membrane Cofactor Protein, Kidney Failure, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Atypical hemolytic uremic syndrome, Escherichia coli, Medicine, human, Chronic, Shiga toxin-hemolytic uremic syndrome, pathogenic variants, Complement Activation, Allele frequency, Atypical Hemolytic Uremic Syndrome, 030304 developmental biology, 0303 health sciences, Transplantation, biology, C5b-9, CD46, business.industry, Shiga toxin producing E coli-hemolytic uremic syndrome, complement factor H, High-Throughput Nucleotide Sequencing, Shiga toxin, CD46 protein, Complement System Proteins, medicine.disease, 3. Good health, Complement system, Minor allele frequency, complement gene variant, Nephrology, Factor H, Immunology, hemolytic uremic syndrome, biology.protein, business, Genetic Background, Biomarkers, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; BACKGROUND AND OBJECTIVES: Inherited complement hyperactivation is critical for the pathogenesis of atypical hemolytic uremic syndrome (HUS) but undetermined in postdiarrheal HUS. Our aim was to investigate complement activation and variants of complement genes, and their association with disease severity in children with Shiga toxin-associated HUS.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Determination of complement biomarkers levels and next-generation sequencing for the six susceptibility genes for atypical HUS were performed in 108 children with a clinical diagnosis of post-diarrheal HUS (75 Shiga toxin-positive, and 33 Shiga toxin-negative) and 80 French controls. As an independent control cohort, we analyzed the genotypes in 503 European individuals from the 1000 Genomes Project.RESULTS: During the acute phase of HUS, plasma levels of C3 and sC5b-9 were increased, and half of patients had decreased membrane cofactor protein expression, which normalized after 2 weeks. Variants with minor allele frequency
Published: 2019
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7. [Kidney injury in children and adolescents with leptospirosis in France]

Author: Sarah, De Thomasis, Hugues, Flodrops, Brigitte, Llanas, Édouard, Martinez Casado, Sylvie, Cloarec, Christine, Pietrement, and Ariane, Zaloszyc
Subjects: Adult, Male, Adolescent, Humans, Female, Leptospirosis, Acute Kidney Injury, Child, Kidney, Anti-Bacterial Agents, Retrospective Studies
Abstract: Leptospirosis is an anthropozoonosis with polymorphic clinical symptoms and a high variability of severity, ranging from flu-like syndrome to severe acute kidney injury. This disease is highly incident in tropical regions but there is a trend towards increasing incidence in metropolitan France and in Reunion Island. The objective of this study was to describe the epidemiological, clinical, laboratory and therapeutic characteristics of the pediatric leptospirosis in metropolitan France and in Reunion Island.We performed a retrospective analysis of leptospirosis cases hospitalized in University hospitals where members of the Paediatric Nephrology Society work in France between January 2008 and December 2020, 6 centers reported leptospirosis cases, one center had one patient in consultation but lack of available data and 10 centers did not find any case.A total of 21 cases were reported (mean age 13.4±3.4years), mostly boys (ratio 6:1). Out of 21 patients, 95% had fever, 71% were presenting with myalgia, 81% with thrombocytopenia, and 76% with gastrointestinal symptoms. Regarding kidney impairment, 18 patients (86%) had acute kidney injury, including 4 (19%) with oligoanuria, but none of them required acute dialysis. About 30% of patients had biological signs of tubulopathy including hypophosphatemia, hypokalemia, or tubular proteinuria. No death due to the disease occurred. The therapeutic management followed the current guidelines with the use of antibiotic therapy by amoxicillin or 3rd generation cephalosporins with symptomatic treatment. When there was biological control after exit, creatinine decreased.In this multicenter retrospective study, we report 21 children with leptospirosis with a significant proportion of acute kidney injury, the outcome was favorable. Children do not seem to be at high risk of chronic kidney disease progression but nephrology follow-up has not been systematically carried out. Compared to studies performed in adults, the prognosis was better and hepatic impairment was rare. Compared to other pediatric studies, conjunctivitis was not a common symptom but kidney injury and survival appeared to be similar. Children were presenting with anicteric renal presentation. The casebook wasn't exhaustive and didn't include the other overseas territories, which account for the highest proportion of leptospirosis infection.Leptospirosis is an infection which may lead to multivisceral failure with kidney involvement conditioning the outcome. Despite a better prognosis in children, it remains important to quickly diagnose this infection in order to start appropriate antibiotic therapy and perform a kidney function monitoring.
Published: 2021

8. Long-term kidney and liver outcome in 50 children with autosomal recessive polycystic kidney disease

Author: Guillaume Dorval, Jean-Daniel Delbet, Rémi Salomon, Thomas Blanc, Brigitte Llanas, Dominique Debray, Pauline Krug, Florence Lacaille, Nathalie Biebuyck, Muriel Girard, Frances Tilley, Olivia Boyer, Christophe Chardot, Anne Couderc, Laurence Heidet, Saoussen Krid, Nicolas Garcelon, Cécile Courivaud, Marina Charbit, Marc Fila, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Robert Debré Paris, Hôpital Robert Debré, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU de Bordeaux Pellegrin [Bordeaux], CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Health data- and model- driven Knowledge Acquisition (HeKA), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE)
Subjects: Male, Pediatrics, medicine.medical_specialty, Adolescent, Cholangitis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, ARPKD, PKHD1, 030204 cardiovascular system & hematology, Liver transplantation, Esophageal and Gastric Varices, Kidney, 03 medical and health sciences, Cystic kidney disease, Young Adult, 0302 clinical medicine, Polycystic kidney disease, Hypertension, Portal, medicine, Humans, Child, Portal hypertension, Children, Kidney transplantation, Polycystic Kidney, Autosomal Recessive, Retrospective Studies, Transplantation, business.industry, Infant, Newborn, Infant, medicine.disease, Long-term outcome, Autosomal Recessive Polycystic Kidney Disease, Nephrology, Child, Preschool, Pediatrics, Perinatology and Child Health, Congenital hepatic fibrosis, Liver function, business
Abstract: International audience; BackgroundAutosomal recessive polycystic kidney disease (ARPKD) is a rare ciliopathy characterized by congenital hepatic fibrosis and cystic kidney disease. Lack of data about long-term follow-up makes it difficult to discuss timing and type of organ transplantation. Our objectives were to evaluate long-term evolution and indications for transplantation, from birth to adulthood.MethodsNeonatal survivors and patients diagnosed in postnatal period with ARPKD between 1985 January and 2017 December from 3 French pediatric centers were retrospectively enrolled in the study.ResultsFifty patients with mean follow-up 12.5 ± 1 years were enrolled. ARPKD was diagnosed before birth in 24%, and at mean age 1.8 years in others. Thirty-three patients were 3 episodes in three children). Liver function was normal in all patients. Nine children received a kidney transplant without liver complications. A 20-year-old patient received a combined liver-kidney transplant (CLKT) for recurrent cholangitis, and a 15-year-old boy an isolated liver transplant for uncontrollable variceal bleeding despite portosystemic shunt.ConclusionsLong-term outcome in patients with ARPKD is heterogeneous, and in this cohort did not depend on age at diagnosis except for blood pressure. Few patients required liver transplantation. Indications for liver or combined liver-kidney transplantation were limited to recurrent cholangitis or uncontrollable portal hypertension. Liver complications after kidney transplantation were not significant.
Published: 2021
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9. Low incidence of SARS-CoV-2, risk factors of mortality and the course of illness in the French national cohort of dialysis patients

Author: Cécile Couchoud, Florian Bayer, Carole Ayav, Clémence Béchade, Philippe Brunet, François Chantrel, Luc Frimat, Roula Galland, Maryvonne Hourmant, Emmanuelle Laurain, Thierry Lobbedez, Lucile Mercadal, Olivier Moranne, Abdelhamid Abbassi, Alain Debure, Abdallah Guerraoui, Abdelatif Benmoussa, Abdelaziz Hamani, Abdelaziz Ziane, Abdelhamid Nefti, Abdelkader Hadj, Abderrahim El Amari, Abderrahmane Ghazali, Abo Bakr Abd El Fatah Mohamed, Achour Laradi, Adel Ben Ahmed, Adel Sahar, Adele Pillet, Adeline Lacraz, Adnan Moinat, Afshin Massoumi, Agathe Pardon, Agnes Caillette Beaudoin, Agnes Chapelet Debout, Agnes Mariot, Ahmed Rachi, Aida Afiani, Aime Remy Boula, Al Jalaby, Alain Cremault, Alain Fournier, Alain Jeanson, Alain Lyon, Alain Nony, Alain Robert, Alain Slingeneyer, Alanor Agnes Labatide, Albane Brodin Sartorius, Albert Bensman, Albert Fournier, Alex Ranlin, Alex Vido Sandor, Alexandra Colombo, Alexandra Duhem, Alexandra Stancu, Alexandre Dufay, Alexandre Dumoulin, Alexandre Ebel, Alexandre Klein, Alexandre Martin, Alexandre Mouneimne, Alexandre Seidowsky, Alfio De Martin, Alfredo Zannier, Ali Aizel, Ali Hafi, Ali Zineddine Diddaoui, Alim Heyani, Alina Mocanu, Alina Preda, Aline Hafi, Aline Talaszka, Alyette Duquesne, Amar Amaouche, Amel Ghemmour, Amelie Simon, Amina Skalli, Amine Boukadida, Amr Ekhlas Ragab Eid, Ana Fedorca, Anabelle Baillet, Anais Poyet, Ancuta Bouffandeau Giorgita, Anderson Ratsimbazafy, Andre Pruna, Angel Argiles, Angelo Testa, Ann Karolien Vandooren, Anne Jolivot, Anne Kolko Labadens, Anne Lataste, Anne Maisin, Anne Paris, Anne Sechet, Anne Wuillai, Anne Elisabeth Heng, Anne Gaelle Josse, Anne Helene Querard, Anne Helene Reboux, Anne Laure Adra, Anne Laure Faller, Anne Laure Leclerc, Anne Laure Poitou, Annie Lahoche Manucci, Antoine Jacquet, Antoine Pommereau, Antoine Thierry, Arezki Adem, Arielle Chapelet, Arnaud Del Bello, Arnaud Delezire, Arnaud Garnier, Arnaud Guerard, Arnaud Klisnick, Arnaud Lionet, Arnaud Roccabianca, Arnaud Stolz, Arthur Capdeville, Asma Allal, Assem Alrifai, Assetou Diarrassouba, Assia Djema, Assia Ferhat Carre, Astrid Godron Dubrasquet, Atman Haddj Elmrabet, Audrey Jegado, Aurelia Bertholet Thomas, Aurelie Davourie Salandre, Aurelie Pajot, Aurelien Lorthioir, Aurelien Tiple, Aurore Sury, Ayman Abokasem, Ayman Sarraj, Bachir Henaoui, Baher Chaghouri, Bassem Wehbe, Beatrice Ball, Beatrice Viron, Belkassem Issad, Benedicte Hodemon Corne, Benedicte Janbon, Benjamin Deroure, Benjamin Savenkoff, Benoit Jonon, Benoit Vendrely, Benyakoub Djelaleddine, Bernard Ohry, Bernard Painchart, Bernard Strullu, Bernard Temperville, Bertin Ebikili, Bertrand Hacq, Bertrand Morel, Bilal Aoun, Blanca Muniz, Bouchra Chlih, Brahim Amara, Brice Mayor, Brigitte Gilson, Brigitte Llanas, Brigitte Zins, Bruno Bourgeon, Bruno Coevoet, Bruno Guery, Bruno Legallicier, Bruno Paris, Bruno Ranchin, Bruno Seigneuric, Camelia Ghiciuc Dita, Camelia Prelipcean, Carine Achard Hottelart, Carine Diet, Carlos Frangie, Carlos Vela, Carmina Muresan, Carole Deprele, Caroline Araujo, Caroline Bidault, Caroline Creput, Caroline Delclaux, Caroline Du Halgouet, Caroline Favennec, Caroline Freguin, Caroline Gourraud Vercel, Caroline Mesguen, Caroline Ndomo Obama, Caroline Poitou, Caroline Preissig Dirhold, Caroline Roubiou, Catherine Albert, Catherine Bessin, Catherine De Marion Gaja, Catherine Godart, Catherine Lasseur, Catherine Leocardi, Catherine Lumbroso, Catherine Melander, Catherine Michel, Catherine Quere Maurouard, Catherine Rouannet, Catherine Taddei, Cathy Verove, Cecile Guiraud, Cecile Tafelin, Cecile Turc Baron, Cedric Formet, Cedric Pinier, Celia Lessore De Ste Foy, Celine Granolleras, Chaouki Bennini, Charles Cartou, Charles Chazot, Charlotte Jouzel, Cherif Badid, Christa Roubicek, Christel Viaud, Christelle Verrier, Christian Chuet, Christian Combe, Christian Dabot, Christian Duvic, Christian Emond, Christian Lagarde, Christian Lamotte, Christian Pain, Christiane Mousson, Christie Lorriaux, Christine Beauchamp, Christine Fumeron, Christine Le Gurun, Christine Leroy, Christine Pietrement, Christine Richer, Christophe Bouaka, Christophe Charasse, Christophe Goupy, Christophe Ridel, Cindy Castrale, Cindy Detourne, Clair Francois, Claire Presne, Claire Trivin, Clarissa Von Kotze, Claude Bernard, Claude Bonniol, Claude Desvergnes, Claude Raharivelina, Claudia Nistor, Claudine Gueret, Claudine Lloret, Claudine Saltiel, Clelia Rosati, Clementine Rabate, Corina Stanescu, Corinne Ferrandini, Corinne Guibergia, Corinne Lemoine, Corinne Passeron, Cynthia Kahil, Cyril Garrouste, Cyril Vo Van, Cyrille Jolimoy, Dalila Kesraoui, Damien Jolly, Damien Thibaudin, Dan Teboulle, Daniel Daubresse, Daniel Louvet, Daniel Rasamimanantsoa, Daniel Toledano, Daniela Babici, Daniela David, Daniela Dincu, Danielle Bruno, Delia May, Delphine Haussaire, Delphine Henriet Viprey, Denis Bugnon, Denis Fouque, Denis Morin, Derradji Nour, Diab Mohamed Mahmoud, Diana Istrati Cristescu, Didier Aguilera, Didier Coste, Didier Hamel, Didier Le Chapois, Didier Testou, Dilaver Erbilgin, Djamal Dahmane, Doan Bui Quang, Dominique Bertrand, Dominique Besnier, Dominique Blanchier, Dominique Briffa, Dominique Caux, Dominique Durand, Dominique Fleury, Dominique Guerrot, Dominique Hestin, Dominique Jaubert, Dominique Joly, Dominique Lombart, Dominique Pagniez, Dominique Pierre, Dominique Schohn, Donatien Ikonga, Dorina Visanica, Dorothee Bazin, Edouard Boury, Edouard Maksour, Ekoue Agbonon, Elarbi Harrami, Elena Marcu, Elena Tudorache, Elisabeth Caniot, Elisabeth Semjen, Elisabeth Tomkiewicz, Elise Scheidt, Elke Gaboriau, Elodie Lamouroux, Elsa Guiard, Elsa Martin Passos, Emerson Nsembani, Emilie Fache, Emilie Kalbacher, Emilie Pambrun, Emilie Pincon, Emma Allain Launay, Emmanuel Baron, Emmanuel Dupuis, Emmanuel Villar, Emmanuelle Charlin, Emmanuelle Hecquet, Emmanuelle Kohler, Emmanuelle Rosier, Enrique Figueroa, Eric Azoulay, Eric Canivet, Eric Daugas, Eric Gauthier, Eric Laruelle, Eric Le Guen, Eric Legrand, Eric Moumas, Eric Postec, Eric Prinz, Eric Renaudineau, Estelle Desport, Estelle Ricard Sutra, Etienne Berard, Etienne Ged, Etienne Robin, Eve Vilaine, Evelyne Bargas, Evelyne Mac Namara, François Combarnous, Fatima Yazbeck, Fabien Gerard, Fabien Metivier, Fabien Parazols, Fabien Soulis, Fabrice Garnier, Fadhila Pech Messaoudene, Fadi Haidar, Fanny Boullenger, Fanny Lepeytre, Fanny Leroy, Fares Frejate, Farid Bellahsene, Farid Bellhasene, Farid Saidani, Fatouma Toure, Faycal Kriaa, Fazia Nemmar, Fernando Vetromile, Florence Chalmin, Florence Lucats, Florence Sens, Florence Villemain, Florent Plasse, Fouad Lebhour, Francis Schillinger, Franck Berge, Franck Bourdon, Franck Bridoux, Franck Reynaud, Francois Babinet, Francois Basse, Francois Chantrel, Francois Clair, Francois Coulomb, Francois De Cornelissen, Francois Glowacki, Francois Marchal, Francois Maurice, Francois Nobili, Francois Pourreau, Francois Provot, Francois Roux Amani, Francoise Broux, Francoise Bulte, Francoise Heibel, Francoise Leonetti, Francoise Moussion Schott, Frank Le Roy, Frederic Besson, Frederic Lavainne, Frederic Tollis, Frederique Bocquentin, Frederique Meeus, Frederique Vecina, Friederike Von Ey, Gabriel Balit, Gabriel Choukroun, Gabriel Gruget, Gabriel Huchard, Gabriella Golea, Gabrielle Duneau, Gaelle Lefrancois, Gaelle Pelle, Gaetan Lebrun, Genevieve Dumont, Georges Brillet, Georges Deschenes, Georges Mourad, Georges Stamatakis, Geraldine Cazajous, Geraldine D'ythurbide, Geraldine Robitaille Wiart, Gerard Cardon, Gerard Champion, Gerard Deschodt, Gerard Mangenot, Gerard Motte, Gerard Schortgen, Ghada Boulahia, Ghassan Maakaroun, Ghylene Bourdat Michel, Gilbert Zanetta, Gilles Hufnagel, Gilles Messier, Giorgina Piccoli, Gregoire Couvrat Desvergnes, Guillaume Bobrie, Guillaume Bonnard, Guillaume Clement, Guillaume Jean, Guillaume Queffeulou, Guillaume Seret, Guillaume Vernin, Guy Delavaud, Guy Lambrey, Guy Rostoker, Gwenaelle Poussard, Gwenaelle Roussey Kesler, H. Leon, Habib Aboubekr, Hacene Boulechfar, Hacene Sekhri, Hadia Hebibi, Hadjira Benalia, Hafed Fessi, Hafsabhai Atchia, Haiat Bittar, Hakim Maiza, Hakim Mazouz, Hamid El Ali, Hammouche Bougrida, Hans Van Der Pijl, Hassan Lokmane, Hassane Izzedine, Hassen Adda, Helene De Preneuf, Helene Leray, Helene Philippot, Henri Boulanger, Henri Merault, Henri Renaud, Herve Bonarek, Herve Maheut, Hilaire Nzeyimana, Hocine Mehama, Hocine Zaidi, Hugo Weclawiak, Hugues Flodrops, Huseyin Karaaslan, Ibrahim Haskour, Ihssen Belhadj, Imad Almoubarak, Imad Haddad, Ines Castellano, Ines Ferrandiz, Ioana Daniliuc, Ioana Darie, Ioana Enache, Ionut Prunescu, Irenee Djiconkpode, Irina Shahapuni, Isabelle Bouchoule, Isabelle Devriendt, Isabelle Kazes, Isabelle Kolb, Isabelle Landru, Isabelle Poli, Isabelle Rey, Isabelle Segalen, Isabelle Selcer, Isabelle Vernier, Isabelle Vrillon, Ismahane Guenifi, J. Dominique Gheerbrandt, Jacky Potier, Jacques Becart, Jacques Cledes, Jacques Ducros, Jacques Duvic, Jacques Fourcade, Jacques Gaultier, Jacques Jurine, Jacques Lebleu, Jacques Ollier, Jacques Ibsen Charles, Jamal Yazji, Janette Mansour, Jean Arnautou, Jean Brocard, Jean Carolfi, Jean Montoriol, Jean Baptiste Gouin, Jean Bernard Palcoux, Jean Christophe Bendini, Jean Claude Aldigier, Jean Claude Alphonse, Jean Daniel Delbet, Jean Francois Bonne, Jean Francois Cantin, Jean Francois De Fremont, Jean Francois Dessassis, Jean Francois Subra, Jean Francois Valentin, Jean Francois Verdier, Jean Jacques Dion, Jean Jacques Haultier, Jean Jacques Montseny, Jean Louis Bacri, Jean Louis Bouchet, Jean Luc Mahe, Jean Marc Chalopin, Jean Marc Gabriel, Jean Marc Hurot, Jean Marc Lanau, Jean Marie Batho, Jean Marie Coulibaly, Jean Michel Hardin, Jean Michel Marc, Jean Michel Poux, Jean Michel Rebibou, Jean Michel Tivollier, Jean Noel Ottavioli, Jean Paul Faucon, Jean Paul Imiela, Jean Paul Jaulin, Jean Paul Masselot, Jean Paul Ortiz, Jean Philippe Bourdenx, Jean Philippe Devaux, Jean Philippe Hammelin, Jean Pierre Rivory, Jean Pierre Wauquier, Jean Rene Larue, Jean Rene Mondain, Jean Sebastien Borde, Jean Simon Virot, Jean Yves Bosc, Jedjiga Achiche, Jennifer Parasote, Jeremie Diolez, Jerome Harambat, Jerome Potier, Jerome Sampol, Jihad Mustel, Jean Jacques Lefevre, Jocelyne Maurizi, Joel Gamberoni, Joelle Claudeon, Joelle Terzic, Joffrey Rogol, Johnny Sayegh, Jorge Cardozo, Jose Brasseur, Jose Guiserix, Joseph Barsumau, Julie Albaret, Julie Beaume, Julie Sohier Attias, Julien Dehay, Julien Hogan, Julien Journet, Julien Ott, Juliette Baleynaud, Justine Bacchetta, Justine Faucher, Kamel Yousfi, Karim Dardim, Karine Clabault, Karine Moreau, Kedna Thomas, Khaled Sirajedine, Khalil Chedid, Khalil El Kaeoui, Khalil El Karoui, Khedidja Bouachi, Kheira Hue, Khuzama El Nasser, Kodso Akposso, Kristian Kunz, Krzysztof Bijak, Lilia Kihal, L. Rasoloarijaona, Laid Harbouche, Larbi Bencheikh, Larbie Lamriben, Latifa Hanafi, Laura Braun Parvez, Laure Champion, Laure Croze, Laure Eprinchard, Laure Patrier, Laurence Nicolet, Laurence Vrigneaud, Laurent Duflot, Leandre Mackaya, Leila Chenine, Leon Odry, Lili Taghipour Tamiji, Lilia Antri Bouzar, Liliane Ngango Nga Messi, Lionel Le Mouellic, Lise Mandart, Lise Weis, Lise Marie Pouteau, Lora Georgieva, Lorita Vitanova, Lotfi Chalabi, Luc Delvallez, Luc Fromentin, Luc Marty, Luc Monjot, Luciana Spataru, Lucie Bessenay, Lucie Boissinot, Lucie Wajsbrot, Lucien Rakoff, Ludivine Lebourg, Lydie Perez, Lyliane Lafage, Lynda Azzouz, Madeleine Dumoulin, Messaoud Ouziala, Maan Joseph, Mabrouk Brahimi, Maeva Wong Fat, Magalie Fort, Magued Nakhla, Mahdi Abtahi, Mahen Albadawy, Mahmoud Alouach, Mahmoud Mezghani, Maite Daroux, Maklouf Boukelmoune, Malek Dhib, Malik Touam, Malina Dubau, Mamadou Balde, Man Nguyen Khoa, Manfred Ismer, Manolie Mehdi, Manon Laforet, Marc Bouiller, Marc Eugene, Marc Fila, Marc Hazzan, Marc Kribs, Marc Ladriere, Marc Lebot, Marc Padilla, Marc Souid, Marcel Marraoui, Maren Burbach, Maria Manescu, Maria Eugenia Noguera Gonzalez, Mariana Revenco, Marianne Terrasse, Marie Essi, Marie Alice Macher, Marie Beatrice Nogier, Marie Cecile Cazin, Marie Christine Schweitzer Camoin, Marie Christine Thouret, Marie Claude Hannaert, Marie France Servel, Marie Helene Chabannier, Marie Jeanne Coudert Krier, Marie Noelle Catoliquot, Marie Paule Guillodo, Marie Sophie Gavard, Marie Xaviere Vairon Codaccioni, Marina Rabec, Marine Freist, Marion Gauthier, Marion Lemaire, Marion Mehrenberger, Marion Venot, Marios Pongas, Marlene Beaubrun Diant, Martial Levannier, Martine Bertaux, Mathieu Jablonski, Mathieu Sacquepee, Mathilde Dargelos, Mathilde Lemoine, Mathilde Tamain, Matthieu Monge, Matthieu Reberolle, Maud Cousin, Maud Francois, Maurice Baron, Maxime Hoffmann, Maxime Ingwiller, Maxime Touzot, Mederick Mohajer, Mehadji Maaz, Melanie Hanoy, Melanie Marroc, Melodie Cuny, Menno Van Der Straaten, Mf. Serveaux, Michel Basteri, Michel Fen Chong, Michel Hecht, Michel Massad, Michel Normand, Michel Olmer, Michel Tolani, Michel Tsimaratos, Michele Hemery, Michele Kessler, Miguel Esposito, Milad Shenouda, Mimi Kareche, Mina Khalili, Mirella Diaconita, Mohamad Khair Rifard, Mohamed Aladib, Mohamed Belmouaz, Mohamed Brahim, Mohamed Diouani, Mohamed Fodil Cherif, Mohamed Jamali, Mohamed Maghlaoua, Mohamed Meddeb, Mohamed Ramdane, Mohamed Rifaat, Mohamed Sharifull Islam, Mohamed Adnan Abbade, Mokhtar Amrandi, Mokhtar Chawki, Monica Ciobotaru, Monica Indrieis, Monique Chanas, Monique Hoarau, Monzer Tomeh, Moufida Bellou, Mouloud Bouzernidj, Mounia Ammor, Mounir Guergour, Mountassir Benzakour, Mourad Hachicha, Moussa Coulibaly, Mustafa Smati, Mustapha Al Morabiti, Mustapha Amirou, Myriam Isnard, Myriam Pastural, Myriam Pujo, Nourredine Boumendjel, Nabil Majbri, Nabila Goumri, Nadege Mingat, Nader Bassilios, Nadia Kerkeni, Nadia Sedrati, Nadia Soltani, Nadine Maroun, Nadine Neyrat, Nahn Luang, Najeh El Esper, Naji Ammar, Nasredine Ghali, Nasser Hamdini, Natacha Noel, Natacha Potelune, Nathalie Maisonneuve, Nathalie Pertuiset, Nathalie Raynal, Nathalie Vittoz, Nazim Terki, Nelly Castin, Nestor Nankeu, Nicolas Bouvier, Nicolas Keller, Nicolas Legros, Nicolas Peters, Nicolas Quirin, Nicole Lefrancois, Nicole Monnier, Nicole Rance, Niels Bruckmann, Noel Mertens, Nolwenn Lorcy, Olivia Gilbert, Olivier Coldefy, Olivier Drouineau, Olivier Dunand, Olivier Fritz, Olivier Imhoff, Olivier Kourilsky, Olivier Lavelle, Olivier Papin, Olivier Roques, Ophelie Le Maner, Oussamah Fikri Benbrahim, Pablo Antonio Erina Torres, Pablo Antonio Urena Torres, Paolo Malvezzi, Pascal Bindi, Pascal Cluzel, Pascal Fontanier, Pascal Wheatley, Pascale Depraetre, Pascale Dubosq, Pascale Halin, Pascale Sebahoun, Pascale Siohan, Pascale Testevuide, Patrice Deteix, Patrice Nolen, Patricia Hue, Patricia Lemarchand, Patrick Donnadieu, Patrick Fievet, Patrick Fohrer, Patrick Francais, Patrick Giraud, Patrick Hallonet, Patrick Henri, Patrick Michaut, Patrick Niaudet, Patrick Pauly, Patrick Thomas, Patrik Deleaval, Paul Finielz, Paul Stroumza, Paule Hardy Yverneau, Pauline Caillard, Pedro Palacin, Perrine Aubertin, Philippe Attias, Philippe Chauveau, Philippe Coindre, Philippe Coste, Philippe Dubot, Philippe Fournier, Philippe Hiernaux, Philippe Jousset, Philippe Lan Yue Wah, Philippe Lang, Philippe Le Cacheux, Philippe Martin Dupont, Philippe Michel, Philippe Mirgaine, Philippe Moriniere, Philippe Nicoud, Philippe Rieu, Philippe Rousseau, Philippe Sporer, Philippe Thorel, Philippe Vanhille, Philippe Vigeral, Philippe Zaoui, Pierre Bataille, Pierre Brignon, Pierre Filipozzi, Pierre Housset, Pierre Peyronnet, Pierre Ramperez, Pierre Vautrin, Pierre Alexandre Michel, Pierre Francois Westeel, Pierre Louis Carron, Pierre Yves Durand, Pierrot Parent, Piotr Seniuta, François Kuentz, Rabah Fraoui, Rachel Tetaz, Rachid Amaria, Rachid Bourouma, Rachid Djeffal, Rachida Nebbad, Radia Allal, Radu Dimulescu, Rafaat Boustani, Rafik Mesbah, Raifat Makdassi, Raji Diab, Raluca Puslenghea, Raoul Roura, Rateb Khayat, Raymond Azar, Raymond Frayssinet, Regine Monkam, Rehouni Boulahrouz, Remi Boudet, Renato Demontis, Renaud Gansey, Rene Cuvelier, Renee Schmitt, Reschad Noordally, Reynald Binaut, Rezkallah Latif, Richard Dufresne, Richard Montagnac, Richard Reade, Robert Genin, Robert Novo, Rocsana Fickl, Roger Dufresne, Roger Magnol, Roland Issautier, Romain Mortelette, Ronan Delaval, Ronan Lohro, Roseline M'barga, S. Beau, Clémentine Dupuis, Marie Jacques Vidil, Sabria Hacini, Said Dahmoune, Saliha Lekhal, Salima Ahriz Sakso, Salima Saksi, Salvatore Citarda, Samir Boubenider, Samuel Kassis, Sandra Verhille, Sandrine Genestier, Sandrine Muller, Saoussen Krid, Sarah Richter, Sebastien Delbes, Sebastien Mailliez, Sebastien Veillon, Sébastien Nony, Seddick Benarbia, Severine Beaudreuil, Sidi Ali Benyaghla, Simon Duquennoy, Simona Baluta, Simona Boncila, Sonia Mzoughi, Sonia Ribal, Sophie Acamer, Sophie Chauvet, Sophie Girerd, Sophie Ozenne, Sophie Parahy, Sophie Rubens Duval, Sophie Taque, Soraya Menouer, Soumaya Chargui, Stanislas Bataille, Stephane Barbier, Stephane Billion, Stephane Roueff, Stephane Torner, Stephane Jean Martin, Stephanie Coupel, Sylvie Cloarec, Sylvie Lavaud, Sylvie Leou, T. Chatelet, Tania Onesta, Tassadit Benhabib, Tayeb Bensalem, Theodora Dimulescu, Theophile Sawadogo, Thibault Dolley Hitze, Thierry Baranger, Thierry Boudemaghe, Thierry Hannedouche, Thierry Krummel, Thierry Milcent, Thomas Dervaux, Thomas Guincestre, Thomas Kofman, Thomas Raphael, Thomas Sadreux, Tim Ulinski, Tiphaine Guyon Roger, Tomas Serrato, Tomek Kofman, Tony Wong, Toufik Boubia, Ubald Assogba Gbindoun, Usama Khuzaie, Valerie Caudwell, Valerie Chatelet, Valerie Crougneau, Valerie De Precigout, Valerie Drouillat, Valerie Galantine, Valerie Granveau Hugot, Valerie Leroy, Veronique Boubia, Veronique Falque, Veronique Fournier, Veronique Queron, Veronique Viviani, Victor Gueuttin, Victor Panescu, Victorio Menoyo Calonge, Viet Nguyen, Vincent Allot, Vincent Delattre, Vincent Leduc, Vincent Pradier, Violaine Emal Aglae, Viorica Badulescu, Virginia Molina, Virginie Besson, Virginie Chaigne, Waddah Jaber, Wael Boudi, Wael El Haggan, Wen Qin Guillon, Wided Tabbi Aneni, William Hanf, Wladimir Kohn, Xavier Bellenfant, Xavier Moreau Gaudry, Yahsou Delmas, Yannick Knefati, Yannick Saingra, Yannick Tirolien, Youssef Mann, Yvan Brunak, Yves Dimitrov, Yves Doussy, Yves Tanter, Zaid Benabid, Zaara Soltani, Zacharia Boukerroucha, Zafer Takla, Zana Ramanantsialonina, Zara Dickson, Zead Tubail, Zoe Koochaki Pour, Zohra Boukhalfa, Zohra Jacquot, Agence de la biomédecine [Saint-Denis la Plaine], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Université de Caen Normandie (UNICAEN), Normandie Université (NU), CALYDIAL Vienne, Partenaires INRAE, Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Armand Trousseau [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de néphrologie et transplantation rénale [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Service d'Epidémiologie et Evaluations Cliniques [CHRU Nancy] (Pôle S2R), Centre Universitaire des Maladies Rénales [CHU Caen] (CUMR Caen), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), 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), Groupe hospitalier de la région de Mulhouse Sud-Alsace (GHRMSA), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Aide à la Décision pour une Médecine Personnalisé - Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - EA 2415 (AIDMP), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Assistance Publique - Hôpitaux de Marseille (APHM), Service de diabétologie [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Service de Diabétologie [CHU Pitié-Salpétrière], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Male, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Hemodialysis, Home, Disease, MESH: COVID-19 / therapy, registry, Ambulatory Care Facilities, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, MESH: Aged, 80 and over, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Risk Factors, 80 and over, Prevalence, covid, dialysis, epidemiology, mortality, Aged, Aged, 80 and over, COVID-19, Case-Control Studies, Critical Care, Female, France, Humans, Incidence, Middle Aged, Patient Acuity, Protective Factors, Registries, Renal Dialysis, SARS-CoV-2, Sex Factors, Hypoalbuminemia, MESH: France / epidemiology, education.field_of_study, Incidence (epidemiology), 3. Good health, MESH: COVID-19 / epidemiology, Nephrology, Hemodialysis, medicine.medical_specialty, Population, Lower risk, Article, 03 medical and health sciences, MESH: Sex Factors, Internal medicine, medicine, MESH: SARS-CoV-2, MESH: Renal Dialysis / statistics & numerical data, education, Dialysis, Vascular disease, business.industry, medicine.disease, Former Smoker, MESH: Critical Care / statistics & numerical data, 030104 developmental biology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Home, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH: Hemodialysis, Home / statistics & numerical data
Abstract: The aim of this study was to estimate the incidence of COVID-19 disease in the French national population of dialysis patients, their course of illness and to identify the risk factors associated with mortality. Our study included all patients on dialysis recorded in the French REIN Registry in April 2020. Clinical characteristics at last follow-up and the evolution of COVID-19 illness severity over time were recorded for diagnosed cases (either suspicious clinical symptoms, characteristic signs on the chest scan or a positive reverse transcription polymerase chain reaction) for SARS-CoV-2. A total of 1,621 infected patients were reported on the REIN registry from March 16th, 2020 to May 4th, 2020. Of these, 344 died. The prevalence of COVID-19 patients varied from less than 1% to 10% between regions. The probability of being a case was higher in males, patients with diabetes, those in need of assistance for transfer or treated at a self-care unit. Dialysis at home was associated with a lower probability of being infected as was being a smoker, a former smoker, having an active malignancy, or peripheral vascular disease. Mortality in diagnosed cases (21%) was associated with the same causes as in the general population. Higher age, hypoalbuminemia and the presence of an ischemic heart disease were statistically independently associated with a higher risk of death. Being treated at a selfcare unit was associated with a lower risk. Thus, our study showed a relatively low frequency of COVID-19 among dialysis patients contrary to what might have been assumed., Graphical abstract
Published: 2020
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10. Hemolytic uremic syndrome associated with Bordetella pertussis infection in a 2-month-old infant carrying a pathogenic variant in complement factor H

Author: Véronique Frémeaux-Bacchi, Brigitte Llanas, Astrid Godron-Dubrasquet, Lubka T. Roumenina, Hélène Langlois-Meurinne, Iona Madden, Jérôme Harambat, and Julie Guichoux
Subjects: Male, Nephrology, Hemolytic anemia, medicine.medical_specialty, Bordetella pertussis, Whooping Cough, medicine.drug_class, medicine.medical_treatment, Antibiotics, 030232 urology & nephrology, 030204 cardiovascular system & hematology, Antibodies, Monoclonal, Humanized, Polymorphism, Single Nucleotide, Peritoneal dialysis, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Internal medicine, Humans, Medicine, Blood Transfusion, Complement Activation, Atypical Hemolytic Uremic Syndrome, Binding Sites, biology, business.industry, Infant, Newborn, Acute kidney injury, Infant, Eculizumab, medicine.disease, biology.organism_classification, Anti-Bacterial Agents, 3. Good health, Complement Factor H, Factor H, Complement C3b, Pediatrics, Perinatology and Child Health, Immunology, business, Peritoneal Dialysis, Infant, Premature, medicine.drug
Abstract: Hemolytic uremic syndrome (HUS) has been associated with a number of infectious agents. We report here the case of an infant with severe Bordetella pertussis infection who developed HUS. A 2-month-old preterm male was admitted for severe Bordetella pertussis infection. Symptoms leading to a diagnosis of hemolytic uremic syndrome (HUS) rapidly appeared: hemolytic anemia, thrombocytopenia, and acute kidney injury. He was treated with 25 days of peritoneal dialysis and received complement-targeting therapy with eculizumab (five injections over 2 months), in addition to blood transfusions, antibiotics, and respiratory support. The outcome was favorable. The genetic workup found a complement factor H gene variant which has been associated with atypical HUS. This variant was located in the C3b-binding site and functional tests revealed that it perturbed the regulatory activity of factor H. This case suggests that pertussis is a strong trigger of HUS and that complement investigations are necessary to guide treatment and understand the pathophysiology.
Published: 2018
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11. Long-term outcome of diarrhea-associated hemolytic uremic syndrome is poorly related to markers of kidney injury at 1-year follow-up in a population-based cohort

Author: Yahsou Delmas, Astrid Godron-Dubrasquet, Catherine Monet-Didailler, Brigitte Llanas, Jérôme Harambat, and Iona Madden
Subjects: Male, Nephrology, Time Factors, 030232 urology & nephrology, 030204 cardiovascular system & hematology, Kidney, Diarrhea-associated Hemolytic Uremic Syndrome, 0302 clinical medicine, Risk Factors, Prevalence, Child, Escherichia coli Infections, education.field_of_study, Proteinuria, Shiga-Toxigenic Escherichia coli, Incidence, Age Factors, Acute kidney injury, Acute Kidney Injury, Prognosis, 3. Good health, medicine.anatomical_structure, Child, Preschool, Disease Progression, Female, France, medicine.symptom, Glomerular Filtration Rate, Diarrhea, medicine.medical_specialty, Adolescent, Population, Renal function, Risk Assessment, 03 medical and health sciences, Internal medicine, medicine, Humans, Renal Insufficiency, Chronic, education, Retrospective Studies, urogenital system, business.industry, Infant, medicine.disease, Hemolytic-Uremic Syndrome, Pediatrics, Perinatology and Child Health, business, Kidney disease
Abstract: Hemolytic uremic syndrome due to Shiga toxin–producing E. coli (STEC-HUS) is the main cause of acute kidney injury in young children. Most fully recover kidney function; however, some develop long-term sequelae. We aimed to determine whether kidney injury 1 year after HUS onset is associated with long-term kidney outcome in pediatric STEC-HUS. A retrospective population-based study of children
Published: 2018
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12. Conduite à tenir devant un rein unique

Author: A. Godron-Dubrasquet, Jérôme Harambat, C. Didailler, and Brigitte Llanas
Subjects: medicine.medical_specialty, Urinary system, 030232 urology & nephrology, Urology, Renal function, 030204 cardiovascular system & hematology, urologic and male genital diseases, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Kidney, Creatinine, Proteinuria, urogenital system, business.industry, Glomerulosclerosis, medicine.disease, female genital diseases and pregnancy complications, Endocrinology, medicine.anatomical_structure, chemistry, Pediatrics, Perinatology and Child Health, medicine.symptom, business, Glomerular hyperfiltration, Kidney disease
Abstract: Solitary functioning kidneys form an important subgroup of congenital anomalies of the kidney and urinary tract (CAKUT). A solitary kidney can be congenital or acquired after unilateral nephrectomy and is often associated with ipsilateral urogenital anomalies. Both types of solitary functioning kidney are associated with an increased risk of chronic kidney disease (CKD). A low functional nephron number results in compensatory glomerular hypertension and enlargement of remnant nephrons, indicating glomerular hyperfiltration. Glomerular hyperfiltration may lead to glomerulosclerosis, which further results in hypertension, proteinuria, and decline of the glomerular filtration rate (GFR) in the long run. About 20-30% of patients with solitary functioning kidney have hypertension, proteinuria, or reduced GFR during childhood, especially those with associated CAKUT. Regular and lifetime monitoring (including growth, blood pressure, serum creatinine, proteinuria or microalbuminuria, and renal ultrasound) is required. The frequency and modality of follow-up should be adapted to individual risk for CKD. Early detection of renal injury and timely nephroprotective measures are critical.
Published: 2017
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13. Donor-targeted serotherapy as a rescue therapy for steroid-resistant acute GVHD after HLA-mismatched kidney transplantation

Author: Juliette Leon, Nathalie Aladjidi, Romain Berthaud, Armance Marchal, Jean Luc Taupin, Rémi Salomon, Baptiste Lamarthée, Rachid Djoudi, Romain Lévy, Marina Charbit, Sylvie Gross, Julien Zuber, Bénédicte Neven, Pierre Tiberghien, Astrid Godron-Dubrasquet, Michael Dussiot, Sarah Winter, Stéphane Blanche, Isabelle Jollet, Jonathan Visentin, Marina Cavazzana, Virginie Renac, Marion Rabant, Saoussen Krid, Nathalie Gouge‐Biebuyck, Brigitte Llanas, Olivia Boyer, Lise Allard, Isabelle André, Florence Lacaille, Melissa Ould Rabah, and Pauline Krug
Subjects: Adoptive cell transfer, Transplantation Conditioning, medicine.medical_treatment, T cell, Graft vs Host Disease, Human leukocyte antigen, 030230 surgery, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Immunology and Allergy, Humans, Pharmacology (medical), Child, Kidney transplantation, Transplantation, biology, business.industry, Immunization, Passive, Immunosuppression, medicine.disease, Kidney Transplantation, Histocompatibility, surgical procedures, operative, medicine.anatomical_structure, Immunology, biology.protein, Steroids, Antibody, business
Abstract: Acute graft-versus-host disease (GVHD) is a rare but frequently lethal complication after solid organ transplantation. GVHD occurs in unduly immunocompromised hosts but requires the escalation of immunosuppression, which does not discriminate between host and donor cells. In contrast, donor-targeted therapy would ideally mitigate graft-versus-host reactivity while sparing recipient immune functions. We report two children with end-stage renal disease and severe primary immune deficiency (Schimke syndrome) who developed severe steroid-resistant acute GVHD along with full and sustained donor T cell chimerism after isolated kidney transplantation. Facing a therapeutic dead end, we used a novel strategy based on the adoptive transfer of anti-HLA donor-specific antibodies (DSAs) through the transfusion of highly selected plasma. After approval by the appropriate regulatory authority, an urgent nationwide search was launched among more than 3800 registered blood donors with known anti-HLA sensitization. Adoptively transferred DSAs bound to and selectively depleted circulating donor T cells. The administration of DSA-rich plasma was well tolerated and notably did not induce antibody-mediated rejection of the renal allografts. Acute GVHD symptoms promptly resolved in one child. This report provides a proof of concept for a highly targeted novel therapeutic approach for solid organ transplantation-associated GVHD.
Published: 2019

14. Mycophenolic Acid Pharmacokinetics and Relapse in Children with Steroid–Dependent Idiopathic Nephrotic Syndrome

Author: Aymeric Dallocchio, Flavio Bandin, Brigitte Llanas, L. Ichay, Astrid Godron, Stéphane Bouchet, Peggy Gandia, F Saint-marcoux, Vincent Guigonis, Jérôme Harambat, Karine Brochard, Stéphane Decramer, Denis Morin, Pierre Marquet, and Stéphanie Tellier
Subjects: Male, medicine.medical_specialty, Nephrotic Syndrome, Epidemiology, Population, 030232 urology & nephrology, Critical Care and Intensive Care Medicine, Mycophenolate, 030226 pharmacology & pharmacy, Gastroenterology, Mycophenolic acid, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Recurrence, Prednisone, Internal medicine, medicine, Humans, Immunologic Factors, education, Glucocorticoids, Retrospective Studies, Transplantation, education.field_of_study, Systemic lupus erythematosus, medicine.diagnostic_test, business.industry, Original Articles, Mycophenolic Acid, medicine.disease, Surgery, Nephrology, Therapeutic drug monitoring, Area Under Curve, Child, Preschool, Female, business, Nephrotic syndrome, medicine.drug
Abstract: Background and objectives Therapeutic drug monitoring of mycophenolic acid can improve clinical outcome in organ transplantation and lupus, but data are scarce in idiopathic nephrotic syndrome. The aim of our study was to investigate whether mycophenolic acid pharmacokinetics are associated with disease control in children receiving mycophenolate mofetil for the treatment of steroid–dependent nephrotic syndrome. Design, setting, participants, & measurements This was a retrospective multicenter study including 95 children with steroid–dependent nephrotic syndrome treated with mycophenolate mofetil with or without steroids. Area under the concentration-time curve of mycophenolic acid was determined in all children on the basis of sampling times at 20, 60, and 180 minutes postdose, using Bayesian estimation. The association between a threshold value of the area under the concentration-time curve of mycophenolic acid and the relapse rate was assessed using a negative binomial model. Results In total, 140 areas under the concentration-time curve of mycophenolic acid were analyzed. The findings indicate individual dose adaptation in 53 patients (38%) to achieve an area under the concentration-time curve target of 30–60 mg·h/L. In a multivariable negative binomial model including sex, age at disease onset, time to start of mycophenolate mofetil, previous immunomodulatory treatment, and concomitant prednisone dose, a level of area under the concentration-time curve of mycophenolic acid >45 mg·h/L was significantly associated with a lower relapse rate (rate ratio, 0.65; 95% confidence interval, 0.46 to 0.89; P=0.01). Conclusions Therapeutic drug monitoring leading to individualized dosing may improve the efficacy of mycophenolate mofetil in steroid–dependent nephrotic syndrome. Additional prospective studies are warranted to determine the optimal target for area under the concentration-time curve of mycophenolic acid in this population.
Published: 2016
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15. Generation of induced pluripotent stem cells-derived hepatocyte-like cells for ex vivo gene therapy of primary hyperoxaluria type 1

Author: Julie, Estève, Jean-Marc, Blouin, Magalie, Lalanne, Lamia, Azzi-Martin, Pierre, Dubus, Audrey, Bidet, Jérôme, Harambat, Brigitte, Llanas, Isabelle, Moranvillier, Aurélie, Bedel, François, Moreau-Gaudry, and Emmanuel, Richard
Subjects: Hyperoxaluria, Primary, Induced Pluripotent Stem Cells, Mutation, Hepatocytes, Humans, Genetic Therapy, Cellular Reprogramming, Transaminases
Abstract: Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder of the liver metabolism due to functional deficiency of the peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). AGT deficiency results in overproduction of oxalate which complexes with calcium to form insoluble calcium-oxalate salts in urinary tracts, ultimately leading to end-stage renal disease. Currently, the only curative treatment for PH1 is combined liver-kidney transplantation, which is limited by donor organ shortage and lifelong requirement for immunosuppression. Transplantation of genetically modified autologous hepatocytes is an attractive therapeutic option for PH1. However, the use of fresh primary hepatocytes suffers from limitations such as organ availability, insufficient cell proliferation, loss of function, and the risk of immune rejection. We developed patient-specific induced pluripotent stem cells (PH1-iPSCs) free of reprogramming factors as a source of renewable and genetically defined autologous PH1-hepatocytes. We then investigated additive gene therapy using a lentiviral vector encoding wild-type AGT under the control of the liver-specific transthyretin promoter. Genetically modified PH1-iPSCs successfully provided hepatocyte-like cells (HLCs) that exhibited significant AGT expression at both RNA and protein levels after liver-specific differentiation process. These results pave the way for cell-based therapy of PH1 by transplantation of genetically modified autologous HLCs derived from patient-specific iPSCs.
Published: 2018

16. Complement Gene Variants and Shiga Toxin-Producing

Author: Véronique, Frémeaux-Bacchi, Anne-Laure, Sellier-Leclerc, Paula, Vieira-Martins, Sophie, Limou, Theresa, Kwon, Annie, Lahoche, Robert, Novo, Brigitte, Llanas, François, Nobili, Gwenaëlle, Roussey, Mathilde, Cailliez, Tim, Ulinski, Georges, Deschênes, Corinne, Alberti, François-Xavier, Weill, Patricia, Mariani, and Chantal, Loirat
Subjects: Male, Time Factors, Shiga-Toxigenic Escherichia coli, Age Factors, Genetic Variation, Infant, Complement System Proteins, Original Articles, Prognosis, Risk Assessment, Phenotype, Gene Frequency, Risk Factors, Child, Preschool, Host-Pathogen Interactions, Disease Progression, Humans, Kidney Failure, Chronic, Female, Genetic Predisposition to Disease, France, Complement Activation, Escherichia coli Infections, Atypical Hemolytic Uremic Syndrome, Retrospective Studies
Abstract: BACKGROUND AND OBJECTIVES: Inherited complement hyperactivation is critical for the pathogenesis of atypical hemolytic uremic syndrome (HUS) but undetermined in postdiarrheal HUS. Our aim was to investigate complement activation and variants of complement genes, and their association with disease severity in children with Shiga toxin–associated HUS. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Determination of complement biomarkers levels and next-generation sequencing for the six susceptibility genes for atypical HUS were performed in 108 children with a clinical diagnosis of post-diarrheal HUS (75 Shiga toxin–positive, and 33 Shiga toxin–negative) and 80 French controls. As an independent control cohort, we analyzed the genotypes in 503 European individuals from the 1000 Genomes Project. RESULTS: During the acute phase of HUS, plasma levels of C3 and sC5b-9 were increased, and half of patients had decreased membrane cofactor protein expression, which normalized after 2 weeks. Variants with minor allele frequency
Published: 2018

17. Clinical and genetic heterogeneity in familial steroid-sensitive nephrotic syndrome

Author: Imen Chabchoub, Didier Lacombe, Marion Sallée, Phillippe Dolhem, Dominique Durand, Karin Dahan, Pierre Ronco, Eric Rondeau, Sylvie Cloarec, Julien Hogan, Gérard Champion, David Ribes, Hubert Nivet, Laurent Mesnard, Georges Deschênes, Thierry Krummel, Khalil El Karoui, Claire Pouteil Noble, Christine Pietrement, Yahsou Delmas, Olivier Gribouval, Olivia Boyer, Tim Ulinski, N. Mohsin, Patrick Niaudet, Guillaume Dorval, Aurélie Hummel, Vanesa Martinez-Barquero, Mongia Hachicha, Véronique Baudouin, Corinne Antignac, Marie-Josèphe Tête, Michel Fischbach, Paloma Maria Parvex, Hassib Chehade, Rémi Salomon, Brigitte Llanas, Dominique Chauveau, Jacques Dantal, Jean-Pierre Grünfeld, S. Benoit, Nassim Kamar, Loïc de Pontual, Eduardo Machuca, Pierre Cochat, Vincent Guigonis, Maryvonne Hourmant, Zelal Ekinci, Chokri Chouchane, Michel Tsimaratos, Laboratoire des Maladies Rénales Héréditaires, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Molecular bases of hereditary kidney diseases: nephronophthisis and hypodysplasia (Equipe Inserm U1163), Néphropathies héréditaires et rein en développement (UMR_S 983), CHU Necker - Enfants Malades [AP-HP]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hedi Chaker Hospital [Sfax], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Département de Néphrologie et Transplantation d'organes, Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Université de Monastir - University of Monastir (UM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Département de Pédiatrie, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Institute of Pathology and Genetics, Immunointervention dans les allo et xénotransplantations, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM)-ITUN, Service de Néphrologie-transplantation-dialyse [Bordeaux], CHU Bordeaux [Bordeaux], Service de néphrologie et pédiatrie générale [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Centre hospitalier de Saint-Quentin, Unité Mixte de Recherches sur les Herbivores - UMR 1213 (UMRH), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA), Kocaeli Academy for Solidarity, Centre d'infectiologie Necker-Pasteur [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Service de Pédiatrie, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de néphrologie pédiatrique [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Department of Pediatrics, Service de Néphrologie pédiatrique [Hôpital Robert Debré, Paris], Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de Néphrologie - Hypertension Artérielle Dialyse - Transplantation, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Service de néphrologie et hémodialyse [CHU de Strasbourg], CHU Strasbourg, Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre de Référence du Sud Ouest des Maladies Rénales Rares, CHU Toulouse [Toulouse]-Hôpital des Enfants, Remodelage et Reparation du Tissu Renal, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sultan Qaboos University (SQU), Service de Néphrologie, Hôpital de Clocheville, Geneva University Hospital (HUG), Centre Hospitalier Universitaire de Reims (CHU Reims)-American Memorial Hospital (Reims), Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHU Tenon [APHP], Service de Néphrologie et Dialyses [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Centre recherche en CardioVasculaire et Nutrition (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Néphrologie Pédiatrique [Trousseau], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Département de Néphrologie et Transplantation d'organes [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Jean Verdier [AP-HP], CHU Tenon [AP-HP], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Pasteur [Paris], Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, Glucocorticoids/therapeutic use, Adult, Male, Nephrotic Syndrome, Adolescent, Nephrotic Syndrome/drug therapy/genetics, 030232 urology & nephrology, Disease, Biology, medicine.disease_cause, HLA-DQ alpha-Chains, 03 medical and health sciences, Genetic Heterogeneity, Young Adult, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], HLA-DQ alpha-Chains/genetics, medicine, Humans, Genetic Predisposition to Disease, Young adult, Preschool, Child, Gene, Glucocorticoids, Exome sequencing, ComputingMilieux_MISCELLANEOUS, Genetics, Mutation, ddc:618, Membrane Glycoproteins, Genetic heterogeneity, Infant, Sequence Analysis, DNA, Membrane Glycoproteins/genetics, Middle Aged, medicine.disease, 3. Good health, DNA/methods, 030104 developmental biology, Nephrology, Child, Preschool, Pediatrics, Perinatology and Child Health, Cohort, Female, Nephrotic syndrome, Sequence Analysis
Abstract: Familial steroid-sensitive nephrotic syndrome (SSNS) is a rare condition. The disease pathophysiology remains elusive. However, bi-allelic mutations in the EMP2 gene were identified, and specific variations in HLA-DQA1 were linked to a high risk of developing the disease. Clinical data were analyzed in 59 SSNS families. EMP2 gene was sequenced in families with a potential autosomal recessive (AR) inheritance. Exome sequencing was performed in a subset of 13 families with potential AR inheritance. Two variations in HLA-DQA1 were genotyped in the whole cohort. Transmission was compatible with an AR (n = 33) or autosomal dominant (AD, n = 26) inheritance, assuming that familial SSNS is a monogenic trait. Clinical features did not differ between AR and AD groups. All patients, including primary (n = 7) and secondary steroid resistant nephrotic syndrone (SRNS), (n = 13) were sensitive to additional immunosuppressive therapy. Both HLA-DQA1 variations were found to be highly linked to the disease (OR = 4.34 and OR = 4.89; p
Published: 2018
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18. Prevalence of Novel MAGED2 Mutations in Antenatal Bartter Syndrome

Author: Amélie Ryckewaert, Nadine Jay, Aurélia Bertholet-Thomas, Gilles Morin, Georges Deschênes, Cyrielle Treard, Vincent Guigonis, Rémi Salomon, Denis Morin, Brigitte Llanas, Rosa Vargas-Poussou, Daniele Bruno, Stéphane Decramer, Djamal Djeddi, François Nobili, Anne Blanchard, Isabelle Vrillon, Tackwa Khalifeh, Christine Pietrement, Françoise Broux, Sophie Dreux, Isabelle Roncelin, Anne Legrand, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Toulouse [Toulouse], Service de Pédiatrie médicale [CHU Limoges], CHU Limoges, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre de Référence du Sud Ouest des Maladies Rénales Rares, CHU Toulouse [Toulouse]-Hôpital des Enfants, CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Amiens-Picardie, Service de pédiatrie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de néphrologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), and École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Proband, Male, Pediatrics, Epidemiology, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, 030232 urology & nephrology, Critical Care and Intensive Care Medicine, 0302 clinical medicine, Mutation Rate, Pregnancy, Prenatal Diagnosis, Prevalence, Missense mutation, Frameshift Mutation, X chromosome, Sequence Deletion, Sanger sequencing, education.field_of_study, Pregnancy Outcome, genetic renal disease, Adaptor Proteins, 3. Good health, Phenotype, Nephrology, Cohort, symbols, Female, France, Polyhydramnios, medicine.medical_specialty, X Chromosome, RNA Splicing, Population, Bartter syndrome, Frameshift mutation, 03 medical and health sciences, symbols.namesake, pediatric nephrology, Antigens, Neoplasm, medicine, Humans, Genetic Predisposition to Disease, Antigens, education, Adaptor Proteins, Signal Transducing, Retrospective Studies, Transplantation, business.industry, Signal Transducing, Bartter Syndrome, Original Articles, medicine.disease, 030104 developmental biology, Mutation, molecular genetics, Neoplasm, business
Abstract: 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.
Published: 2018
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19. La cystinose chez l’adulte : une maladie systémique

Author: Aurélia Bertholet-Thomas, Robert Novo, Brigitte Llanas, Cyril Goizet, Gabriel Choukroun, Aude Servais, and Stéphane Decramer
Subjects: Nephrology
Abstract: 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.
Published: 2015
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20. Clinical and Genetic Spectrum of Bartter Syndrome Type 3

Author: Maria Mileva, Sandrine Lemoine, Christiane Mousson, Elsa Seys, Rosa Vargas-Poussou, Mathilde Cailliez, Gwenaëlle Roussey-Kesler, Aurélia Bertholet-Thomas, Paul Cozette, Theresa Kwon, Anne Blanchard, Guylhène Bourdat-Michel, Pauline Krug, Jean Sébastien Borde, Jacques Teulon, Christophe Simian, Laurence Dubourg, Robert Novo, Isabelle Vrillon, Bertrand Knebelmann, Brigitte Llanas, Djamal Djeddi, Dominique Chaveau, Stephen B. Walsh, Olga Andrini, François Nobili, Jean Daniel Delbet, Marc Fila, Georges Deschênes, Mathilde Keck, Ferielle Louillet, Lamisse Mansour-Hendili, Elodie Merieau, Stéphane Decramer, Noémie Jourde-Chiche, Marie-Pierre Lavocat, Pierre-Yves Courand, Luisa Mota-Vieira, Guillaume Bobrie, Pediatric Nephrology Unit, American Memorial Hospital, Reims University Hospital, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Service de Génétique [CHU HEGP], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Cardiologie [Hôpital Croix- Rousse, HCL] (Centre d'excellence de la Société européenne d'hypertension artérielle), Hospices Civils de Lyon (HCL)-Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Génétique, Union nationale des coopératives d’élevage et d’insémination animale (UNCEIA), Unité de Néphrologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence des Maladies Rénales Rares Néphrogones, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Nephrology Unit, Clinique du Vert Galant, Tremblay-en-France, Nephrology Unit, Centre hospitalier de Saintonge, Saintes, Centre Hospitalo-Universitaire de Grenoble (CHU de Grenoble), CHU Grenoble, Service de pédiatrie multidisciplinaire [Hôpital de la Timone Enfants - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Assistance Publique - Hôpitaux de Marseille (APHM), Pediatric Nephrology Unit, Centre Hospitalier du Pays d'Aix, Nephrology Unit, Centre Hospitalier du Pays d'Aix, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Métabolomique et maladies métaboliques, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Référence du Sud Ouest des Maladies Rénales Rares, CHU Toulouse [Toulouse]-Hôpital des Enfants, CHU Toulouse [Toulouse], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Vascular research center of Marseille (VRCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Service de néphrologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Pédiatrie médicale et médecine de l'adolescent [Amiens], CHU Amiens-Picardie, Service de pédiatrie néonatale et réanimation - neuropédiatrie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Hôpital Charles Nicolle [Rouen]-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Department of Pediatrics, Centre Hospitalier Pierre Oudot de Bourgoin-Jallieu, Bourgoin-Jallieu, Molecular Genetics and Pathology Unit, Hospital of Divino Espirito Santo of Ponta Delgada, Service de néphrologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de néphrologie pédiatrique [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Department of Aeronautical and Automotive Engineering, Loughborough University, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Santé Lyon Est - Louis Léopold Ollier, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Union Nationale des Coopératives Agricoles d'Elevage et d'Insémination Animale, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Unité d'hypertension artérielle, Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), 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), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), 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), Service de nephrologie pédiatrique, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Université de Paris - Faculté de Médecine Paris Centre (UP Médecine Paris Centre), Université de Paris (UP), Service de Génétique [AP-HP Hôpital Européen Georges Pompidou, Paris], Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Grenoble (CHU de Grenoble), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Centre de néphrologie et transplantation rénale [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Service de pédiatrie néonatale et réanimation - neuropédiatrie [Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université de Lyon, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte [CHU-Necker] (MARHEA), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Charles Nicolle [Rouen], and Normandie Université (NU)-Normandie Université (NU)-CHU Rouen
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], Nonsense mutation, 030232 urology & nephrology, Bartter syndrome, urologic and male genital diseases, Hypocalciuria, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Tubulopathy, Clinical Research, Internal medicine, Genotype, medicine, Humans, Child, Genetic Association Studies, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, CLCNKB, biology, business.industry, Bartter Syndrome, Infant, General Medicine, Gitelman syndrome, medicine.disease, 3. Good health, Bartter's syndrome, 030104 developmental biology, Endocrinology, Nephrology, Child, Preschool, Mutation, biology.protein, Female, medicine.symptom, business
Abstract: 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.
Published: 2017
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21. 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
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22. Outbreak of Escherichia coli O104:H4 haemolytic uraemic syndrome in France: outcome with eculizumab

Author: Benjamin Clouzeau, Armel Reffet, Cécile Bordes, Hiba Bachir, P. Rolland, Christian Combe, Benoît Vendrely, Sophie Skopinski, Adeline Lacraz, Sébastien Helou, Brigitte Llanas, Hoang-Nam Bui, Didier Gruson, and Yahsou Delmas
Subjects: Adult, Diarrhea, Male, medicine.medical_specialty, Thrombotic microangiopathy, Renal function, Context (language use), Antibodies, Monoclonal, Humanized, Kidney, Gastroenterology, Disease Outbreaks, CLINICAL SCIENCE, chemistry.chemical_compound, haemolytic uraemic syndrome, Internal medicine, complement inhibition, Escherichia coli, medicine, Humans, Adverse effect, Escherichia coli Infections, Transplantation, Creatinine, Shiga-Toxigenic Escherichia coli, business.industry, Acute kidney injury, Middle Aged, Acute Kidney Injury, Eculizumab, medicine.disease, thrombotic microangiopathy, Treatment Outcome, chemistry, Nephrology, Child, Preschool, Hemolytic-Uremic Syndrome, Immunology, Female, eculizumab, France, medicine.symptom, business, medicine.drug
Abstract: Background An outbreak of haemolytic uraemic syndrome (HUS) due to Shiga toxin-secreting Escherichia coli (STEC) O104:H4 from contaminated fenugreek sprouts occurred in June 2011 near Bordeaux, France. In the context of this outbreak, all patients were treated with the monoclonal anti-C5 antibody, eculizumab. Methods The diagnosis of HUS was made based on haemolytic anaemia, low platelet count and acute kidney injury. Data were obtained from initial gastrointestinal symptoms to the end of follow-up 10 weeks after the start of eculizumab. Results Among 24 cases of STEC gastroenteritis, HUS developed in nine patients (eight adults and one child), 6 (median; range 3-12) days after digestive symptoms begun. The median (range) highest or lowest biological values were platelet count 26 (range 14-93) G/L; haemoglobin 6.6 (range 5-10.7) g/dL; LDH 1520 (range 510-2568) IU/L; creatinine 152 (range 48-797) µmol/L. All patients had extra-renal complications (liver 9, pancreas 5, brain 3 and heart 3). Two patients were dialysed, and one was ventilated. After failure of plasma exchange to increase platelets in the first three patients, eculizumab was administered in all nine patients, 0-4 days after HUS diagnosis (median 1 day). One patient with very severe neurological HUS received immunoadsorption. Outcome was favourable in all patients, with rapid normalization of haemoglobin, platelets, LDH levels, renal function and neurological improvement. There were no deaths and no serious adverse events related to eculizumab. Conclusions Early treatment of O104:H4 STEC-HUS by eculizumab was associated with a rapid and efficient recovery. Controlled prospective evaluation of eculizumab in STEC-HUS is warranted.
Published: 2013
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23. Long-term outcome of children treated with rituximab for idiopathic nephrotic syndrome

Author: Stéphanie Tellier, Stéphane Decramer, Arnaud Garnier, Brigitte Llanas, Aurélia Bertholet-Thomas, Sylvie Nathanson, Flavio Bandin, Mathilde Cailliez, Vincent Guigonis, Christine Pietrement, Olivier Dunand, L. Ichay, and Karine Brochard
Subjects: Male, Nephrology, medicine.medical_specialty, Pediatrics, Nephrotic Syndrome, Time Factors, Idiopathic Nephrotic Syndrome, Antibodies, Monoclonal, Murine-Derived, immune system diseases, hemic and lymphatic diseases, Internal medicine, medicine, Humans, Immunologic Factors, Child, Retrospective Studies, business.industry, Infant, Treatment Outcome, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, Rituximab, business, medicine.drug
Abstract: 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.
Published: 2013
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24. Late diagnosis of primary hyperoxaluria type III

Author: Emmanuel Richard, Cécile Acquaviva, Jérôme Harambat, Renaud de la Faille, Brigitte Llanas, Stéphane Bouchet, and Jean-Marc Blouin
Subjects: Male, medicine.medical_specialty, Delayed Diagnosis, medicine.medical_treatment, Urinary system, Clinical Biochemistry, 030232 urology & nephrology, Gene Expression, Urine, 030204 cardiovascular system & hematology, urologic and male genital diseases, Glyceric Acids, Kidney, Gastroenterology, Nephrectomy, Primary hyperoxaluria, 03 medical and health sciences, 0302 clinical medicine, Urolithiasis, Internal medicine, medicine, Humans, Carcinoma, Renal Cell, Aged, business.industry, Oxo-Acid-Lyases, General Medicine, medicine.disease, Kidney Neoplasms, Glycolates, Late diagnosis, Hyperoxaluria, Primary, Mutation, Etiology, Primary Hyperoxaluria Type III, business, Clear cell
Abstract: We report the case of a 78-year-old patient with late diagnosis of hyperoxaluria type III (PH3). He developed renal failure after nephrectomy for clear cell papillary renal carcinoma and complained of recurrent urolithiasis for some 30 years, whose aetiology was never identified. Biochemical laboratory investigations of urine and urolithiasis composition revealed marked hyperoxaluria but normal concentrations of urinary glyceric and glycolic acid as well as stones of idiopathic calcium-oxalate appearance. Furthermore, the dietary survey showed excessive consumption of food supplements containing massive amounts of oxalate precursors. However, the persistence of excessive hyperoxaluria after his eating habits was changed leading us to perform molecular genetic testing. We found heterozygous mutations of the recently PH3-associated HOGA1 gene when sequencing PH genes. This is the first description of late diagnosis primary PH3 in a patient with several additional pro-lithogenic factors. This case illustrates the importance of undertaking a complete biological work-up to determine the aetiology of hyperoxaluria. This may reveal underdiagnosed primary hyperoxaluria, even in older patients.
Published: 2016

25. Prediction of steroid-sparing agent use in childhood idiopathic nephrotic syndrome

Author: Sandrine Leroy, Astrid Godron, Sandrine Ernould, Claire Rigothier, Brigitte Llanas, and Jérôme Harambat
Subjects: Male, Nephrology, medicine.medical_specialty, Pediatrics, Nephrotic Syndrome, Time Factors, Adolescent, Kaplan-Meier Estimate, Idiopathic Nephrotic Syndrome, Risk Assessment, Disease-Free Survival, Decision Support Techniques, Hospitals, University, stomatognathic system, Recurrence, Risk Factors, Internal medicine, Steroid sparing, Humans, Medicine, Child, Adverse effect, Proportional Hazards Models, Retrospective Studies, Drug Substitution, business.industry, Proportional hazards model, Remission Induction, Infant, Retrospective cohort study, medicine.disease, stomatognathic diseases, Treatment Outcome, ROC Curve, Area Under Curve, Child, Preschool, Multivariate Analysis, Pediatrics, Perinatology and Child Health, Female, Steroids, business, Risk assessment, Nephrotic syndrome, Immunosuppressive Agents
Abstract: About half of children with steroid-sensitive idiopathic nephrotic syndrome (INS) will develop steroid dependency or a frequently relapsing course requiring steroid-sparing agents (SSA). Because of the adverse effects of prolonged steroid treatment, the early identification of children at high risk of requiring SSA may be a useful diagnostic tool to tailor the therapeutic strategy. The aim of this study was to identify predictors of the need for SSA and derive a predictive model.This was a retrospective hospital-based cohort study which included all children with steroid-responsive INS followed for at least 4.5 months. Cox regression modeling and decision curve analysis were performed.A total of 120 children (81 boys) with INS were included and followed up for a median time of 6.7 (range 0.4-24.1) years. Median age at diagnosis was 3.4 years. Seventy-two (60 %) children required a SSA after a median time of 10 months following initial diagnosis. Male children, age at disease onset, methylprednisolone pulse use, and time to achieve first remission were significantly associated with the outcome. Time to achieve remission only remained significant after adjustment: hazard ratio (HR) =1.9 [95 % confidence interval (CI) 1.5-2.5] if considered as a continuous variable, and HR=4.1 (95 % CI 1.9-8.6) when dichotomized using the 9-day threshold. The area under the receiver operating curve of the related predictive model was 0.81 (95 % CI 0.74-0.89), and the decision curve analysis demonstrated that this model performed better than any other strategy.Time to first remission is a strong predictor of the need for SSA in pediatric INS. Further prospective and impact studies are warranted to confirm the accuracy and benefit of our prediction model.
Published: 2012
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26. 06Adverse effects of rituximab used in children with idiopathic nephrotic syndrome. A multicentric retrospective study

Author: Ferielle Louillet, R. Novo, Elodie Merieau, Roman Klifa, François Nobili, Olivier Dunand, Gérard Champion, F. Laliève, Ariane Zaloszyc, Olivia Boyer, V. Lefranc, S. Crepin, Etienne Bérard, N. Jay, Sophie Taque, Justine Bacchetta, Djamal Djeddi, J.D. Delbet, D. Postil, Gwenaelle Roussey, C. Samaille, S. Tellier, L. De Parscaud, E. Cousin, Brigitte Llanas, Christine Pietrement, C. Rousset, M. Cailliez, C. Bahans, L. Ichay, Paloma Maria Parvex, and Vincent Guigonis
Subjects: Pediatrics, medicine.medical_specialty, business.industry, Hemodynamics, Retrospective cohort study, Disease, Idiopathic Nephrotic Syndrome, Alternative treatment, Relative risk, Pediatrics, Perinatology and Child Health, medicine, Rituximab, business, Adverse effect, medicine.drug
Abstract: Introduction Rituximab (RTX) is an effective alternative treatment for severe idiopathic nephrotic syndrome in children. Nevertheless, the actual indication of RTX within the therapeutic strategy remains controversial, given the lack of data on the safety of this treatment in this setting. Objective To retrospectively collect and describe all severe and significant adverse effects that had occurred in children treated with RTX for idiopathic nephrotic syndrome. Patients and methods All participating centres within the SNP network were asked to fill an online database for all their patients treated with RTX for INS. Data were collected from the patients’ medical charts. Severe or significant adverse effects were defined as follow: any event that led to (i) a vital risk, (ii) a hospitalization or a prolongation of hospitalization, (iii) the occurrence of sequelae or (iiii) the interruption of RTX therapy. Results Twenty-three centres participated to the study. In total, 196 cases were collected on October 10th. The mean age at diagnosis was 4.7 (± 3.2) years. The mean duration of disease was 7.5 (± 4.3) years when RTX was first used. The mean follow-up was 3.2 (± 2.5) years and 1.5 (± 1.7) years since the first and the last infusion of RTX respectively. Adverse effects were reported in 6.6% of cases during the infusion (dyspnea = 6, cardiac arrhythmia = 1, hemodynamic instability = 1, others = 7), and in 13.1% of cases after the infusion (in relation with neutropenia = 6, low IgM = 3, low IgG = 6, infectious disorder = 14, cardiac = 2, liver = 1, kidney = 1, digestive = 2, neurological = 2, others = 6, several complications can be present in the same patient). The main consequences of these adverse effects were: non-planned hospitalizations (n = 30), modifications or interruptions of RTX treatment (n = 6), significant invalidity (n = 3). A single adverse effect led to a life-threatening situation. Conclusion Adverse effects were reported in 18.9% of these 196 patients treated by RTX for INS. RTX treatment was interrupted or modified in 6 cases. Only 4 adverse effects led to severe consequences (either life threatening event or significant invalidity). These results will help to evaluate the benefit/risk ratio or RTX for INS in children. This is an ongoing study, therefore results can be different when they will be presented during the meeting.
Published: 2017
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27. French cohort of transient antenatal Bartter syndrome with MAGED2 mutations

Author: François Nobili, Djamal Djeddi, Aurélia Bertholet-Thomas, A. Ryckewaert, Stéphane Decramer, L de Parscau, Brigitte Llanas, C. Treard, Christine Pietrement, T. Khalifeh, R. Vargas-Poussou, Denis Morin, G. Morin, Anne Legrand, and Laurence Dubourg
Subjects: Polyhydramnios, CLCNKB, Pregnancy, Pediatrics, medicine.medical_specialty, medicine.diagnostic_test, biology, business.industry, Gestational age, medicine.disease, Bartter syndrome, Polyuria, Pediatrics, Perinatology and Child Health, Amniocentesis, biology.protein, Medicine, Gestation, medicine.symptom, business
Abstract: 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.
Published: 2017
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28. Successful treatment with rituximab for acute refractory thrombotic thrombocytopenic purpura related to acquired ADAMTS13 deficiency: A pediatric report and literature review

Author: Delphine Lamireau, Yahsou Delmas, Brigitte Llanas, Olivier Brissaud, Jer ome Harambat, and Anne Ryman
Subjects: Male, Hemolytic anemia, Pediatrics, medicine.medical_specialty, Thrombotic thrombocytopenic purpura, ADAMTS13 Protein, Intensive Care Units, Pediatric, Critical Care and Intensive Care Medicine, Antibodies, Monoclonal, Murine-Derived, hemic and lymphatic diseases, Outcome Assessment, Health Care, Atypical hemolytic uremic syndrome, medicine, Humans, Immunologic Factors, Child, Pediatric intensive care unit, Purpura, Thrombotic Thrombocytopenic, business.industry, Organ dysfunction, Autoantibody, medicine.disease, ADAM Proteins, Pediatrics, Perinatology and Child Health, Vomiting, Rituximab, medicine.symptom, business, medicine.drug
Abstract: Objective To report the case of a child with severe autoimmune thrombotic thrombocytopenic purpura (TTP) resistant to plasma exchange and steroids who was successfully treated with rituximab. Design Case report and review of the literature on pediatric acquired TTP. The report was approved by an independent local ethics committee. Setting Pediatric intensive care unit in a tertiary care children's hospital. Patient A 10-yr-old boy was referred to the emergency unit with fever, vomiting, confusion, hemolytic anemia, thrombocytopenia, and mild acute renal failure. An atypical hemolytic uremic syndrome was suspected, and plasma exchange was started urgently. The patient was refractory to plasma therapy and presented critical complications. After a diagnosis of acquired TTP attributable to anti-ADAMTS13 autoantibodies had been made, he was treated with rituximab, which resulted in a stable clinical remission. Interventions Rituximab therapy. Measurements and main results Clinical remission. Conclusions TTP is a rare but life-threatening condition in children that is characterized by hemolytic anemia, thrombocytopenia, and signs of ischemic organ dysfunction. If renal involvement is present, TTP may be misdiagnosed as hemolytic uremic syndrome, but reliable screening for ADAMTS13 activity and anti-ADAMTS autoantibodies allow us to distinguish the two entities and provide adequate therapy.
Published: 2011
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29. L’hétérogénéité d’expression phénotypique de la mutation du gène TCF2 codant pour HNF-1β illustrée par une famille

Author: Christian Combe, Claire Rigothier, Jean-François Subra, Brigitte Llanas, and Jérôme Harambat
Subjects: Nephrology, urologic and male genital diseases
Abstract: Resume La mutation du gene TCF2, de transmission autosomique dominante codant pour la proteine HNF1β, est associee a un diabete de type Mody5, des anomalies morphologiques renales, des malformations urogenitales et des anomalies biologiques hepatiques a type de cholestase. Cette mutation du gene d’HNF-1β a ete identifiee au sein d’une famille dont nous rapportons la presentation phenotypique tres heterogene entre les differents membres : atteinte renale a type de nephrocalcinose ou de kystes, syndrome polyuropolydipsique, diabete de type Mody5, malformations genitales. L’analyse genetique a identifie une mutation de l’exon 4 du gene TCF2. L’existence dans une famille d’une atteinte renale malformative pleiomorphe (kystes, agenesie ou hypoplasie renale, insuffisance renale), associee a un diabete de type Mody, avec une transmission autosomique dominante, doit faire rechercher une mutation du gene TCF2, l’une des maladies genetiques renales les plus frequentes.
Published: 2009
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30. A 10-year-old boy with dark urine and acute kidney injury: answer

Author: Delphine Lamireau, Charles Joussain, Brigitte Llanas, Caroline Espil-Taris, Valérie De Précigout, Jérôme Harambat, and Christine Vianey-Saban
Subjects: Nephrology, medicine.medical_specialty, Kidney, business.industry, Acute kidney injury, medicine.disease, Gastroenterology, Surgery, Diarrhea, Regimen, medicine.anatomical_structure, Internal medicine, Pediatrics, Perinatology and Child Health, medicine, Carnitine palmitoyltransferase II, Carnitine palmitoyltransferase II deficiency, medicine.symptom, business, Rhabdomyolysis
Abstract: Keywords Rhabdomyolysis.Acute kidney injury.Carnitine palmitoyltransferase II deficiencyAbbreviationsAKI acute kidney injuryacyl-CoAs acylcoenzyme A derivativesCPT II carnitine palmitoyltransferase II deficiencyFAO fatty acid β-oxidationAnswers1. Severe rhabdomyolysis related to a mild form ofcarnitine palmitoyltransferase II (CPT II) deficiency.Diagnosis was suspected clinically by the occurrence ofsevere and recurrent rhabdomyolysis and based on theacylcarnitine profile. The diagnosis was confirmed bythe measurement of CPT II enzyme activity andsubsequent molecular analysis.2. First, the patient had a genetic disorder of lipidmetabolism, namely, a mild form of CPT II deficiency,which was responsible for the severe rhabdomyolysis,which in turn can be triggered by fever, exercise, andcold. Furthermore, viral myositis is a common cause ofrhabdomyolysis in children [1], and rapid testing forInfluenza A was positive in our patient. Influenzainfection-related severe rhabdomyolysis has alreadybeen reported [2]. Life-threatening rhabdomyolysismay be a consequence of any Influenza infection inpatients with CPT II deficiency [3].3. The primary cause of acute kidney injury (AKI) inthis patient is the rhabdomyolysis. Rhabdomylolysismay not be the only cause of AKI. Indeed, ourpatient also presented with diarrhea and occasionalvomiting and was probably dehydrated. Finally, acumulative dose of 60 mg/kg body weight ofibuprofen was given as self-medication 1 day priorto admission. All of these elements may havecontributed to a deterioration of the renal functiondue to hypoperfusion and/or vasoconstriction.4. The management regimen includes the treatment ofrhabdomyolysis-induced AKI and the prevention offurther rhabdomyolysis episodes.Supportive treatment of rhabdomyolysis consists of theearly and aggressive repletion of fluids. Alkalinization of
Published: 2011
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31. [Cystinosis in adults: A systemic disease]

Author: Aude, Servais, Cyril, Goizet, Aurélia, Bertholet-Thomas, Stéphane, Decramer, Brigitte, Llanas, Gabriel, Choukroun, and Robert, Novo
Subjects: Adult, Adolescent, Cysteamine, Cystinosis, Humans, Kidney Failure, Chronic, Renal Insufficiency, Cystine Depleting Agents, Fanconi Syndrome, Kidney Transplantation
Abstract: Cystinosis is a multisystemic autosomal recessive disorder characterized by an intra-lysosomal accumulation of cystine. It is due to a defect of cystine transport through the membrane of the lysosome. The classical infantile form is characterized by a proximal tubulopathy, corneal cystine crystals and progressive renal failure, leading to end stage renal disease before 20 years of age in 90% of cases in historical cohorts. It is the most common cause of Fanconi syndrome in children. Due to recent progress in renal transplantation and to the specific treatment with cysteamine, patients survival improved significantly in the last years and adult nephrologists take care of such patients. However, disease evolution is characterized by other complications: endocrinological (hypothyroidism, diabetes, male hypogonadism), neuromuscular and of the central nervous system. Cysteamine delays the onset of these complications. A multidisciplinary team should take care of these patients, even if the nephrologist remains in first line. Apart from infantile form, there is a juvenile form, with a later onset, and an adult form, which may be only ocular, although renal involvement may be associated. The aim of this revue is to summarize actual knowledge of the disease to provide guidance to adult nephrologist to take care of his patients.
Published: 2014

32. Towards a new point of view on the phenotype of patients with a 17q12 microdeletion syndrome

Author: Denis Morin, Sylvie Bourthoumieu, Catherine Yardin, Lucie Bessenay, Brigitte Llanas, Annie Lahoche, Loïc De Parscau, Emilie Dizier, Didier Lacombe, Claire Bahans, Fanny Laffargue, Vincent Guigonis, Cécile Laroche, Marie-Ange Delrue, Sylvie Cloarec, Emmanuelle Taupiac, and Véronique Baudouin
Subjects: Nephrology, Male, Pediatrics, medicine.medical_specialty, Pathology, Adolescent, Central Nervous System Diseases, Internal medicine, medicine, Pervasive developmental disorder, Humans, Prospective Studies, Child, Dental Enamel, In Situ Hybridization, Fluorescence, Hepatocyte Nuclear Factor 1-beta, business.industry, Mental Disorders, Genetic disorder, Neuropsychology, Infant, Microdeletion syndrome, Kidney Diseases, Cystic, HNF1B, medicine.disease, Phenotype, Diabetes Mellitus, Type 2, Child, Preschool, Pediatrics, Perinatology and Child Health, Medical genetics, Autism, Female, France, Chromosome Deletion, business, Chromosomes, Human, Pair 17
Abstract: Objective17q12 microdeletion syndrome involves 15 genes, including HNF1B, and is considered to confer a high risk of neuropsychiatric disorders. Patients with HNF1B gene deletion diagnosed secondary to renal disorders are only very rarely reported to have neuropsychiatric disorders. Interestingly, however, when tested, patients with HNF1B gene deletion are found to have 17q12 deletion. This brings into question the extent to which 17q12 deletion is genuinely associated with severe neuropsychological disorders and in which patients. In this study, we sought to confirm 17q12 microdeletion in kidney patients initially diagnosed with HNF1B gene deletion and evaluate neuropsychological disorders in these patients compared with those with HNF1B point mutation.Patients and designThirty-nine children with HNF1B disorders (26 with deletions) diagnosed secondary to renal abnormalities were included in this prospective study and tested for 17q12 microdeletion and neuropsychological disorders.ResultsThe same 17q12 microdeletion found in patients with neuropsychological disorders was identified in all of our patients with HNF1B deletion. Neurological examinations found no severe impairments except for one patient with autism. No significant differences were found between patients with deletions and those with point mutations as concerns learning abilities and schooling. Nevertheless, patients with deletions tended to have lower developmental quotients and more difficulties at school.ConclusionsComplete deletion of the HNF1B gene and 17q12 microdeletion syndrome are actually the same genetic disorder. The neuropsychological phenotype of patients appears less severe when 17q12 deletion is diagnosed secondary to kidney rather than neuropsychological abnormalities. These data may influence antenatal counselling.
Published: 2014

33. Atypical hematologic and renal manifestations in neurofibromatosis type I: coincidence or pathophysiological link?

Author: Charlotte Jubert, Brigitte Llanas, Cyril Goizet, Dominique Vidaud, Julien Van-Gils, Jérôme Harambat, Yves Perel, and Didier Lacombe
Subjects: Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Nephrotic Syndrome, Neurofibromatosis 1, Adolescent, Mutation, Missense, Proto-Oncogene Mas, Pallor, Nephritic syndrome, Internal medicine, Genetics, Medicine, Missense mutation, Humans, Neurofibromatosis, Child, neoplasms, Genetics (clinical), Neurofibromatosis type I, Neurofibromin 1, biology, business.industry, Cafe-au-Lait Spots, Axillary freckling, General Medicine, medicine.disease, Dermatology, Pedigree, Endocrinology, biology.protein, medicine.symptom, business, Nephrotic syndrome
Abstract: Neurofibromatosis type 1 (NF1) is an autosomal dominant, multi-system, neurocutaneous disorder that predisposes to the development of benign and malignant tumors with a birth incidence rate of 1 in 2500–3000. 50% of cases are sporadic. The diagnosis is exclusively based on clinical assessment with clinical diagnostic criteria such as cafe-au-lait spots, neurofibromas, axillary or groin freckling, Lisch nodules, optic pathway glioma, bony dysplasia and first-degree relative with NF1. We report a family with NF1 in which two members presented atypical clinical features in addition to the classical diagnostic criteria. Three relatives affected by NF1, a father and two of his three sons, are described. The clinical diagnosis was originally worn in all three cases, with the association many spots cafe-au –lait over the entire body and some axillary freckling as well as first-degree relative. One case presented an Acute Myeloid Leukemia (AML) type 2 at 10 years of age diagnosed before the revelation of bicytopenia associated pallor and isolated asthenia. A second case presented a nephrotic syndrome at 4 years of age due to the association of hydrops with headache and asthenia. Direct sequencing of NF1 led to identify the familial mutation, a previously unreported heterozygous missense mutation c.3443C > A, p.Ala1148Glu in exon 20 which segregated with all three affected patients. The family described in this report confirms the high clinical variability of NF1, even intrafamilial, and raises the question as to whether rare features such as AML and nephrotic syndrome are associated with NF1. Some NF1 patients presenting glomerular diseases or AML have rarely been reported, but due to the small number of cases described the mechanisms underlying these associations are poorly understood. However, it seems important to be aware of the possible occurrence of nephritic syndrome and/or malignant blood diseases in NF1 patients.
Published: 2014

34. Acute renal cortical necrosis due to acquired antiprotein S antibodies

Author: Marie-Françoise Hurtaud-Roux, Hadji Djaffar, Brigitte Llanas, Solène Evrard, Georges Deschênes, Theresa Kwon, Ferielle Louillet, Véronique Baudouin, and Anis Larakeb
Subjects: Male, Nephrology, medicine.medical_specialty, Pathology, Protein S Deficiency, Necrosis, Anemia, medicine.medical_treatment, Kidney, Protein S, Chickenpox, Renal cortical necrosis, Internal medicine, medicine, Humans, Protein S deficiency, Enoxaparin, Glucocorticoids, Autoantibodies, Ultrasonography, biology, business.industry, Anticoagulants, Infant, Plasmapheresis, medicine.disease, Magnetic Resonance Imaging, Treatment Outcome, medicine.anatomical_structure, Pulse Therapy, Drug, Pediatrics, Perinatology and Child Health, biology.protein, Kidney Cortex Necrosis, medicine.symptom, business
Abstract: Although varicella is a common disease of childhood, renal complications are quite rare. We report here the interesting case of a-22 month-old boy exhibiting renal cortical necrosis related to an acquired protein S deficiency following varicella. Ten days after the vesicle eruption appearance, he presented with ecchymosed heels, oligoanuric kidney failure, anemia [hemoglobin (Hb) 78 g/L], schizocytosis (2.5%), but normal platelet count. Kidney sonography and magnetic resonance imaging evoked renal cortical necrosis. All together, these features suggested acquired protein S deficiency secondary to varicella. Strikingly, it was confirmed by a dramatic decrease in protein S plasma activity and a huge increase in immunoglobulin (Ig)G antibodies against protein S in the plasma. Anticoagulation therapy in addition with plasmapheresis and steroid pulses allowed a dramatic decrease in the antibodies against protein S and recovery of normal protein S activity. Undelayed diagnosis and treatment did not avoid kidney insufficiency but prevented life-threatening complications. In the light of this case report, protein S deficiency due to antibody inhibition should be carefully monitored anytime in the context of varicella when kidney insufficiency or necrosis occurs.
Published: 2009
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35. Hemolytic uremic syndrome complicating Mycoplasma pneumoniae infection

Author: Astrid Godron, Jérôme Harambat, Catherine Monet, Brigitte Llanas, Sabine Pereyre, CHU Bordeaux [Bordeaux], USC infections humaines à mycoplasmes et Chlamydiae, Institut National de la Recherche Agronomique (INRA), and Université Sciences et Technologies - Bordeaux 1
Subjects: Male, Nephrology, medicine.medical_specialty, Mycoplasma pneumoniae, Thrombotic microangiopathy, [SDV]Life Sciences [q-bio], medicine.disease_cause, urologic and male genital diseases, children, Internal medicine, hemic and lymphatic diseases, Pneumonia, Mycoplasma, medicine, Humans, business.industry, Infant, Microangiopathic hemolytic anemia, medicine.disease, mycoplasma pneumoniae, Anti-Bacterial Agents, respiratory tract diseases, thrombotic microangiopathy, Pneumonia, Treatment Outcome, medicine.anatomical_structure, Hemolytic-Uremic Syndrome, Pediatrics, Perinatology and Child Health, Immunology, Alternative complement pathway, hemolytic uremic syndrome, Complication, business, Biomarkers, Respiratory tract
Abstract: Mycoplasma pneumoniae can cause various extrapulmonary manifestations but, to our knowledge, no case of Mycoplasma pneumoniae associated with hemolytic uremic syndrome (HUS) has been reported. We describe a 1-year-old boy with M. pneumoniae respiratory tract infection and associated microangiopathic hemolytic anemia, slightly decreased platelet count and mild renal impairment, suggesting a diagnosis of HUS. Assuming M. pneumoniae infection was the cause of HUS in this case, the different possible mechanisms, including an atypical HUS due to preexisting complement dysregulation, an alternative complement pathway activation induced by M. pneumoniae infection at the acute phase, an autoimmune disorder, and a direct role of the bacteria in inducing endothelial injury, are discussed. The signs of HUS resolved with treatment of the M. pneumoniae infection. Hemolytic uremic syndrome may be an unusual complication of M. pneumoniae infection.
Published: 2013
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36. Household transmission of haemolytic uraemic syndrome associated with Escherichia coli O104:H4, south-western France, June 2011

Author: B Le Bihan, G. Gault, F Terrier, Yahsou Delmas, Nathalie Ong, Brigitte Llanas, Benoît Vendrely, Joana Simões, Desjardin M, Patricia Mariani-Kurkdjian, B. Aldabe, P. Rolland, Charron M, Christian Combe, C Castor, François-Xavier Weill, Cellule INVS Région Aquitaine, Institut de Veille Sanitaire (INVS), Université de Bordeaux (UB), Centre National de Référence - National Reference Center Escherichia coli, Shigella et Salmonella (CNR-ESS), Institut Pasteur [Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Militaire Robert Picqué, ARS Région Aquitaine, and Institut Pasteur [Paris] (IP)
Subjects: Male, MESH: Shiga-Toxigenic Escherichia coli, Epidemiology, medicine.disease_cause, Disease Outbreaks, law.invention, Feces, 0302 clinical medicine, Escherichia coli O104:H4, law, 030212 general & internal medicine, MESH: Disease Outbreaks, Index case, Escherichia coli Infections, MESH: Treatment Outcome, Family Characteristics, 0303 health sciences, Shiga-Toxigenic Escherichia coli, MESH: Escherichia coli, MESH: Feces, Anti-Bacterial Agents, 3. Good health, MESH: Diarrhea, Treatment Outcome, Transmission (mechanics), MESH: Hemolytic-Uremic Syndrome, Child, Preschool, France, Adult, Diarrhea, [SDV.TOX.TCA]Life Sciences [q-bio]/Toxicology/Toxicology and food chain, Microbiology, Incubation period, MESH: Contact Tracing, 03 medical and health sciences, Virology, MESH: Anti-Bacterial Agents, Escherichia coli, medicine, MESH: Family Characteristics, Humans, MESH: Escherichia coli Infections, MESH: Humans, 030306 microbiology, business.industry, MESH: Child, Preschool, Public Health, Environmental and Occupational Health, Outbreak, MESH: Adult, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Male, Abdominal Pain, Cephalosporins, MESH: Abdominal Pain, MESH: France, MESH: Cephalosporins, Hemolytic-Uremic Syndrome, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Contact Tracing, Haemolytic-uraemic syndrome, business
Abstract: International audience; Following the outbreak of haemolytic uraemic syndrome (HUS) on June 2011 in south-western France, household transmission due to Escherichia coli O104:H4 was suspected for two cases who developed symptoms 9 and 10 days after onset of symptoms of the index case. The analysis of exposures and of the incubation period is in favour of a secondary transmission within the family. Recommendations should be reinforced to prevent person-to-person transmission within households.
Published: 2011
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37. A 10-year-old boy with dark urine and acute kidney injury

Author: Charles, Joussain, Delphine, Lamireau, Caroline, Espil-Taris, Valérie, De Précigout, Christine, Vianey-Saban, Brigitte, Llanas, and Jérôme, Harambat
Subjects: Male, Carnitine O-Palmitoyltransferase, Humans, Acute Kidney Injury, Child, Metabolism, Inborn Errors, Rhabdomyolysis
Published: 2010

38. Severe transient ADAMTS13 deficiency in pneumococcal-associated hemolytic uremic syndrome

Author: Olivier Brissaud, Anne Ryman, Delphine Lamireau, Jérôme Harambat, Sybille Pelras, Brigitte Llanas, Frédéric Villega, Yahsou Delmas, and Paul Nolent
Subjects: Hemolytic anemia, business.industry, Autoantibody, Thrombotic thrombocytopenic purpura, Acute kidney injury, ADAMTS13 Protein, Context (language use), macromolecular substances, Pneumonia, Pneumococcal, medicine.disease, ADAMTS13, Schistocyte, Pneumonia, ADAM Proteins, Nephrology, hemic and lymphatic diseases, Child, Preschool, Pediatrics, Perinatology and Child Health, Immunology, Hemolytic-Uremic Syndrome, medicine, Humans, Female, business
Abstract: Thrombotic microangiopathies comprise different entities, including hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), and several other conditions. TTP is characterized by hemolytic anemia, thrombocytopenia, and multiorgan failure. TTP is the result of severe von Willebrand factor multimer cleaving protease (ADAMTS13) deficiency that is either inherited or the result of acquired autoantibodies. We report a critically ill 2-year-old girl with invasive pneumococcal disease associated HUS (p-HUS) whose condition was complicated by severe ADAMTS13 deficiency, without detectable inhibitor, in a context of multiple organ failure. The patient recovered with supportive treatment, and ADAMTS13 activity normalized without plasmatherapy. Severe ADAMTS13 deficiency appears to be a manifestation of transient endothelial cell injury in the context of severe sepsis, including invasive p-HUS. The choice of appropriate therapy should not be based on this finding.
Published: 2010

39. Long-term effects of cyclophosphamide therapy in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome

Author: Aurélia Bertholet-Thomas, Pierre Cochat, Benoît Cammas, François Bouissou, Nawel Afroukh-Hacini, Bruno Ranchin, Vincent Guigonis, Brigitte Llanas, Jérôme Harambat, Denis Morin, Stéphane Decramer, and Salih Bendeddouche
Subjects: Male, medicine.medical_specialty, Nephrotic Syndrome, Time Factors, Cyclophosphamide, growth, Gastroenterology, Time, Cohort Studies, Interquartile range, Adrenal Cortex Hormones, Recurrence, Internal medicine, medicine, Humans, Survival rate, Retrospective Studies, Transplantation, Cumulative dose, business.industry, Retrospective cohort study, medicine.disease, Survival Rate, Endocrinology, Treatment Outcome, Nephrology, Child, Preschool, idiopathic nephrotic syndrome, cyclophosphamide, Female, business, Nephrotic syndrome, Body mass index, Immunosuppressive Agents, steroids, Cohort study, medicine.drug
Abstract: Background. It has been demonstrated that alkylating agents such as cyclophosphamide (CYP) are effective in reducing the risk of relapse in frequently relapsing (FRNS) and steroid-dependent nephrotic syndrome (SDNS). Little is known about prognostic factors in SDNS and FRNS treated by CYP. The objectives of this study are to determine long-term outcomes and factors associated with sustained remission in these patients. Methods. We retrospectively studied the data from 143 children (104 boys) with SDNS and FRNS treated with CYP in six centres over 15 years. Relapse-free survival was estimated by Kaplan–Meier method. The determinants of long-term remission were assessed by univariate and multivariate analyses using Cox proportional hazard models. Results. Median age at diagnosis was 3.7 years (interquartile range: IQR 2.3–5.9), and median follow-up was 7.8 years (IQR 4.0–11.8). CYP treatment was introduced after a median time of 1.7 years (IQR 0.7–5.9) after diagnosis. Patients received a median cumulative dose of 168 mg/kg (IQR 157–197) body weight. Relapse-free survival was 65%, 44%, 27% and 13% after 6 months, 1 year, 2 years and 5 years, respectively. In multivariate analysis, sustained remission >2 years was associated with age at treatment >5 years (P = 0.02) and cumulative dose of CYP >170 mg/kg (P = 0.02). Frequently relapsing versus steroid-dependent status and female gender were predictors of borderline significance. Height and body mass index standard deviation score were significantly influenced by CYP treatment. Conclusion.In our study, long-term efficacy of cyclophosphamide in steroid-responsive nephrotic syndrome is disappointing. Further well-designed trials are required to evaluate the efficacy of other steroid-sparing agents. NEPHROLOGY DIALYSIS TRANSPLANTATION, ISSN : 0931-0509, DOI : 10.1093/ndt/gfq405, Issue :1, Volume : 26, pp. 178–184, 2011. ; ; ; steroids
Published: 2010

40. Renal impairment in children with cystic fibrosis

Author: Jérôme Harambat, Annick Andrieux, Stéphanie Bui, Albert Iron, Michael Fayon, Fabienne Nacka, and Brigitte Llanas
Subjects: Pulmonary and Respiratory Medicine, Male, medicine.medical_specialty, Adolescent, Cystic Fibrosis, Renal function, urologic and male genital diseases, Gastroenterology, Cystic fibrosis, Liver disease, Urolithiasis, Antibiotics, Internal medicine, medicine, Odds Ratio, Prevalence, Albuminuria, Humans, Hypercalciuria, Pediatrics, Perinatology, and Child Health, Longitudinal Studies, Renal Insufficiency, Nephrotoxicity, Child, Retrospective Studies, Hyperoxaluria, business.industry, Infant, Newborn, Infant, Odds ratio, Kidney disease, medicine.disease, female genital diseases and pregnancy complications, Endocrinology, Child, Preschool, Pediatrics, Perinatology and Child Health, Microalbuminuria, Female, France, medicine.symptom, business, Glomerular Filtration Rate
Abstract: Background Due to the improvement in life expectancy in cystic fibrosis (CF), co-morbidities such as renal function impairment may be more frequent. Aim To determine the prevalence of renal disease in children with CF and to identify associated risk factors. Methods A single-center retrospective study analyzing the genetic, clinical and therapeutic characteristics of 112 children. The estimated glomerular filtration rate (GFR), microalbuminuria and lithiasic risk factors were assessed. Results The median calculated GFR (Schwartz) was 123, 161 and 155ml/min/1.73m 2 in children aged 1, 6 and 15years, respectively. The cumulative dose of aminoglycosides was not correlated to GFR. Microalbuminuria was present in 22/38 patients. Hyperoxaluria was observed in 58/83 patients and was associated with a severe genotype, pancreas insufficiency and liver disease. Hypercalciuria, hyperuricuria and hypocitraturia were identified in 16/87, 15/83 and 57/76 patients, respectively. Conclusion Renal impairment in CF has various presentations. There appears to be low levels of renal impairment in children with CF. However, the risk of oxalocalcic urolithiasis is enhanced, and GFR may be underestimated by the Schwartz formula. Further studies using measured GFR techniques are thus warranted.
Published: 2009

41. [Phenotypic heterogeneity of TCF2's gene mutation coding for HNF-1 beta in a single family]

Author: Claire, Rigothier, Jérôme, Harambat, Brigitte, Llanas, Jean-François, Subra, and Christian, Combe
Subjects: Adult, Male, Genetic Carrier Screening, Infant, Newborn, Exons, Kidney, Pedigree, Phenotype, Diabetes Mellitus, Type 2, Mutation, Humans, Abnormalities, Multiple, Female, Infant, Premature, Hepatocyte Nuclear Factor 1-beta
Abstract: TCF2 gene's mutation of autosomal dominant inheritance, encoding for the HNF-1 beta transcription factor, is associated with monogenic Mody5 diabetes, renal structural and urogenital abnormalities, and hepatic cholestasis. We have identified a family with HNF-1 beta gene's mutation, and very different phenotypic expression: renal abnormalities with cysts, nephrocalcinosis, polyuropolydipsic syndrome, Mody5 diabetes, genital malformations. Molecular analysis identified a mutation of exon 4 of the TCF2 gene. The coexistence in the same family of pleiomorphic renal malformations (cysts, renal agenesia or hypoplasia, renal failure) with Mody-type diabetes, with an autosomal inheritance must lead to the search for a mutation of TCF2, one of the most frequent genetic renal diseases.
Published: 2008

42. Intestinal Microsporidiosis due to Enterocytozoon bieneusi in a Pediatric Kidney Transplant Recipient Successfully Treated with Fumagillin

Author: Astrid Godron, Axelle Couret, Brigitte Llanas, Jérôme Harambat, and Isabelle Accoceberry
Subjects: Transplantation, medicine.medical_specialty, biology, business.industry, Treatment outcome, biology.organism_classification, medicine.disease, Gastroenterology, Kidney transplant recipient, Intestinal microsporidiosis, Internal medicine, Medicine, Enterocytozoon, Enterocytozoon bieneusi, Fumagillin, business, Kidney transplantation, medicine.drug
Published: 2013
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43. Pancreatic pseudocyst complicating hemolytic-uremic syndrome

Author: Brigitte Llanas, Michael Fayon, Muriel Brun, Philippe Jouvencel, Laurent Rebouissoux, Eric Dobremez, and Thierry Lamireau
Subjects: Hemolytic anemia, medicine.medical_specialty, Pancreatic pseudocyst, business.industry, Gastroenterology, medicine.disease, Kidney, Surgery, Diagnosis, Differential, Recurrence, Child, Preschool, Pediatrics, Perinatology and Child Health, Amylases, Hemolytic-Uremic Syndrome, Pancreatic Pseudocyst, medicine, Humans, Kidney Failure, Chronic, Platelet, Female, Complication, business, Kidney disease, Ultrasonography
Published: 2003

44. Renal outcome in long-term survivors from severe acute kidney injury in childhood

Author: Marianne Viaud, Brigitte Llanas, and Jérôme Harambat
Subjects: Nephrology, medicine.medical_specialty, Pediatrics, business.industry, medicine.medical_treatment, MEDLINE, Acute kidney injury, Renal function, Acute Kidney Injury, medicine.disease, Term (time), Text mining, Internal medicine, Pediatrics, Perinatology and Child Health, medicine, Humans, Kidney Failure, Chronic, Renal replacement therapy, business
Published: 2011
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45. A 10-year-old boy with dark urine and acute kidney injury: question

Author: Jérôme Harambat, Valérie De Précigout, Christine Vianey-Saban, Brigitte Llanas, Charles Joussain, Delphine Lamireau, and Caroline Espil-Taris
Subjects: medicine.medical_specialty, Creatinine, Hyperkalemia, biology, business.industry, medicine.medical_treatment, Acute kidney injury, Diuresis, Metabolic acidosis, medicine.disease, Gastroenterology, chemistry.chemical_compound, chemistry, Nephrology, Internal medicine, Pediatrics, Perinatology and Child Health, medicine, biology.protein, Creatine kinase, Hemodialysis, medicine.symptom, business, Intensive care medicine, Rhabdomyolysis
Abstract: A previously healthy 10-year-old boy presented to the Pediatric Emergency Unit during the winter with fever, myalgias, and muscular weakness since the previous day. The urine had turned a dark-brown color. The patient also had diarrhea and occasional vomiting for 2 days. The parents explained that a total dose of 2.1 g of ibuprofen (i.e., 60 mg/kg) had been administered as self-medication the day before. Upon admission, the patient’s blood pressure was 113/ 78 mmHg, and his heart rate was 123/min. Axillary temperature was 39.5°C. Physical examination showed muscular weakness in both legs and flank tenderness. The findings of the respiratory, cardiac, and neurological examinations were normal. The test results on admission were as follows: rapid testing for Influenza A was positive; urine dipstick was positive for bilirubin (3+), blood (3+), and protein (3+). Laboratory tests showed a creatine kinase level of 318,000 U/l, urea nitrogen 18 mmol/l, creatinine 214 μmol/l, bicarbonate 16 mmol/l, and potassium 5 mmol/l. A diagnosis of massive rhabdomyolysis with acute kidney injury (AKI) was made. Rhabdomyolysis progressed with a peak creatine kinase level of 348,000 U/l, lactate dehydrogenase 124,000 U/l, serum myoglobin 42,873 μg/l, aspartate aminotransferase 7,122 IU/l, alanine aminotransferase 1,462 IU/l, metabolic acidosis, hyperkalemia of 5.2 mmol/l, hypocalcemia of 1.5 mmol/l, and hyperphosphoremia of 2.7 mmol/l. Ultrasound imaging showed enlarged kidneys with a loss of corticomedular differentiation. Despite aggressive intravenous hydration with normal saline and urine alkalinization with sodium bicarbonate, urinary output decreased, and the patient developed anuric renal failure on day 2 with a creatinine level of 663 μmol/l and urea nitrogen level of 35 mmol/l. Hemodialysis was initiated on day 2. Nine hemodialysis sessions were necessary until day 16. The patient had no cardiac complication. His condition improved, with diuresis The answer to this question can be found at doi:10.1007/s00467-0111767-3.
Published: 2011
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46. A short stay observation unit improves care in the paediatric emergency care setting

Author: Thierry Lamireau, Brigitte Llanas, and Michael Fayon
Subjects: Male, medicine.medical_specialty, Pediatrics, Care setting, medicine, Humans, Letters to the Editor, Service (business), business.industry, Infant, Newborn, Infant, Admission rate, Length of Stay, medicine.disease, Infant newborn, Hospitalization, Short stay, Child, Preschool, Pediatrics, Perinatology and Child Health, Emergency medicine, Female, Medical emergency, France, business, Emergency Service, Hospital, Hospital Units, Paediatric emergency, Observation unit
Abstract: Editor,—The number of admissions to hospital emergency departments is increasing, by up to five per cent a year.1 Most of these children are under 5 years of age, and they may come straight to hospital without any preceding medical examination.2 Although a short stay observation unit (SSOU) has been proved essential for a good emergency service,3 few publications have looked at its influence on the admission rate in paediatrics.4 We analysed the activity of a SSOU opened in 1992 in the paediatric emergency department (PED) of the Children's Hospital of Bordeaux. We also looked at the number of total admissions to the PED and …
Published: 2000

47. Prevalence of renal impairment in children with cystic fibrosis (CF)

Author: M. Fayon, Brigitte Llanas, Stéphanie Bui, Jérôme Harambat, Fabienne Nacka, and Annick Andrieux
Subjects: musculoskeletal diseases, Pulmonary and Respiratory Medicine, medicine.medical_specialty, business.industry, Internal medicine, Pediatrics, Perinatology and Child Health, medicine, Pediatrics, Perinatology, and Child Health, medicine.disease, business, Cystic fibrosis, Gastroenterology
Published: 2009
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48. Pharyngeal Injury During Percutaneous Endoscopic Gastrostomy in a Child

Author: Thierry Lamireau, Brigitte Llanas, and Mickaël Fayon
Subjects: medicine.medical_specialty, medicine.medical_treatment, Retrognathia, Percutaneous endoscopic gastrostomy, Gastroscopy, Humans, Medicine, Pneumomediastinum, Laparoscopy, Intubation, Gastrointestinal, Gastrostomy, medicine.diagnostic_test, business.industry, Pharynx, Infant, Newborn, Gastroenterology, medicine.disease, Infant newborn, Surgery, medicine.anatomical_structure, Pediatrics, Perinatology and Child Health, Female, Pharyngeal injury, business
Published: 1998
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49. Rituximab therapy for childhood-onset systemic lupus erythematosus

Author: M. Willems, Bruno Ranchin, Rémi Salomon, Isabelle Koné-Paut, Elie Haddad, Chantal Loirat, Fadi Fakhouri, Albert Bensman, Tim Ulinski, Thierry Leblanc, Georges Deschênes, Pierre Cochat, Brigitte Bader-Meunier, Niaudet P, Brigitte Llanas, and Pascal Pillet
Subjects: Adult, medicine.medical_specialty, Adolescent, Cyclophosphamide, Lupus nephritis, Azathioprine, Kidney Function Tests, Gastroenterology, Antibodies, Monoclonal, Murine-Derived, immune system diseases, Prednisone, hemic and lymphatic diseases, Internal medicine, medicine, Humans, Immunologic Factors, Lupus Erythematosus, Systemic, Lymphocyte Count, Child, Retrospective Studies, Lupus erythematosus, business.industry, Autoimmune Cytopenia, Age Factors, Antibodies, Monoclonal, medicine.disease, Cross-Sectional Studies, Treatment Outcome, Pediatrics, Perinatology and Child Health, Immunology, Female, Rituximab, France, Autoimmune hemolytic anemia, business, medicine.drug
Abstract: Objective To describe the safety and efficacy of rituximab in the treatment of childhood-onset systemic lupus erythematosus (SLE). Study design We conducted a French multicenter retrospective study of childhood-onset SLE treated with rituximab. Results Eleven girls with severe SLE, including 8 girls with class IV or V lupus nephritis, 2 girls with severe autoimmune cytopenia, and 1 girl with antiprothrombin antibody with severe hemorrhage, were treated with rituximab. The mean age at onset of rituximab treatment was 13.9 years. Patients received 2 to 12 intravenous infusions of rituximab (350-450 mg/m2/infusion), with corticosteroids. Six patients also received different standard immunosuppressive agents, including Cyclophosphamide (2 patients). Remission was achieved in 6 of 8 patients with lupus nephritis and in the 2 patients with autoimmune cytopenia. Steroid therapy was tapered in 5 patients who responded to treatment, and low-dose prednisone treatment was maintained in 1 patient. The mean follow-up period was 13.2 months (range, 6-26 months), and remission lasted in all who patients who responded to treatment, except 1 patient who was successfully retreated with a second course of rituximab. Anti-double-stranded DNA antibody levels decreased in 6 of 11 patients, and anticardiolipin antibody levels decreased in 3 of 4 patients. Severe adverse events developed in 5 patients. Effective depletion of peripheral blood B cells was observed in 7 of 8 patients who were examined, and this paralleled the remission. Conclusion Rituximab may be an effective co-therapy; however, further investigations are required because severe adverse events occurred in 45% of the patients in this study.
Published: 2006
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50. Phase 1/2 Study of Lumasiran for Treatment of Primary Hyperoxaluria Type 1: A Placebo-Controlled Randomized Clinical Trial

Author: William van’t Hoff, David Erbe, Pierre Cochat, Daniella Magen, Patrick Haslett, Jaap W. Groothoff, Jiandong Lu, Yaacov Frishberg, Pushkal Garg, Georges Deschênes, Akshay Vaishnaw, Sandeep Talamudupula, Ulrike Lorch, Sally-Anne Hulton, Jérôme Harambat, Tracy L. McGregor, John C. Lieske, Dawn S. Milliner, Bahru A. Habtemariam, Shaare Zedek Medical Center [Jerusalem, Israel], Hôpital Robert Debré, University of Amsterdam [Amsterdam] (UvA), Birmingham Women's and Children's NHS Foundation Trust, Ruth Children's Hospital [Haifa, Israel] (RCH), CHU Bordeaux [Bordeaux], Great Ormond Street Hospital for Children [London] (GOSH), Richmond Pharmacology Ltd [London, United Kingdom] (RP), Mayo Clinic [Rochester], Alnylam Pharmaceuticals [Cambridge, MA, USA], Hospices Civils de Lyon (HCL), Université de Lyon, study collaborators: Asela Bandara, Jonathan Bowen, Wei Li Chong, Simon Coates, Patrick De Barr, Janine De Beer, Juleen Gayed, Timothy Hill, Alex Kotak, Junko Ono, Jorg Taubel, Meera Thayalan, Robynne Wong, Christoph Coch, Martin Coenen, Markus Feldkotter, Nils Henning Heiland, Maximilian Hohenadel, Bernd Hoppe, Henriette Kyrieleis, Gesa Schalk, Lucy Cooper, Asheeta Gupta, David Milford, Mordi Muorah, Justine Bacchetta, Delphine Bernoux, Aurelia Bertholet-Thomas, Elodie Cheyssac, Aurelie Portefaix, Bruno Ranchin, Anne-Laure Sellier-Leclerc, Brigitte Llanas, Veronique Baudouin, Anne Couderc, Julien Hogan, Florentia Kaguelidou, Theresa Kwon, Anne Maisin, David Sas, Rachel Becker-Cohen, Efrat Ben-Shalom, Choni Rinat, Shimrit Tzvi Behr, Detlef Bockenhauer, Bshara Mansour, Shirley Pollack, Sander Garrelfs, Michiel Oosterveld, Shabbir Moochhala, Stephen Walsh, Lavanya Kamesh, Graham Lipkin, Admin, Oskar, Paediatric Nephrology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and ARD - Amsterdam Reproduction and Development
Subjects: Male, Epidemiology, 030232 urology & nephrology, Renal Agents, Critical Care and Intensive Care Medicine, Gastroenterology, Oxalosis, law.invention, Primary hyperoxaluria, 0302 clinical medicine, Randomized controlled trial, law, Medicine, Single-Blind Method, RNA, Small Interfering, Child, Oxalates, 0303 health sciences, Plasma oxalate, 16. Peace & justice, 3. Good health, Nephrocalcinosis, Nephrology, Female, Adult, medicine.medical_specialty, Lumasiran, Adolescent, Urinary system, Kidney stones, Placebo, Young Adult, 03 medical and health sciences, Internal medicine, Primary hyperoxaluria type 1, Humans, Adverse effect, 030304 developmental biology, Transplantation, business.industry, Urinary oxalate, RNAi therapeutics, Original Articles, medicine.disease, Glycolates, Clinical trial, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, RNAi, Hyperoxaluria, Primary, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract: International audience; BACKGROUND AND OBJECTIVES: In the rare disease primary hyperoxaluria type 1, overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an RNA interference therapeutic, suppresses glycolate oxidase, reducing hepatic oxalate production. The objective of this first-in-human, randomized, placebo-controlled trial was to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of lumasiran in healthy participants and patients with primary hyperoxaluria type 1. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This phase 1/2 study was conducted in two parts. In part A, healthy adults randomized 3:1 received a single subcutaneous dose of lumasiran or placebo in ascending dose groups (0.3-6 mg/kg). In part B, patients with primary hyperoxaluria type 1 randomized 3:1 received up to three doses of lumasiran or placebo in cohorts of 1 or 3 mg/kg monthly or 3 mg/kg quarterly. Patients initially assigned to placebo crossed over to lumasiran on day 85. The primary outcome was incidence of adverse events. Secondary outcomes included pharmacokinetic and pharmacodynamic parameters, including measures of oxalate in patients with primary hyperoxaluria type 1. Data were analyzed using descriptive statistics. RESULTS: Thirty-two healthy participants and 20 adult and pediatric patients with primary hyperoxaluria type 1 were enrolled. Lumasiran had an acceptable safety profile, with no serious adverse events or study discontinuations attributed to treatment. In part A, increases in mean plasma glycolate concentration, a measure of target engagement, were observed in healthy participants. In part B, patients with primary hyperoxaluria type 1 had a mean maximal reduction from baseline of 75% across dosing cohorts in 24-hour urinary oxalate excretion. All patients achieved urinary oxalate levels ≤1.5 times the upper limit of normal. CONCLUSIONS: Lumasiran had an acceptable safety profile and reduced urinary oxalate excretion in all patients with primary hyperoxaluria type 1 to near-normal levels. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Study of Lumasiran in Healthy Adults and Patients with Primary Hyperoxaluria Type 1, NCT02706886.
Published: 2021
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