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1. Performance and clinical utility of a new supervised machine-learning pipeline in detecting rare ciliopathy patients based on deep phenotyping from electronic health records and semantic similarity

Author: Carole Faviez, Marc Vincent, Nicolas Garcelon, Olivia Boyer, Bertrand Knebelmann, Laurence Heidet, Sophie Saunier, Xiaoyi Chen, and Anita Burgun
Subjects: Diagnosis support, Electronic health record, Supervised machine learning, Semantic similarity, Imbalanced dataset, Rare disease, Medicine
Abstract: Abstract Background Rare diseases affect approximately 400 million people worldwide. Many of them suffer from delayed diagnosis. Among them, NPHP1-related renal ciliopathies need to be diagnosed as early as possible as potential treatments have been recently investigated with promising results. Our objective was to develop a supervised machine learning pipeline for the detection of NPHP1 ciliopathy patients from a large number of nephrology patients using electronic health records (EHRs). Methods and results We designed a pipeline combining a phenotyping module re-using unstructured EHR data, a semantic similarity module to address the phenotype dependence, a feature selection step to deal with high dimensionality, an undersampling step to address the class imbalance, and a classification step with multiple train-test split for the small number of rare cases. The pipeline was applied to thirty NPHP1 patients and 7231 controls and achieved good performances (sensitivity 86% with specificity 90%). A qualitative review of the EHRs of 40 misclassified controls showed that 25% had phenotypes belonging to the ciliopathy spectrum, which demonstrates the ability of our system to detect patients with similar conditions. Conclusions Our pipeline reached very encouraging performance scores for pre-diagnosing ciliopathy patients. The identified patients could then undergo genetic testing. The same data-driven approach can be adapted to other rare diseases facing underdiagnosis challenges.
Published: 2024
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2. Bone mineral density and growth changes in patients with distal renal tubular acidosis after two-years treatment with a new alkalizing drug (ADV7103)

Author: Aurélia Bertholet-Thomas, Maria A. Manso-Silván, Victor Navas-Serrano, Catherine Guittet, Sophie Joukoff, Justine Bacchetta, Olivia Boyer, Mariano Rodriguez Portillo, and Luc-André Granier
Subjects: ATRd, Bicarbonato plasmático, Calciuria, Citraturia, Crecimiento, Densidad mineral ósea, Diseases of the genitourinary system. Urology, RC870-923
Abstract: Background and objectives: ADV7103 is a new prolonged-release treatment for distal renal tubular acidosis (dRTA), containing potassium citrate and potassium bicarbonate. Since acidosis may affect bone mineral contents, the effects of ADV7103 on bone mineral density (BMD) and growth in patients with dRTA over 24 months were evaluated. Patients and methods: Thirty patients (24 paediatric patients and 6 adults) were included in an open-label extension study after a phase II/III trial. BMD, measured by densitometry, was assessed at baseline and at 24 months. Growth was evaluated throughout the study. Plasma bicarbonate, parathyroid hormone, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D, bone alkaline phosphatase, calciuria and citraturia, were also determined. Safety and treatment compliance were evaluated as well. Results: After 24 months of treatment with ADV7103, mean spine BMD z-score values significantly increased as compared with baseline (p = 0.024). In adults, spine and whole-body densitometry z-scores showed a significant correlation with plasma bicarbonate levels (rS = 0.82 and rS = 0.97, respectively, p 0.5 units in z-scores for height and weight in 18% and 36% of the paediatric patients, respectively. With treatment, plasma bicarbonate concentration and calciuria at the different visits were normal in 69–86% and 93–96% patients, respectively. Only nine treatment-related gastrointestinal AEs of mild/moderate severity, were reported in five patients. Conclusions: Two years of ADV7103 treatment improved growth and increased spine BMD. These results suggest that control of acidosis by ADV7103 treatment improves bone parameters. Resumen: Antecedentes y objetivo: El ADV7103 es un nuevo tratamiento de liberación prolongada para la acidosis tubular renal distal (ATRd), que contiene citrato potásico y bicarbonato potásico. Dado que la acidosis puede afectar al contenido mineral óseo, se ha evaluado el efecto de dicho medicamento a lo largo de 24 meses sobre la densidad mineral ósea (DMO) y el crecimiento en pacientes con ATRd. Pacientes y métodos: Se incluyeron treinta pacientes (24 pediátricos y seis adultos) en un estudio abierto de extensión tras un ensayo clínico de fase II/III. La DMO medida por densitometría se midió al inicio del estudio y los 24 meses. El crecimiento se evaluó a lo largo del estudio. Adicionalmente, se determinaron el bicarbonato plasmático, la parathormona, 25 hidroxivitamina D, 1,25 dihidroxivitamina D, fosfatasa alcalina ósea, calciuria y citraturia. La seguridad y el cumplimento terapéutico también fueron evaluados. Resultados: Tras 24 meses de tratamiento con ADV7103 la media del z-score de DMO de columna aumentó significativamente frente al valor basal (p = 0,024). En los adultos el z-score de la densitometría de columna y corporal total mostró una correlación significativa con los valores de bicarbonato plasmático (rS = 0,82 y rS = 0,97, respectivamente, p < 0,005). Se registró un incremento > 0,5 unidades de z-score para altura y peso en el 18 y 36%, respectivamente, de los pacientes pediátricos. Con el tratamiento, la concentración plasmática de bicarbonato y la calciuria fueron normales en las diferentes visitas en un 69-86% y un 93-96% de los pacientes, respectivamente. Solamente se notificaron nueve eventos adversos gastrointestinales relacionados con el tratamiento, todos de intensidad leve/moderada en cinco pacientes. Conclusiones: Dos años de tratamiento con ADV7103 mejoraron el crecimiento y la DMO de columna. Estos resultados sugieren que el control de la acidosis con dicho tratamiento provoca una mejora de parámetros óseos.
Published: 2023
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3. Long-term renal outcome in methylmalonic acidemia in adolescents and adults

Author: Myriam Dao, Jean-Baptiste Arnoux, Frank Bienaimé, Anaïs Brassier, François Brazier, Jean-François Benoist, Clément Pontoizeau, Chris Ottolenghi, Pauline Krug, Olivia Boyer, Pascale de Lonlay, and Aude Servais
Subjects: Methylmalonic acidemia, Chronic kidney disease, Measured glomerular filtration rate, Estimated glomerular filtration rate, Tubulopathy, Medicine
Abstract: Abstract Background Chronic kidney disease (CKD) is one of the main long-term prognosis factors in methylmalonic acidemia (MMA), a rare disease of propionate catabolism. Our objective was to precisely address the clinical and biological characteristics of long-term CKD in MMA adolescent and adult patients. Patients and methods In this retrospective study, we included MMA patients older than 13 years who had not received kidney and/or liver transplantation. We explored tubular functions, with special attention to proximal tubular function. We measured glomerular filtration rate (mGFR) by iohexol clearance and compared it to estimated glomerular filtration rate (eGFR) by Schwartz formula and CKD-EPI. Results Thirteen patients were included (M/F = 5/8). Median age was 24 years (13 to 32). Median mGFR was 57 mL/min/1.73 m2 (23.3 to 105 mL/min/1.73 m2). Ten out of 13 patients had mGFR below 90 mL/min/1.73 m2. No patient had significant glomerular proteinuria. No patient had complete Fanconi syndrome. Only one patient had biological signs suggestive of incomplete proximal tubulopathy. Four out of 13 patients had isolated potassium loss, related to a non-reabsorbable anion effect of urinary methylmalonate. Both Schwartz formula and CKD-EPI significantly overestimated GFR. Bias were respectively 16 ± 15 mL/min/1.73 m2 and 37 ± 22 mL/min/1.73 m2. Conclusion CKD is a common complication of the MMA. Usual equations overestimate GFR. Therefore, mGFR should be performed to inform therapeutic decisions such as dialysis and/or transplantation. Mild evidence of proximal tubular dysfunction was found in only one patient, suggesting that other mechanisms are involved.
Published: 2021
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4. Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function

Author: Mathilda Bedin, Olivia Boyer, Aude Servais, Yong Li, Laure Villoing-Gaudé, Marie-Josephe Tête, Alexandra Cambier, Julien Hogan, Veronique Baudouin, Saoussen Krid, Albert Bensman, Florie Lammens, Ferielle Louillet, Bruno Ranchin, Cecile Vigneau, Iseline Bouteau, Corinne Isnard-Bagnis, Christoph J. Mache, Tobias Schäfer, Lars Pape, Markus Gödel, Tobias B. Huber, Marcus Benz, Günter Klaus, Matthias Hansen, Kay Latta, Olivier Gribouval, Vincent Morinière, Carole Tournant, Maik Grohmann, Elisa Kuhn, Timo Wagner, Christine Bole-Feysot, Fabienne Jabot-Hanin, Patrick Nitschké, Tarunveer S. Ahluwalia, Anna Köttgen, Christian Brix Folsted Andersen, Carsten Bergmann, Corinne Antignac, and Matias Simons
Subjects: Medicine
Published: 2022
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5. COQ6 mutation in patients with nephrotic syndrome, sensorineural deafness, and optic atrophy

Author: R. Justine Perrin, Caroline Rousset‐Rouvière, Florentine Garaix, Aline Cano, John Conrath, Olivia Boyer, and Michel Tsimaratos
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665, Genetics, QH426-470
Abstract: Abstract Introduction Primary coenzyme Q10 (CoQ10) deficiencies are a group of mitochondrial disorders that has proven responsiveness to replacement therapy. Mutations in enzymes involved in the biosynthesis of CoQ10 genes are associated with these deficits. The clinical presentation of this rare autosomal recessive disorder is heterogeneous and depends on the gene involved. Mutations in the COQ2, COQ6, PDSS2, and ADCK4 genes are responsible for steroid‐resistant nephrotic syndrome (SRNS), which is associated with extra‐renal symptoms. Previous studies have reported COQ6 mutations in 11 patients from five different families presenting with SRNS and sensorineural deafness. Case reports Our study reports the cases of two brothers of Turkish origin with renal failure and sensorineural deafness associated with COQ6 mutations responsible of CoQ10 deficiency. Optical symptoms were present in the eldest, that improved with Idebenone. Conclusion/Discussion For the first time, COQ6 mutation with optical involvement is associated with renal and hearing impairment. Although the response to replacement CoQ10 therapy was difficult to evaluate, we think that this treatment was able to stop the disease progression in both patients, and even to prevent the occurrence/development of optical and neurological impairment in the younger brother. Mitochondrial dysfunction secondary to CoQ10 deficiency should always be suspected in patients with SRNS and extra‐renal symptoms. Early recognition of this genetic SRNS is mandatory since SRNS can be avoided by adequate treatment based on CoQ10 supplement or an analogue. All cases of primary CoQ10 deficiency should be treated at an early stage to limit the progression of lesions and prevent the emergence of new symptoms.
Published: 2020
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6. Extracorporeal Shockwave Lithotripsy for Cystine Stones in Children: An Observational, Retrospective, Single-Center Analysis

Author: Nicolas Vinit, Antoine Khoury, Pauline Lopez, Laurence Heidet, Nathalie Botto, Olivier Traxer, Olivia Boyer, Thomas Blanc, and Henri B. Lottmann
Subjects: cystinuria, cystine stone, extracorporeal shockwave lithotripsy, pediatric nephrolithiasis, stone free, Pediatrics, RJ1-570
Abstract: Purpose: Cystinuria is a genetic disorder characterized by a defective reabsorption of cystine and dibasic amino acids leading to development of urinary tract calculi from childhood onward. Cystine lithiasis is known to be resistant to fragmentation. The aim was to evaluate our long-term experience with extracorporeal shockwave lithotripsy (ESWL) used as first-line urological treatment to treat cystine stones in children.Methods: We retrospectively reviewed the charts of all children who underwent ESWL for cystine stone. We assessed the 3-month stone-free rate, according to age, younger (group 1) or older (group 2) than 2 years old.Results: Between 2003 and 2016, 15 patients with a median (IQR) age at first treatment of 48 (15–108) months underwent ESWL in monotherapy. Median age was, respectively, 15 and 108 months in each group. The median (IQR) stone burden was 2,620 (1,202–8,265) mm3 in group I and 4,588 (2,039–5,427) mm3 in group II (p = 0.96). Eleven patients had bilateral calculi. ESWL was repeated on average 2.4 times, with a maximum of 4 for patients of group I, and 4.8 times, with a maximum of 9 for group II (p > 0.05). ESWL in monotherapy was significantly more efficient to reach stone-free status for children under 2 years of age: 83% vs. 6.2% (p = 0.040). The median (IQR) follow-up of the study was 69 (42–111) months.Conclusion: ESWL appears as a valid urological option for the treatment of cystine stones, in young children. Even if cystine stones are known to be resistant to fragmentation, we report 83% of stone-free status at 3 months with ESWL used in monotherapy in children under 2 years old with cystinuria. In older children, the success rate is too low to recommend ESWL as a first line approach.
Published: 2021
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7. Defects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome

Author: Christelle Arrondel, Sophia Missoury, Rozemarijn Snoek, Julie Patat, Giulia Menara, Bruno Collinet, Dominique Liger, Dominique Durand, Olivier Gribouval, Olivia Boyer, Laurine Buscara, Gaëlle Martin, Eduardo Machuca, Fabien Nevo, Ewen Lescop, Daniela A. Braun, Anne-Claire Boschat, Sylvia Sanquer, Ida Chiara Guerrera, Patrick Revy, Mélanie Parisot, Cécile Masson, Nathalie Boddaert, Marina Charbit, Stéphane Decramer, Robert Novo, Marie-Alice Macher, Bruno Ranchin, Justine Bacchetta, Audrey Laurent, Sophie Collardeau-Frachon, Albertien M. van Eerde, Friedhelm Hildebrandt, Daniella Magen, Corinne Antignac, Herman van Tilbeurgh, and Géraldine Mollet
Subjects: Science
Abstract: The biosynthesis of N6-threonylcarbamoylated adenosine 37 in tRNA (t6A) involves the YRDC enzyme and the KEOPS complex. Here, the authors report mutations in YRDC and the KEOPS component GON7 in Galloway-Mowat syndrome and determine the crystal structure of a GON7-containg subcomplex that suggests a role in KEOPS complex stability.
Published: 2019
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8. Influenza vaccination among children with idiopathic nephrotic syndrome: an investigation of practices

Author: Roman Klifa, Julie Toubiana, Alizée Michel, Nathalie Biebuyck, Marina Charbit, Laurence Heidet, Saoussen Krid, Pauline Krug, Rémi Salomon, and Olivia Boyer
Subjects: Influenza, Vaccination, Idiopathic nephrotic syndrome, Practices, Efficacy, Safety, Diseases of the genitourinary system. Urology, RC870-923
Abstract: Abstract Background Annual influenza vaccination is recommended for all children with idiopathic nephrotic syndrome (INS) in France. Consequently, the Social Security automatically sends prescriptions to all patients suffering from a chronic disease. The aim of this study was to evaluate the follow-up to these recommendations. Methods We conducted a monocentric retrospective investigation of practices. We included all children with steroid-sensitive INS in remission who attended our clinics from January 1st 2015 to January 1st 2017, resided in France and had a valid phone number. Data were collected from May 2017 to June 2017 through a phone interview and review of clinical charts. Results 75 patients met the inclusion criteria. The parents of 57 children could be reached by phone and agreed to participate to the survey. 35/57 (61.4%) declared having received a prescription during the 2016–2017 campaign. Only 14 children (24.6%) were vaccinated. 17/43 (39.5%) parents of unvaccinated children had concerns about the safety of the vaccine, 16/43 (37.2%) were not aware of the recommendations, 5/43 (11.6%) had been recommended by their physician not to vaccinate their child, 3/43 (7%) forgot to have them vaccinated and 2/43 (4.6%) reported no reason. 13/43 (30%) unvaccinated children presented a relapse during the flu season - 2/13 during an influenza-like illness - whereas 1/14 (7%) immunized children presented a relapse during the six months of post-vaccination follow-up. Relapse rates were not increased in vaccinated children compared to unvaccinated children (p = 0.15), nor in the 6 months following vaccination compared to the 6 months prior (1/14 vs 5/14, p = 0.20). Conclusions 1)
Published: 2019
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9. Aetiology, course and treatment of acute tubulointerstitial nephritis in paediatric patients: a cross-sectional web-based survey

Author: Atif Awan, Michael Riordan, Ipek Kaplan Bulut, Sevgin Taner, Francesco Emma, Jakub Zieg, Olivia Boyer, Nakysa Hooman, Lars Pape, Robert Woroniecki, Timo Jahnukainen, Matthias Hansen, Sarah Wente-Schulz, Marina Aksenova, Cahyani Gita Ambarsari, Francesca Becherucci, Marc Fila, Telma Francisco, Ibrahim Gokce, Bora Gülhan, Mahmoud Kallash, Konstantinos Kamperis, Sherene Mason, Antonio Mastrangelo, Francesca Mencarelli, Bogna Niwinska-Faryna, Rina R Rus, Seha Saygili, Erkin Serdaroglu, Rezan Topaloglu, Enrico Vidal, Sibel Yel, Kathrin Buder, Elisabeth AM Cornelissen, Maria del Mar Espino Hernández, Markus Kemper, Julie Maquet, Fernando Santos, and Ulrike Walden
Subjects: Medicine
Abstract: Background Acute tubulointerstitial nephritis (TIN) is a significant cause of acute renal failure in paediatric and adult patients. There are no large paediatric series focusing on the aetiology, treatment and courses of acute TIN.Patients, design and setting We collected retrospective clinical data from paediatric patients with acute biopsy-proven TIN by means of an online survey. Members of four professional societies were invited to participate.Results Thirty-nine physicians from 18 countries responded. 171 patients with acute TIN were included (54% female, median age 12 years). The most frequent causes were tubulointerstitial nephritis and uveitis syndrome in 31% and drug-induced TIN in 30% (the majority of these caused by non-steroidal anti-inflammatory drugs). In 28% of patients, no initiating noxae were identified (idiopathic TIN). Median estimated glomerular filtration rate (eGFR) rose significantly from 31 at time of renal biopsy to 86 mL/min/1.73 m2 3–6 months later (p
Published: 2021
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10. Late Onset of ANCA Vasculitis as a Side Effect of Levamisole Treatment in Nephrotic Syndrome

Author: Silvia Bernardi, Samantha Innocenti, Marina Charbit, and Olivia Boyer
Subjects: ANCA-vasculitis, nephrotic syndrome, Levamisole, children, case report, Medicine (General), R5-920
Abstract: Levamisole is effectively used in steroid-dependent nephrotic syndrome and the more frequent side effects reported are cytopenia and liver enzymes alterations. Several studies have demonstrated that this drug can induce high titers of circulating perinuclear antineutrophil cytoplasmic autoantibodies (ANCA) and vasculitis, most of them occurring in the case of prolonged use. A four-year-old boy that was affected with steroid-dependent nephrotic syndrome was treated with Levamisole as a steroid-sparing agent at a dose of 2 mg/kg/48 h. After initiation of the treatment, the number of relapses drastically decreased, enabling a significant reduction in the cumulative steroid dose. Levamisole was well tolerated, and was therefore administered for several years. At the age of 15, he was also diagnosed with celiac disease. After nine years of continuous Levamisole treatment, he presented with a high fever, hand and foot joint arthritis, and increased levels of total and direct bilirubin. Since the symptoms started two days after the injection of the second dose of the COVID-19 vaccine, it was initially concluded that these manifestations were rare vaccination side effects. Therefore, he did not receive any specific treatments, and Levamisole was continued at the same dose. After an initial improvement, two months later, the patient presented with the same symptoms. Suspecting Levamisole-induced vasculitis, an ANCA titer was measured and this returned positive. Clinical manifestations and double positivity for both myeloperoxidase (MPO) and anti-proteinase 3 (PR3) antibodies argued against the fact that that these findings were secondary to vaccination, cocaine abuse, or celiac disease. Assuming that we were facing a rare drug reaction, Levamisole was promptly interrupted. This resulted in a rapid remission of fever and arthritis improvement, and a decrease in ANCA titers. By reporting this case, we want to raise awareness among clinicians regarding a rare complication of treatment with Levamisole that is often misdiagnosed due to the fact that the current literature lacks univocal guidelines regarding the precise timing of ANCA titrations and the duration of the treatment.
Published: 2022
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11. Efficacy and safety of intravenous immunoglobulin with rituximab versus rituximab alone in childhood-onset steroid-dependent and frequently relapsing nephrotic syndrome: protocol for a multicentre randomised controlled trial

Author: Djamal Djeddi, Julien Hogan, Aubriana Perez, Anne-Laure Sellier-Leclerc, Isabelle Vrillon, Francoise Broux, Francois Nobili, Jerome Harambat, Lucie Bessenay, V Audard, Camille Faudeux, Denis Morin, Christine Pietrement, Stephanie Tellier, Philippe Eckart, Annie Lahoche, G Roussey-Kesler, Tim Ulinski, Olivia Boyer, Emmanuelle Plaisier, Sylvie Cloarec, Anne Jolivot, Vincent Guigonis, Sophie Guilmin-Crepon, Veronique Baudouin, Claire Dossier, and Georges Deschênes
Subjects: Medicine
Abstract: Introduction Guidelines for the treatment of steroid-dependent nephrotic syndrome (SDNS) and frequently relapsing nephrotic syndrome (FRNS) are lacking. Given the substantial impact of SDNS/FRNS on quality of life, strategies aiming to provide long-term remission while minimising treatment side effects are needed. Several studies confirm that rituximab is effective in preventing early relapses in SDNS/FRNS; however, the long-term relapse rate remains high (~70% at 2 years). This trial will assess the association of intravenous immunoglobulins (IVIgs) to rituximab in patients with SDNS/FRNS and inform clinicians on whether IVIg’s immunomodulatory properties can alter the course of the disease and reduce the use of immunosuppressive drugs and their side effects.Methods and analysis We conduct an open-label multicentre, randomised, parallel group in a 1:1 ratio, controlled, superiority trial to assess the safety and efficacy of a single infusion of rituximab followed by IVIg compared with rituximab alone in childhood-onset FRNS/SDNS. The primary outcome is the occurrence of first relapse within 24 months. Patients are allocated to receive either rituximab alone (375 mg/m²) or rituximab followed by IVIg, which includes an initial Ig dose of 2 g/kg, followed by 1.5 g/kg injections once a month for the following 5 months (maximum dose: 100 g).Ethics and dissemination The study has been approved by the ethics committee (Comité de Protection des Personnes) of Ouest I and authorised by the French drug regulatory agency (Agence Nationale de Sécurité du Médicament et des Produits de Santé). Results of the primary study and the secondary aims will be disseminated through peer-reviewed publications.Trial registration number NCT03560011.
Published: 2020
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12. Response to Cysteamine in Osteoclasts Obtained from Patients with Nephropathic Cystinosis: A Genotype/Phenotype Correlation

Author: Thomas Quinaux, Aurélia Bertholet-Thomas, Aude Servais, Olivia Boyer, Isabelle Vrillon, Julien Hogan, Sandrine Lemoine, Ségolène Gaillard, Candide Alioli, Sophie Vasseur, Cécile Acquaviva, Olivier Peyruchaud, Irma Machuca-Gayet, and Justine Bacchetta
Subjects: cystinosis, cysteamine, bone, osteoclast, genotype, Cytology, QH573-671
Abstract: Bone complications of cystinosis have been recently described. The main objectives of this paper were to determine in vitro the impact of CTNS mutations and cysteamine therapy on human osteoclasts and to carry out a genotype-phenotype analysis related to osteoclastic differentiation. Human osteoclasts were differentiated from peripheral blood mononuclear cells (PBMCs) and were treated with increasing doses of cysteamine (0, 50, 200 µM) and then assessed for osteoclastic differentiation. Results are presented as median (min-max). A total of 17 patients (mainly pediatric) were included, at a median age of 14 (2–61) years, and a eGFR of 64 (23–149) mL/min/1.73 m2. Most patients (71%) were under conservative kidney management (CKM). The others were kidney transplant recipients. Three functional groups were distinguished for CTNS mutations: cystinosin variant with residual cystin efflux activity (RA, residual activity), inactive cystinosin variant (IP, inactive protein), and absent protein (AP). PBMCs from patients with residual cystinosin activity generate significantly less osteoclasts than those obtained from patients of the other groups. In all groups, cysteamine exerts an inhibitory effect on osteoclastic differentiation at high doses. This study highlights a link between genotype and osteoclastic differentiation, as well as a significant impact of cysteamine therapy on this process in humans.
Published: 2021
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13. Evaluation of Hydroxychloroquine Blood Concentrations and Effects in Childhood-Onset Systemic Lupus Erythematosus

Author: Noël Zahr, Saik Urien, Christian Funck-Brentano, Hélène Vantomme, Nicolas Garcelon, Isabelle Melki, Margaux Boistault, Olivia Boyer, and Brigitte Bader-Meunier
Subjects: hydroxychloroquine, systemic lupus erythematosus, pharmacokinetics, pharmacodynamics, Medicine, Pharmacy and materia medica, RS1-441
Abstract: Background: Hydroxychloroquine (HCQ) is an antimalarial agent given to patients with systemic lupus erythematosus (SLE) as first-line therapy. It alleviates childhood-onset systemic lupus erythematosus cSLE skin and musculoskeletal disease, decreasing disease activity and flares. HCQ concentration–effect relationships in children remains unknown. This study aimed to investigate the pharmacokinetics of HCQ and possible concentration–effect relationships. Methods: HCQ blood concentrations and effects were obtained during clinical follow-up on different occasions. cSLE flares were defined using the SLE Disease Activity Index (SLEDAI); flare was denoted by a SLEDAI score > 6. Blood concentration was measured using high-performance liquid chromatography with fluorometric detection. Statistical analysis was performed using a nonlinear mixed-effect approach with the Monolix software. Results: A total of 168 blood samples were obtained from 55 pediatric patients. HCQ apparent blood clearance (CL/F) was dependent on patients’ bodyweight and platelet count. Patients with active cSLE had a lower mean blood HCQ concentration compared with inactive cSLE patients (536 ± 294 vs. 758 ± 490 ng/mL, p = 5 × 10−6). Among patients with HCQ blood concentration ≥750 ng/mL, 87.6% had inactive cSLE. Moreover, HCQ blood concentration was a significant predictor of disease status. Conclusion: We developed the first HCQ blood concentration–effect relationship for cSLE associated with active or non-active disease status. A prospective randomized study is necessary to confirm these results.
Published: 2021
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14. Correction: A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies.

Author: Sara Gonçalves, Julie Patat, Maria Clara Guida, Noelle Lachaussée, Christelle Arrondel, Martin Helmstädter, Olivia Boyer, Olivier Gribouval, Marie-Claire Gubler, Geraldine Mollet, Marlène Rio, Marina Charbit, Christine Bole-Feysot, Patrick Nitschke, Tobias B Huber, Patricia G Wheeler, Devon Haynes, Jane Juusola, Thierry Billette de Villemeur, Caroline Nava, Alexandra Afenjar, Boris Keren, Rolf Bodmer, Corinne Antignac, and Matias Simons
Subjects: Genetics, QH426-470
Abstract: [This corrects the article DOI: 10.1371/journal.pgen.1007386.].
Published: 2018
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15. A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies.

Author: Sara Gonçalves, Julie Patat, Maria Clara Guida, Noelle Lachaussée, Christelle Arrondel, Martin Helmstädter, Olivia Boyer, Olivier Gribouval, Marie-Claire Gubler, Geraldine Mollet, Marlène Rio, Marina Charbit, Christine Bole-Feysot, Patrick Nitschke, Tobias B Huber, Patricia G Wheeler, Devon Haynes, Jane Juusola, Thierry Billette de Villemeur, Caroline Nava, Alexandra Afenjar, Boris Keren, Rolf Bodmer, Corinne Antignac, and Matias Simons
Subjects: Genetics, QH426-470
Abstract: Recent evidence suggests that the presence of more than one pathogenic mutation in a single patient is more common than previously anticipated. One of the challenges hereby is to dissect the contribution of each gene mutation, for which animal models such as Drosophila can provide a valuable aid. Here, we identified three families with mutations in ADD3, encoding for adducin-γ, with intellectual disability, microcephaly, cataracts and skeletal defects. In one of the families with additional cardiomyopathy and steroid-resistant nephrotic syndrome (SRNS), we found a homozygous variant in KAT2B, encoding the lysine acetyltransferase 2B, with impact on KAT2B protein levels in patient fibroblasts, suggesting that this second mutation might contribute to the increased disease spectrum. In order to define the contribution of ADD3 and KAT2B mutations for the patient phenotype, we performed functional experiments in the Drosophila model. We found that both mutations were unable to fully rescue the viability of the respective null mutants of the Drosophila homologs, hts and Gcn5, suggesting that they are indeed pathogenic in flies. While the KAT2B/Gcn5 mutation additionally showed a significantly reduced ability to rescue morphological and functional defects of cardiomyocytes and nephrocytes (podocyte-like cells), this was not the case for the ADD3 mutant rescue. Yet, the simultaneous knockdown of KAT2B and ADD3 synergistically impaired kidney and heart function in flies as well as the adhesion and migration capacity of cultured human podocytes, indicating that mutations in both genes may be required for the full clinical manifestation. Altogether, our studies describe the expansion of the phenotypic spectrum in ADD3 deficiency associated with a homozygous likely pathogenic KAT2B variant and thereby identify KAT2B as a susceptibility gene for kidney and heart disease in ADD3-associated disorders.
Published: 2018
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16. Low renal but high extrarenal phenotype variability in Schimke immuno-osseous dysplasia.

Author: Beata S Lipska-Ziętkiewicz, Jutta Gellermann, Olivia Boyer, Olivier Gribouval, Szymon Ziętkiewicz, Jameela A Kari, Mohamed A Shalaby, Fatih Ozaltin, Jiri Dusek, Anette Melk, Aysun K Bayazit, Laura Massella, Lidia Hyla-Klekot, Sandra Habbig, Astrid Godron, Maria Szczepańska, Beata Bieniaś, Dorota Drożdż, Rasha Odeh, Wioletta Jarmużek, Katarzyna Zachwieja, Agnes Trautmann, Corinne Antignac, Franz Schaefer, and PodoNet Consortium
Subjects: Medicine, Science
Abstract: Schimke immuno-osseous dysplasia (SIOD) is a rare multisystem disorder with early mortality and steroid-resistant nephrotic syndrome (SRNS) progressing to end-stage kidney disease. We hypothesized that next-generation gene panel sequencing may unsurface oligosymptomatic cases of SIOD with potentially milder disease courses. We analyzed the renal and extrarenal phenotypic spectrum and genotype-phenotype associations in 34 patients from 28 families, the largest SMARCAL1-associated nephropathy cohort to date. In 11 patients the diagnosis was made unsuspectedly through SRNS gene panel testing. Renal disease first manifested at median age 4.5 yrs, with focal segmental glmerulosclerosis or minimal change nephropathy on biopsy and rapid progression to end-stage kidney disease (ESKD) at median age 8.7 yrs. Whereas patients diagnosed by phenotype more frequently developed severe extrarenal complications (cerebral ischemic events, septicemia) and were more likely to die before age 10 years than patients identified by SRNS-gene panel screening (88 vs. 40%), the subgroups did not differ with respect to age at proteinuria onset and progression to ESKD. Also, 10 of 11 children diagnosed unsuspectedly by Next Generation Sequencing were small at diagnosis and all showed progressive growth failure. Severe phenotypes were usually associated with biallelic truncating mutations and milder phenotypes with biallelic missense mutations. However, no genotype-phenotype correlation was observed for the renal disease course. In conclusion, while short stature is a reliable clue to SIOD in children with SRNS, other systemic features are highly variable. Our findings support routine SMARCAL1 testing also in non-syndromic SRNS.
Published: 2017
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17. Hemolytic Uremic Syndrome: New Developments in Pathogenesis and Treatment

Author: Olivia Boyer and Patrick Niaudet
Subjects: Diseases of the genitourinary system. Urology, RC870-923
Abstract: Hemolytic uremic syndrome is defined by the characteristic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. In children, most cases of HUS are caused by Shiga-toxin-producing bacteria, especially Escherichia coli O157:H7. Common vehicles of transmission include ground beef, unpasteurized milk, and municipal or swimming water. Shiga-toxin-associated HUS is a main cause of acute renal failure in young children. Management remains supportive as there is at present no specific therapy to ameliorate the prognosis. Immediate outcome is most often favourable but long-term renal sequelae are frequent due to nephron loss. Atypical HUS represents 5% of cases. In the past 15 years, mutations in complement regulators of the alternative pathway have been identified in almost 60% of cases, leading to excessive complement activation. The disease has a relapsing course and more than half of the patients either die or progress to end-stage renal failure. Recurrence after renal transplantation is frequent.
Published: 2011
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18. The Smart Data Extractor, a Clinician Friendly Solution to Accelerate and Improve the Data Collection During Clinical Trials.

Author: Sophie Quennelle, Maxime Douillet, Lisa Friedlander, Olivia Boyer, Antoine Neuraz, Anita Burgun, and Nicolas Garcelon
Published: 2023
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19. Acute tubulointerstitial nephritis with or without uveitis: a novel form of post-acute COVID-19 syndrome in children

Author: Marina Avramescu, Pierre Isnard, Sarah Temmam, Agnès Chevalier, Paul Bastard, Mikael Attia, Romain Berthaud, Marc Fila, Claire Dossier, Julien Hogan, Tim Ulinski, Damia Leguevaques, Férielle Louillet, Edouard Martinez Casado, Jean-Michel Halimi, Sylvie Cloarec, Ariane Zaloszyc, Camille Faudeux, Caroline Rousset-Rouvière, Stéphanie Clavé, Jérôme Harambat, Edouard Rollot, Thomas Simon, Megan Nallet-Amate, Bruno Ranchin, Justine Bacchetta, Florence Porcheret, Josselin Bernard, Amélie Ryckewaert, Anne Jamet, Jacques Fourgeaud, Nicolas Da Rocha, Philippe Pérot, Nicolas Kuperwasser, Naïm Bouazza, Marion Rabant, Jean-Paul Duong Van Huyen, Matthieu P Robert, Julien Zuber, Jean-Laurent Casanova, Marc Eloit, Isabelle Sermet-Gaudelus, Olivia Boyer, Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte [CHU-Necker] (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), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Découverte de pathogènes – Pathogen discovery, Institut Pasteur [Paris] (IP), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Rockefeller University [New York], Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), AP-HP Hôpital universitaire Robert-Debré [Paris], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Rouen, Normandie Université (NU), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Strasbourg, Centre Hospitalier Universitaire de Nice (CHU Nice), Assistance Publique - Hôpitaux de Marseille (APHM), CHU Bordeaux [Bordeaux], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hospices Civils de Lyon (HCL), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Pontchaillou [Rennes], Pharmacologie et évaluations thérapeutiques chez l'enfant et la femme enceinte (URP_7323), Université Paris Cité (UPCité), Site Tarnier (hôpital Cochin) - APHP, CIC - Mère Enfant Necker Cochin Paris Centre (CIC 1419), Hôpital Cochin [AP-HP], 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)-Université Paris Cité (UPCité)
Subjects: pediatric, SARS-CoV, Nephrology, [SDV]Life Sciences [q-bio], 2 TINUs, tubule-interstitial nephritis, uveitis, COVID-19
Abstract: BackgroundCOVID-19 is a complex multisystem disease, frequently associated with kidney injury. Since the beginning of the COVID-19 pandemic, we observed a striking increase in the incidence of acute tubulointerstitial nephritis (aTIN) without or with uveitis (TINUs) among children. This prompted us to examine whether SARS-CoV-2 might be the underlying trigger.MethodsWe conducted a French nationwide retrospective cohort study. We included all consecutive children diagnosed with aTIN or TINUs of undetermined cause between April-2020 and March-2021. SARS-CoV-2 antibody responses were tested by a luciferase immunoprecipitation system and compared to age-matched controls. Immunohistochemistry, immunofluorescence and molecular microbiology analyses were performed on kidney biopsies.ResultsForty-eight children were included with a median age at diagnosis of 14.7 years (9.4-17.6). aTIN and TINUs incidence rates increased 3-fold and 12-fold, respectively, compared to pre-pandemic years. All patients had impaired kidney function with a median eGFR of 31.9 ml/min/1.73m² at diagnosis. Kidney biopsies showed lesions of acute tubulointerstitial nephritis and 25% of patients had fibrosis. No patient had concomitant acute COVID-19. All 16 children tested had high anti-N IgG titers and one had anti-S IgGs. Next-generation sequencing failed to detect any infectious agents in kidney biopsies. However, SARS-CoV-2 RNA was detected by PCR in two kidney samples supporting a potential direct link between SARS-CoV-2 and aTIN/TINUs.ConclusionsWe describe a novel form of post-acute COVID-19 syndrome in children, unique in its exclusive kidney and eye involvement, and its distinctive anti-SARS-CoV-2 N+/S-serological profile. Our results support a causal association linking SARS-CoV-2 infection to this newly-reported burst of renal/eye inflammation.
Published: 2023
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20. A multicenter retrospective study of calcineurin inhibitors in nephrotic syndrome secondary to podocyte gene variants

Author: Georgia Malakasioti, Daniela Iancu, Anastasiia Milovanova, Alexey Tsygin, Tomoko Horinouchi, China Nagano, Kandai Nozu, Koichi Kamei, Shuichiro Fujinaga, Kazumoto Iijima, Rajiv Sinha, Biswanath Basu, William Morello, Giovanni Montini, Aoife Waters, Olivia Boyer, Zeynep Yürük Yıldırım, Sibel Yel, İsmail Dursun, Hugh J. McCarthy, Marina Vivarelli, Larisa Prikhodina, Martine T.P. Besouw, Eugene Yu-hin Chan, Wenyan Huang, Markus J. Kemper, Sebastian Loos, Chanel Prestidge, William Wong, Galia Zlatanova, Rasmus Ehren, Lutz T. Weber, Hassib Chehade, Nakysa Hooman, Marcin Tkaczyk, Małgorzata Stańczyk, Michael Miligkos, and Kjell Tullus
Subjects: monogenic steroid-resistant nephrotic syndrome, Nephrology, calcineurin inhibitors, kidney failure
Abstract: While 44-83% of children with steroid-resistant nephrotic syndrome (SRNS) without a proven genetic cause respond to treatment with a calcineurin inhibitor (CNI), current guidelines recommend against the use of immunosuppression in monogenic SRNS. This is despite existing evidence suggesting that remission with CNI treatment is possible and can improve prognosis in some cases of monogenic SRNS. Herein, our retrospective study assessed response frequency, predictors of response and kidney function outcomes among children with monogenic SRNS treated with a CNI for at least three months. Data from 203 cases (age 0-18 years) were collected from 37 pediatric nephrology centers. Variant pathogenicity was reviewed by a geneticist, and 122 patients with a pathogenic and 19 with a possible pathogenic genotype were included in the analysis. After six months of treatment and at last visit, 27.6% and 22.5% of all patients respectively, demonstrated partial or full response. Achievement of at least partial response at six months of treatment conferred a significant reduction in kidney failure risk at last follow-up compared to no response (hazard ratio [95% confidence interval] 0.25, [0.10-0.62]). Moreover, risk of kidney failure was significantly lower when only those with a follow-up longer than two years were considered (hazard ratio 0.35, [0.14-0.91]). Higher serum albumin level at CNI initiation was the only factor related to increased likelihood of significant remission at six months (odds ratio [95% confidence interval] 1.16, [1.08-1.24]). Thus, our findings justify a treatment trial with a CNI also in children with monogenic SRNS.
Published: 2023
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21. An automated histological classification system for precision diagnostics of kidney allografts

Author: Daniel Yoo, Valentin Goutaudier, Gillian Divard, Juliette Gueguen, Brad C. Astor, Olivier Aubert, Marc Raynaud, Zeynep Demir, Julien Hogan, Patricia Weng, Jodi Smith, Rouba Garro, Bradley A. Warady, Rima S. Zahr, Marta Sablik, Katherine Twombley, Lionel Couzi, Thierry Berney, Olivia Boyer, Jean-Paul Duong-Van-Huyen, Magali Giral, Alaa Alsadi, Pierre A. Gourraud, Emmanuel Morelon, Moglie Le Quintrec, Sophie Brouard, Christophe Legendre, Dany Anglicheau, Jean Villard, Weixiong Zhong, Nassim Kamar, Oriol Bestard, Arjang Djamali, Klemens Budde, Mark Haas, Carmen Lefaucheur, Marion Rabant, and Alexandre Loupy
Subjects: General Medicine, General Biochemistry, Genetics and Molecular Biology
Published: 2023
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22. Atteinte neurologique et syndrome néphrotique cortico-résistant

Author: Olivia Boyer, Géraldine Mollet, and Guillaume Dorval
Subjects: General Medicine, General Biochemistry, Genetics and Molecular Biology
Abstract: Les études génétiques portant sur le syndrome néphrotique (SN) héréditaire ont permis d’identifier plus de 60 gènes impliqués dans le développement de formes monogéniques de SN cortico-résistant, isolé ou syndromique, ce dernier étant parfois associé à des troubles neurologiques. Au cours des dernières décennies, diverses études ont établi des liens entre la physiologie des podocytes et celle des neurones, tant sur le plan morphologique (diaphragme de fente et synapse) que fonctionnel (plateformes de signalisation). Des variants dans des gènes codant des protéines s’exprimant dans différents compartiments du podocyte et des neurones sont responsables de phénotypes associant des lésions rénales avec protéinurie à des troubles neurologiques centraux et/ou périphériques. L’objectif de cette revue est de se concentrer sur les syndromes génétiques associant une protéinurie et une atteinte neurologique et de présenter les dernières avancées dans la description de ces troubles neuro-rénaux.
Published: 2023
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23. Overcoming the challenges associated with identification of deep intronic variants by whole genome sequencing

Author: Marie Dirix, Olivier Gribouval, Christelle Arrondel, Saadia Benjelloun, Olivia Boyer, Marina Charbit, Corinne Antignac, Laurence Heidet, and Guillaume Dorval
Subjects: Genetics, Genetics (clinical)
Published: 2023
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24. Clinical Factors and Adverse Kidney Outcomes in Children With Antineutrophil Cytoplasmic Antibody–Associated Glomerulonephritis

Author: Matko Marlais, Tanja Wlodkowski, Nikoleta Printza, Dorothea Kronsteiner, Regina Krisam, Lukas Sauer, Marina Aksenova, Isa Ashoor, Atif Awan, Justine Bacchetta, Ramnath Balasubramanian, Biswanath Basu, Zivile Bekassy, Olivia Boyer, Eugene Yu-hin Chan, Dagmar Csaicsich, Stéphane Decramer, Eiske Dorresteijn, Magdalena Drozynska-Duklas, Loai Akram Eid, Laura Espinosa, Verónica Ferraris, Hana Flögelová, Jessica Forero-Delgadillo, Alessandra Gianviti, Valentina Gracchi, Mercedes López González, Matthias Hansen, Motoshi Hattori, Xu Hong, Nakysa Hooman, Dmytro Ivanov, Hee Gyung Kang, Vasiliki Karava, Ina Kazyra, Adrian Lungu, Stephen Marks, Andrew Maxted, Anna Moczulska, Rebekka Müller, Tatiana Nastausheva, Mattia Parolin, Carmine Pecoraro, Iliana Principi, Cheryl Sanchez-Kazi, Seha Saygili, Raphael Schild, Mohan Shenoy, Rajiv Sinha, Ana Paula Spizzirri, Maria Stack, Maria Szczepanska, Alexey Tsygin, Julia Tzeng, Vaidotas Urbonas, Carlos Zapata, Jakub Zieg, Franz Schaefer, Marina Vivarelli, Kjell Tullus, and Pediatrics
Subjects: Nephrology
Published: 2023

25. Hemolytic-Uremic Syndrome in Children

Author: Olivia Boyer and Patrick Niaudet
Subjects: Pediatrics, Perinatology and Child Health
Published: 2022
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26. Renal arcuate vein thrombosis–induced acute kidney injury: a rare multiple-Hit–mediated disease

Author: Clara Pardinhas, Rui Filipe, Paul Vergnaud, Mathilde Grapin, Elsa Ferrière, Anne Jamet, Jacques Fourgeaud, Nicolas Da Rocha, Philippe Pérot, Olivia Boyer, Marion Rabant, Jean-Paul Duong Van Huyen, Pierre Isnard, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte [CHU-Necker] (MARHEA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), Découverte de pathogènes – Pathogen discovery, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Centre Collaborateur de l'OIE de Détection et identification chez l’homme des pathogènes animaux émergents et développement d’outils pour leur diagnostic / Collaborating Center for the Detection and identification in humans of emerging animal pathogens and development of tools for their diagnoses (CCOIE-OIECC), and Institut Pasteur [Paris] (IP)-Organisation Mondiale de la Santé Animale / World Organisation Animal Health [Paris] (OIE)-Université Paris Cité (UPCité)
Subjects: Transplantation, metatranscriptomics, acute kidney injury, NSAIDs, SARS-CoV-2, Nephrology, [SDV]Life Sciences [q-bio], renal arcuate vein thrombosis
Abstract: Background Renal arcuate vein thrombosis (RAVT) is a rare and recently recognized cause of acute kidney injury (AKI) in young adults. However, the precise incidence and underlying pathophysiologic mechanisms leading to AKI in these patients remain elusive. Methods This study included all patients who underwent a kidney biopsy over a 40-month period sent to the pathology department of Necker-Enfants Malades Hospital, with evidence of RAVT. We performed coagulation tests, genetic testing for thrombophilia, complete urine toxicologic screening and kidney metagenomic sequencing to identify an underlying cause of thrombosis. Results We report five pediatric cases of RAVT discovered on kidney biopsy performed in the setting of unexplained AKI. Investigations did not reveal an underlying cause of thrombosis but only a significant nonsteroidal anti-inflammatory drugs (NSAIDs) use was reported in 4/5 patients, supporting a potential link between NSAIDs use and RAVT. By performing metagenomic sequencing on kidney biopsy samples, we detected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in the kidney of one patient. These results suggest that systemic SARS-CoV-2 infection may also be a key contributing factor of renal thrombosis, particularly by inducing potential endothelial disruption. Conclusions In conclusion, RAVT-induced AKI appears to be a multiple hit–mediated disease in which NSAIDs consumption and viral infection such as SARS-CoV-2 may be crucial contributing factors. These findings may have significant public health implications given the prevalence of NSAIDs use in the general population. Increased awareness and additional study of future cases may lead to a better understanding of this rare cause of AKI in children and young adults.
Published: 2022
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27. Renal outcome and plasma methylmalonic acid levels after isolated or combined liver or kidney transplantation in patients with methylmalonic acidemia: A multicenter analysis

Author: Luca Dello Strologo, Marco Spada, Carlo Dionisi Vici, Marta Ciofi Degli Atti, Michelle Rheault, Anna Kristina Bjerre, Olivia Boyer, Pier Luigi Calvo, Lorenzo D'Antiga, Lyndsay A. Harshman, Friederike Hörster, Stefan Kölker, Timo Jahnukainen, Noël Knops, Pauline Krug, Kai Krupka, Angela Lee, Elena Levtchenko, Stephen D. Marks, Jelena Stojanovic, Laura Martelli, George Mazariegos, Giovanni Montini, Mohan Shenoy, Sangeet Sidhu, Trine Tangeras, Sara Testa, Suresh Vijay, Katarzyna Wac, Lars Wennberg, Waldo Concepcion, Sven F. Garbade, and Burkhard Tönshoff
Subjects: Endocrinology, Liver, Endocrinology, Diabetes and Metabolism, Genetics, Humans, Kidney, Kidney Transplantation, Amino Acid Metabolism, Inborn Errors, Molecular Biology, Biochemistry, Methylmalonic Acid
Abstract: Methylmalonic acidemia (MMAemia) is characterized by accumulation of methylmalonic acid (MMA) in all body tissues. To minimize disease-related complications, isolated kidney (KTx), liver (LTx) or combined liver-kidney transplantation (LKTx) have been suggested. However, the impact of these different transplant strategies on outcome are unclear.In this multicenter retrospective observational study, we compared plasma MMA levels and estimated glomerular filtration rate (eGFR) data of 83 patients. Sixty-eight patients (82%) had a mutsup0/sup-type MMAemia, one patient had a mutsup-/sup-type MMAemia, and seven (7.3%) had an inherited defect in cobalamin metabolism (cblA- or cblB-type MMAemia). Median observation period was 3.7 years (0-15.1 years).Twenty-six (31%) patients underwent KTx, 24 (29%) LTx and 33 (40%) LKTx. Posttransplant, mean plasma MMA concentration significantly decreased in all three cohorts; but at month 12, plasma MMA in KTx (1372 ± 1101 μmol/L) was 7.8-fold higher than in LTx (176 ± 103 μmol/L; Plt; 0.001) and 6.4-fold higher than in LKTx (215 ± 110 μmol/L; Plt; 0.001). Comparable data were observed at month 24. At time of transplantation, mean eGFR in KTx was 18.1 ± 24.3 mL/min/1.73 msup2/sup, in LTx 99.8 ± 29.9 mL/min/1.73 msup2/sup, and in LKTx 31.5 ± 21.2 mL/min/1.73 msup2/sup. At month 12 posttransplant, mean eGFR in KTx (62.3 ± 30.3 mL/min/1.73 msup2/sup) was 33.4% lower than in LTx (93.5 ± 18.3 mL/min/1.73 msup2/sup; P = 0.0053) and 25.4% lower than in LKTx (83.5 ± 26.9 mL/min/1.73 msup2/sup; P = 0.0403).In patients with isolated MMAemia, LTx and LKTx lead to markedly lower plasma MMA levels during the first 2 years posttransplant than KTx and are associated with a better preservation of kidney function. LTx should therefore be part of the transplant strategy in MMAemia.
Published: 2022
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28. Is withdrawal of nocturnal hyperhydration possible in children with primary hyperoxaluria treated with RNAi?

Author: Nathalie Biebuyck, Camille Destombes, Richa Prakash, and Olivia Boyer
Subjects: Nephrology
Published: 2023
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29. Outcome of children with IgA vasculitis with nephritis treated with steroids: a matched controlled study

Author: Anne-Lise Mary, Stéphanie Clave, Caroline Rousset-Rouviere, Etienne Berard, Olivia Boyer, Stéphane Decramer, Marc Fila, Vincent Guigonis, Sylvie Cloarec, Jérôme Harambat, Julien Hogan, Annie Lahoche, Gwenaelle Roussey-Kesler, Ariane Zaloszyc, Tim Ulinski, Cyrielle Parmentier, and Jean-Daniel Delbet
Subjects: Nephrology, Pediatrics, Perinatology and Child Health
Published: 2023
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30. Le syndrome néphrotique de l’enfant : quoi de neuf en 2023 ?

Author: Olivia Boyer and Guillaume Dorval
Subjects: General Medicine
Published: 2023
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31. 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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32. Soluble CD89 is a critical factor for mesangial proliferation in childhood IgA nephropathy

Author: Georges Deschênes, Marion Rabant, Laureline Berthelot, Lilia Abbad, Fanny Canesi, Tim Ulinski, Jennifer Da Silva, Michel Peuchmaur, Patrick J. Gleeson, Renato C. Monteiro, Julien Hogan, Alexandra Cambier, Julie Bex-Coudrat, and Olivia Boyer
Subjects: Autoimmune disease, Proteinuria, business.industry, Kidney Glomerulus, Autoantibody, Glomerulonephritis, IGA, Glomerulonephritis, urologic and male genital diseases, medicine.disease, Glomerular Mesangium, Immunoglobulin A, Nephropathy, Pathogenesis, Mice, Nephrology, Immunology, medicine, Animals, Humans, Mesangial proliferative glomerulonephritis, medicine.symptom, Child, Receptor, business, Cell Proliferation
Abstract: Childhood IgA nephropathy (IgAN) includes a wide spectrum of clinical presentations, from isolated hematuria to acute nephritis with rapid loss of kidney function. In adults, IgAN is an autoimmune disease and its pathogenesis involves galactose deficient (Gd) IgA1, IgG anti-Gd-IgA1 autoantibodies and the soluble IgA Fc receptor (CD89). However, implication of such factors, notably soluble CD89, in childhood IgAN pathogenesis remains unclear. Here, we studied these biomarkers in a cohort of 67 patients with childhood IgAN and 42 pediatric controls. While Gd-IgA1 was only moderately increased in patient plasma, levels of circulating IgA complexes (soluble CD89-IgA and IgG-IgA) and free soluble CD89 were markedly increased in childhood IgAN. Soluble CD89-IgA1 complexes and free soluble CD89 correlated with proteinuria, as well as histological markers of disease activity: mesangial, endocapillary hypercellularity and cellular crescents. Soluble CD89 was found in patient's urine but not in urine from pediatric controls. Mesangial deposits of soluble CD89 were detected in biopsies from patients with childhood IgAN. Serum chromatographic fractions containing covalently linked soluble CD89-IgA1 complexes or free soluble CD89 from patients induced mesangial cell proliferation in vitro in a soluble CD89-dependent manner. Recombinant soluble CD89 induced mesangial cell proliferation in vitro which was inhibited by free soluble recombinant CD71 (also a mesangial IgA receptor) or mTOR blockers. Interestingly, injection of recombinant soluble CD89 induced marked glomerular proliferation and proteinuria in mice expressing human IgA1. Thus, free and IgA1-complexed soluble CD89 are key players in mesangial proliferation. Hence, our findings suggest that soluble CD89 plays an essential role in childhood IgAN pathogenesis making it a potential biomarker and therapeutic target.
Published: 2022
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33. Benign and malignant proliferation in idiopathic nephrotic syndrome: a French cohort study

Author: Clara Cébron, Astrid Godron-Dubrasquet, Nathalie Aladjidi, Gwenaelle Roussey, Olivia Boyer, Marina Avramescu, Veronique Baudouin, Joelle Terzic, Emma Allain-Launay, Frédéric Rieux-Laucat, Stéphane Decramer, Thomas Simon, and Jérôme Harambat
Subjects: Cohort Studies, Nephrotic Syndrome, Treatment Outcome, Nephrology, Child, Preschool, Nephrosis, Lipoid, Remission Induction, Pediatrics, Perinatology and Child Health, Humans, Mycophenolic Acid, Immunosuppressive Agents, Cell Proliferation, Retrospective Studies
Abstract: There seems to be a possible link between nephrotic syndrome (NS) and lymphoproliferative syndrome, but it remains poorly understood.This multicentric and retrospective study focuses on children, who developed idiopathic NS and malignant or benign proliferation between 2000 and 2021.Eleven patients were included, with a median age of 4 years. Only one had a steroid-resistant nephrotic syndrome (SRNS). The maintenance therapy before the proliferation was in majority tacrolimus or mycophenolate mofetil (MMF), but three patients did not receive treatments. The proliferation was mainly a Hodgkin's lymphoma (45%) or a lymphoproliferative disease (36%), in a median time after the NS of two years. Viruses were found in seven cases (EBV in five cases and HHV-8 in two).The association between proliferative syndrome and idiopathic NS may not be fortuitous, possibly with a common lymphocytic disturbance. Genetic analyses could improve the comprehension of these manifestations in the future. A higher resolution version of the Graphical abstract is available as Supplementary information.
Published: 2022
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34. Renal vein thrombosis in neonates: a case series of diagnosis, treatment and childhood kidney function follow-up

Author: Bellaure Ndoudi Likoho, Romain Berthaud, Claire Dossier, Jean-Daniel Delbet, Olivia Boyer, Véronique Baudouin, Marianne Alison, Valérie Biran, Marie-Françoise Hurtaud, Julien Hogan, Theresa Kwon, and Anne Couderc
Subjects: Nephrology, Pediatrics, Perinatology and Child Health
Published: 2023
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35. Clinical practice recommendations for primary hyperoxaluria: an expert consensus statement from ERKNet and OxalEurope

Author: Jaap W. Groothoff, Ella Metry, Lisa Deesker, Sander Garrelfs, Cecile Acquaviva, Reham Almardini, Bodo B. Beck, Olivia Boyer, Rimante Cerkauskiene, Pietro Manuel Ferraro, Luitzen A. Groen, Asheeta Gupta, Bertrand Knebelmann, Giorgia Mandrile, Shabbir S. Moochhala, Agnieszka Prytula, Jovana Putnik, Gill Rumsby, Neveen A. Soliman, Bhaskar Somani, Justine Bacchetta, Paediatric Nephrology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ARD - Amsterdam Reproduction and Development, APH - Methodology, APH - Quality of Care, Graduate School, and Paediatric Urology
Subjects: Nephrology
Abstract: Primary hyperoxaluria (PH) is an inherited disorder that results from the overproduction of endogenous oxalate, leading to recurrent kidney stones, nephrocalcinosis and eventually kidney failure; the subsequent storage of oxalate can cause life-threatening systemic disease. Diagnosis of PH is often delayed or missed owing to its rarity, variable clinical expression and other diagnostic challenges. Management of patients with PH and kidney failure is also extremely challenging. However, in the past few years, several new developments, including new outcome data from patients with infantile oxalosis, from transplanted patients with type 1 PH (PH1) and from patients with the rarer PH types 2 and 3, have emerged. In addition, two promising therapies based on RNA interference have been introduced. These developments warrant an update of existing guidelines on PH, based on new evidence and on a broad consensus. In response to this need, a consensus development core group, comprising (paediatric) nephrologists, (paediatric) urologists, biochemists and geneticists from OxalEurope and the European Rare Kidney Disease Reference Network (ERKNet), formulated and graded statements relating to the management of PH on the basis of existing evidence. Consensus was reached following review of the recommendations by representatives of OxalEurope, ESPN, ERKNet and ERA, resulting in 48 practical statements relating to the diagnosis and management of PH, including consideration of conventional therapy (conservative therapy, dialysis and transplantation), new therapies and recommendations for patient follow-up.
Published: 2023

36. Human kidney-derived hematopoietic stem cells can support long-term multilineage hematopoiesis

Author: Steicy Sobrino, Chrystelle Abdo, Bénédicte Neven, Adeline Denis, Nathalie Gouge-Biebuyck, Emmanuel Clave, Soëli Charbonnier, Tifanie Blein, Camille Kergaravat, Marion Alcantara, Patrick Villarese, Romain Berthaud, Laurène Dehoux, Souha Albinni, Esma Karkeni, Chantal Lagresle-Peyrou, Marina Cavazzana, Rémi Salomon, Isabelle André, Antoine Toubert, Vahid Asnafi, Capucine Picard, Stéphane Blanche, Elizabeth Macintyre, Olivia Boyer, Emmanuelle Six, Julien Zuber, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Etablissement Français du Sang [La Plaine Saint-Denis] (EFS), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), This work was supported by funding from the Emmanuel Boussard and Day Solvay Foundations and the Agence Nationale de la Recherche (ANR-10-IAHU-01 'Investissements d’Avenir' program, ANR-20-CE18-0004). We are grateful to Milena Hasan (Institut Pasteur) for critical advice on cytokine analysis., and ANR-20-CE18-0004,DAISY,Thérapie Cellulaire Régulatrice Spécifique du Donneur par ingénierie génétique(2020)
Subjects: MESH: Humans, [SDV]Life Sciences [q-bio], hematopoietic stem and progenitor cells, MESH: Hematopoiesis, kidney allograft, MESH: Kidney, MESH: Mammals, MESH: Hematopoietic Stem Cells, MESH: T-Lymphocytes, chimerism, Nephrology, MESH: Child, MESH: Animals, MESH: Bone Marrow, MESH: Bone Marrow Transplantation, MESH: Hematopoietic Stem Cell Transplantation
Abstract: International audience; Long-term multilineage hematopoietic donor chimerism occurs sporadically in patients who receive a transplanted solid organ enriched in lymphoid tissues such as the intestine or liver. There is currently no evidence for the presence of kidney-resident hematopoietic stem cells in any mammal species. Graft-versus-host-reactive donor T cells promote engraftment of graft-derived hematopoietic stem cells by making space in the bone marrow. Here, we report full (over 99%) multilineage, donor-derived hematopoietic chimerism in a pediatric kidney transplant recipient with syndromic combined immune deficiency that leads to transplant tolerance. Interestingly, we found that the human kidney-derived hematopoietic stem cells took up long-term residence in the recipient's bone marrow and gradually replaced their host counterparts, leading to blood type conversion and full donor chimerism of both lymphoid and myeloid lineages. Thus, our findings highlight the existence of human kidney-derived hematopoietic stem cells with a self-renewal ability able to support multilineage hematopoiesis.
Published: 2023
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37. Metabolic Disorders Affecting the Kidney

Author: Aude Servais, Olivia Boyer, Myriam Dao, and Friederike Hörster
Published: 2023
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38. Renal Prognosis in Children With Tubulointerstitial Nephritis and Uveitis Syndrome

Author: Corentin Tanne, François Nobili, Christine Pietrement, Emma Allain-Launay, Olivia Boyer, Claire Duflos, Annie Lahoche, Guylhène Bourdat-Michel, Sylvie Cloarec, Ariane Zaloszyc, Lise Allard, Agnès Chevalier, Djamal Djeddi, Tim Ulinski, Stéphane Decramer, Olivier Dunand, Julien Hogan, Justine Bacchetta, Marc Fila, Camille Faudeux, Stéphanie Clavé, Denis Morin, Isabelle Vrillon, Françoise Broux, Sophie Taque, Herrada, Anthony, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Assistance Publique - Hôpitaux de Marseille (APHM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), AP-HP Hôpital universitaire Robert-Debré [Paris], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Rouen, Normandie Université (NU), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), CHU Bordeaux [Bordeaux], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Grenoble, CHU Amiens-Picardie, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Centre Hospitalier Universitaire de Nice (CHU Nice), Service de pédiatrie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Pontchaillou [Rennes], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Strasbourg, Institut de Génomique Fonctionnelle (IGF), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Pediatrics, medicine.medical_specialty, Tubulointerstitial nephritis and uveitis, Renal function, tubulointerstitial nephritis and uveitis syndrome, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Asymptomatic, Dobrin’s syndrome, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Clinical Research, medicine, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, business.industry, Retrospective cohort study, chronic kidney failure, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, pediatric, Nephrology, Dobrin's syndrome, Cohort, outcome, medicine.symptom, business, Uveitis, Kidney disease, Rare disease
Abstract: International audience; Introduction: Tubulointerstitial nephritis (TIN) and uveitis (TINU) syndrome is a rare disease. The renal prognosis is generally thought to be better in children with TINU syndrome than in adults. However, data are scarce. We aimed to investigate the long-term renal prognosis in a French cohort of children with TINU syndrome.Methods: We performed a national retrospective study including 23 French pediatric nephrology centers enrolling patients with TINU syndrome diagnosed between January 2000 and December 2018.Results: A total of 46 patients were included (52% female, median age 13.8 years). At diagnosis of TIN, the median estimated glomerular filtration rate (eGFR) was 30.6 ml/min per 1.73 m2 (4.9-62.8). The median time between diagnosis of uveitis and TIN was 0.4 months (-4.1; +17.1). All patients had anterior uveitis, but 12 (29%) were asymptomatic. Nearly all patients (44 of 46) received steroid treatment, and 12 patients (26%) received a second-line therapy. At last follow-up (median 2.8 years), the median eGFR was 87.5 ml/min per 1.73 m2 (60.3-152.7) and
Published: 2021
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39. Prednisolone pharmacokinetics after oral prednisone administration in paediatric patients with kidney transplant

Author: Camille de Truchis, Naïm Bouazza, Frantz Foissac, Marina Charbit, Laurène Dehoux, Gabrielle Lui, Mégane Ribot, Nelly Briand, Yi Zheng, Jean‐Marc Tréluyer, and Olivia Boyer
Subjects: Pharmacology, Pharmacology (medical)
Abstract: Glucocorticoids are 1 of the primary treatments in paediatric kidney transplantation. The aims of this study were: (i) to build a population pharmacokinetics (PPK) model of free prednisolone, which is the active form of prednisone, in paediatric kidney transplant recipients; (ii) to identify covariates accounting for interindividual variability (IIV) of pharmacokinetics (PK) parameters; and (iii) to investigate drug exposure-safety relationships.Ninety-seven samples were obtained from 39 paediatric kidney transplant recipients (aged 3.4-17.2 years) in order to investigate prednisone PPK. We selected children receiving oral prednisone as part of their immunosuppressive regimen. A PPK analysis was performed using Monolix.A 1-compartment model best described prednisolone concentrations. Large IIV was observed as prednisolone was undetectable at H12 in some patients but could still be detected at H24 in others. Both bodyweight and ciclosporin cotreatment influenced the PK. The clearance (CLThis study is the first analysis of prednisolone PPK in kidney-transplanted children. Some of the IIV in the PK parameters was explained by bodyweight and ciclosporin cotreatment. These data suggest that dose adjustment is required after identifying variability factors to optimize efficacy and limit side effects. The use of therapeutic drug monitoring in kidney-transplanted children may be useful, especially with respect to safety issues.
Published: 2022

40. Long-term health-related quality of life outcomes of adults with pediatric onset of frequently relapsing or steroid-dependent nephrotic syndrome

Author: Antoine Durrbach, Philippe Zaoui, Aurélie Bourmaud, Olivia Boyer, Alexandre Hertig, Olivier Fritz, Isabelle Tostivint, Agnès Dumas, Vincent L.M. Esnault, Alain Wynckel, Jacques Dantal, Moglie Le Quintrec, S. Guilmin-Crépon, Dominique Chauveau, Dil Sahali, Corinne Alberti, Dominique Guerrot, Claire Dossier, Marie-Sophie Meuleman, Stéphane Burtey, Alexandre Karras, Claire Rigothier, François Provôt, Philippe Remy, Eric Daugas, Karine Dahan, Vincent Audard, Hélène Mellerio, Marie-Pascale Morin, Aurélie Hummel, Ziad A. Massy, Fallou Leye, CHU Henri Mondor, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre d'Investigation Clinique 1426 (CIC 1426), 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), Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Département de Néphrologie [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), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), AP-HP Hôpital universitaire Robert-Debré [Paris], Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Bordeaux [Bordeaux], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Toulouse [Toulouse], 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), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Service d'Urgences néphrologiques et transplantation rénale [CHU Tenon], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (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)-Sorbonne Université (SU), 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), Service de Néphrologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre Hospitalier Universitaire de Nice (CHU Nice), Hôpital Ambroise Paré [AP-HP], Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, CHU Pitié-Salpêtrière [AP-HP], CHU Pontchaillou [Rennes], CHU Grenoble, Centre Hospitalier de La Rochelle (CHR), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Necker - Enfants Malades [AP-HP], CHU Henri Mondor [Créteil], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Urgences néphrologiques et transplantation rénale [CHU Tenon], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP]
Subjects: Adult, Male, Quality of life, Pediatrics, medicine.medical_specialty, Nephrotic Syndrome, Multivariate analysis, Population, Family life, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Education, Idiopathic nephrotic syndrome, Recurrence, medicine, Humans, Prospective Studies, Long-term outcomes, Child, education, Prospective cohort study, Fatigue, education.field_of_study, business.industry, Standardized mortality ratio, Socioprofessional status, Nephrology, Marital status, Female, Steroids, business, Psychosocial, Immunosuppressive Agents
Abstract: International audience; Background: Long-term psychosocial outcomes and health-related quality of life (HRQOL) in adults with pediatric onset of frequently relapsing or steroid-dependent idiopathic nephrotic syndrome (FRNS or SDNS) remain to be determined.Methods: In this prospective cohort study, 59 adults with pediatric onset of FRNS/SDNS and persistent active glomerular disease in adulthood completed the GEDEPAC-2 questionnaire exploring 11 well-being domains. Data were compared to the French general population (FGP) with standardized incidence ratio ([SIR]; adjusted for period, age, gender). Regression models were performed to identify predictive factors of psychosocial well-being.Results: In 82% of cases, the questionnaire was completed while the participants (n = 59; 47 men; median age = 32 years; median number of relapses = 13) were in complete remission (under specific therapy in 76% of cases). Participants had higher educational degree than in the FGP (SIR = 6.3; p < 0.01) and more frequently a managerial occupation (SIR = 3.1; p < 0.01). Social integration was acceptable with regard to marital status and experience of sexual intercourse, but experiences of discrimination were far more frequent (SIR = 12.5; p < 0.01). The SF-12 mental component summary (MCS) score was altered (Z-score = - 0.6; p < 0.01) and mean multidimensional fatigue inventory (MFI-20) global fatigue score appeared high (12). Transfer from pediatric to adult healthcare was followed by a period of discontinued care for 33% of participants. Multivariate analysis revealed a close relationship between MFI-20, physical health, and MCS.Conclusions: This study shows that pediatric onset FRNS and SDNS may have a long-term negative impact on mental HRQOL and highlights the impact of fatigue, which is often not adequately considered in routine care.
Published: 2021
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41. ANCA associated vasculitis in children

Author: Silvia Bernardi, Laure Seugé, and Olivia Boyer
Subjects: Transplantation, Nephrology
Published: 2022

42. Diagnostic dilemma in a 3-year-old girl with acute nephritic syndrome and hematologic abnormalities: Questions

Author: Samantha Innocenti, Silvia Bernardi, Maud Prévot, Antonin Saldmann, Maud Tusseau, Alexandre Belot, Jean-Paul Duong Van Huyen, and Olivia Boyer
Subjects: Nephrology, Pediatrics, Perinatology and Child Health
Published: 2022

43. Diagnostic dilemma in a 3-year-old girl with acute nephritic syndrome and hematologic abnormalities: Answers

Author: Samantha Innocenti, Silvia Bernardi, Maud Prévot, Antonin Saldmann, Maud Tusseau, Alexandre Belot, Jean-Paul Duong Van Huyen, and Olivia Boyer
Subjects: Nephrology, Pediatrics, Perinatology and Child Health
Published: 2022

44. Multicentric Carpotarsal Osteolysis Syndrome Associated Nephropathy: Novel Variants of MAFB Gene and Literature Review

Author: Stefania Drovandi, Francesca Lugani, Olivia Boyer, Edoardo La Porta, Paolo Giordano, Aurélie Hummel, Bertrand Knebelmann, Joséphine Cornet, Genevieve Baujat, Beata S. Lipska-Ziętkiewicz, Gian Marco Ghiggeri, Gianluca Caridi, and Andrea Angeletti
Subjects: multicentric carpotarsal syndrome, monogenic kidney disease, hereditary podocytopathy, glomerulonephritis, nephrotic syndrome, renal failure, General Medicine
Abstract: Multicentric carpo-tarsal osteolysis (MCTO) is a rare osteolysis syndrome mainly involving carpal and tarsal bones usually presenting in early childhood. MCTO has autosomal dominant inheritance with heterozygous mutation in the MAFB gene. The skeletal disorder is often associated with chronic kidney disease. Data on clinical characterization and best treatment option of MCTO-associated nephropathy are scarce and mostly limited to case reports. With the aim to better define the phenotype and long-term outcomes of MCTO-associated nephropathy, we launched an online survey through the Workgroup for hereditary glomerulopathies of the European Rare Kidney Disease Network (ERKNet). Overall, we collected clinical and genetic data of 54 MCTO patients, of which 42 previously described and 12 new patients. We observed a high rate of kidney involvement (70%), early age of kidney disease onset, nephrotic-range proteinuria, and a kidney survival around of 40% at long-term follow-up. Our finding confirmed the heterogeneity of clinical manifestations and widen the spectrum of phenotypes resulting from MCTO-associated nephropathy. Furthermore, we report the first case of complete remission after treatment with cyclosporine A. We demonstrated that multidisciplinary care is essential for MCTO patients and early referral to nephrologists is therefore warranted to facilitate prompt treatment.
Published: 2022
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45. Genotype-phenotype description of Vitamin-D Dependent Rickets 1A: CYP27B1 p.(Ala129Thr) variant induces a milder disease

Author: Marie-Noëlle Méaux, Jérôme Harambat, Anya Rothenbuhler, Juliane Léger, Peter Kamenicky, Sylvie Soskin, Olivia Boyer, Emese Boros, Pascal D’Anella, Brigitte Mignot, Maite Gebhart, Philippe Vic, Nicolas Richard, Béatrice Thivichon-Prince, Bruno Francou, Agnès Linglart, Justine Bacchetta, Arnaud Molin, INSERM1033, CHU Bordeaux [Bordeaux], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service d'endocrinologie pédiatrique [CHU Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence des Maladies Endocriniennes Rares de la Croissance [APHP Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Cité (UPCité), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Les Hôptaux universitaires de Strasbourg (HUS), CHU Strasbourg, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Signalisation Hormonale, Physiopathologie Endocrinienne et Métabolique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Physiologie et physiopathologie endocriniennes (PHYSENDO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, HUE, Erika, and École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Endocrinology, VDDR1A, CYP27B1, Endocrinology, Diabetes and Metabolism, Biochemistry (medical), Clinical Biochemistry, [SDV.BA.MVSA] Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Genotype-phenotype, Biochemistry, 1-alpha hydroxylase, Rickets
Abstract: IntroductionVitamin D–dependent rickets type 1A (VDDR1A) is a rare genetic disease associated with loss-of-function variations in the gene encoding the vitamin D–activating enzyme 1α-hydroxylase (CYP27B1). Phenotype-genotype correlation is unclear. Long-term outcome data are lacking. The objective of this study was to describe characteristics and outcomes to search for a phenotype-genotype correlation.MethodsWe retrospectively collected clinical data, genetic features, and outcomes from 24 genetically confirmed cases from 10 French centers; results are presented as median (min–max).ResultsClinical symptoms at diagnosis (age, 1.5 [0.5-8.7] years) were mainly bone and neurological abnormalities, and laboratory data showed hypocalcemia (1.97 [1.40-2.40] mmol/L), hypophosphatemia (−3.4 [−13.4 to (−)0.2] SD score for age), low 25OHD and low 1,25(OH)2D3, secondary hyperparathyroidism with PTH at 6.6 (1.3-13.7) times the upper limit for normal (ULN; PTH expressed as ULN to homogenize data presentation), and increased alkaline phosphatase (1968 [521-7000] IU/L). Bone radiographs were abnormal in 83% of patients. We identified 17 variations (11 missense, 3 frameshift, 2 truncating, and 1 acceptor splice site variations) in 19 families (homozygous state in 58% [11/19]). The partial loss-of-function variation p.(Ala129Thr) was associated with a milder phenotype: older age at diagnosis, higher serum calcium (2.26 vs 1.85 mmol/L), lower PTH (4.7 vs 7.5 ULN), and lower alkaline phosphatase (759 vs 2082 IU/L). Patients were treated with alfacalcidol. Clinical (skeletal, neurological), biochemical, and radiological outcomes were satisfactory, and complications occurred if there was bad adherence.ConclusionOverall, our findings highlight good outcomes under substitutive treatment and the need of a closer follow-up of eyes, teeth, kidneys, and blood pressure in VDDR1A.
Published: 2022
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46. Importance of clinical practice guidelines to practicing pediatric nephrologists and IPNA survey

Author: Pankaj Hari, Koichi Nakanishi, Dieter Haffner, Paula A. Coccia, Olivia Boyer, Arvind Bagga, Melvin Bonilla-Felix, Hong Xu, Khalid Alhasan, Giovanni Montini, Susan Samuel, Ali Duzova, and Ill So Ha
Subjects: medicine.medical_specialty, Attitude of Health Personnel, business.industry, 030232 urology & nephrology, Guideline, 030204 cardiovascular system & hematology, Pediatrics, Scientific evidence, Nephrologists, Clinical Practice, 03 medical and health sciences, Cross-Sectional Studies, 0302 clinical medicine, Trustworthiness, Nephrology, Surveys and Questionnaires, Family medicine, Practice Guidelines as Topic, Pediatrics, Perinatology and Child Health, Humans, Medicine, business, Regional differences, Pediatric population
Abstract: Clinical practice guidelines (CPGs) are systematically developed statements backed by scientific evidence to assist practitioners in management in clinical practice. An international cross-sectional survey was conducted by the IPNA to examine the perceptions of pediatric nephrologists on guidelines and their usage and to identify important diseases for future clinical practice guidelines (CPGs). The survey found that the majority of pediatric nephrologists find CPGs useful in clinical practice and admitted to using them most of the time. Developing CPGs is challenging and there are standards available to develop trustworthy guidelines. While evidence-based global guidelines are ideal, pediatric nephrologists expressed the desire that they address regional differences. Most respondents (89.2%) to the survey agreed that adult guidelines did not cover the pediatric perspective adequately and 71.4% opined that consensus-based pediatric guidelines can be developed when evidence for the pediatric population is lacking. The development of high-quality practice guidelines requires substantial resources and may not be feasible in resource-poor countries. Adaptation of an existing guideline has been suggested as an alternative and the ADAPTE collaboration provides a systematic approach to adapting guidelines. Several diseases where pediatric guidelines are needed as a priority including IgA and C3 glomerulopathy were identified in the survey. Implementation of guideline-based care is challenging and the survey found that lack of availability of guidelines (43%) and resources (22.8%) are important reasons for poor implementation in lower-middle and low-income countries. Perceived complexity of guidelines, physician attitudes, and lack of training also contribute to non-adherence to guidelines.
Published: 2021
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47. Arterial abnormalities identified in kidneys transplanted into children during the COVID-19 pandemic

Author: Carmen Capito, Sabine Sarnacki, Yves Heloury, Laurène Dehoux, Olivia Boyer, Marina Charbit, Elisa Zanelli, Florence Lacaille, Thomas Blanc, Sarah Temmam, Nathalie Boddaert, Marianne Leruez-Ville, Marc Eloit, Marion Rabant, C. Chardot, Laureline Berteloot, Cécile Lozach, Myriam Pastural, Isabelle Sermet-Gaudelus, Romain Berthaud, Nicolas Garcelon, Service de radiologie 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), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de néphrologie pédiatrique [CHU Necker], Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte [CHU-Necker] (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), Découverte de pathogènes – Pathogen discovery, Institut Pasteur [Paris] (IP), Université Paris Cité (UPCité), Service de chirurgie et urologie pédiatrique [CHU-Necker], Pediatric Surgery and Urology Department, AP-HP, Hôpital Universitaire Necker-Enfants malades, Plateforme Data Science = Data Science Platform, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Gastro-Entérologie, Hépatologie et Nutrition pédiatriques (CHU Necker - Enfants Malades [AP-HP]), Agence de la biomédecine [Saint-Denis la Plaine], Département de Pathologie [CHU Necker], Université Sorbonne Paris Cité (USPC)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Laboratoire de Virologie [CHU Necker], National Cystic Fibrosis Reference Center [CHU Necker] (CNR - INSERM U1151), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Fédération pour la recherche en explorations et thérapeutiques innovantes in utéro (FETUS - EA 7328), Université Paris Descartes - Paris 5 (UPD5), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: Male, kidney disease: immune / inflammatory, medicine.medical_treatment, Constriction, Pathologic, Kidney, MESH: Kidney Transplantation, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Child, clinical research / practice, MESH: COVID-19, Immunology and Allergy, Pharmacology (medical), kidney transplantation / nephrology, Child, Arteries, medicine.anatomical_structure, Female, Vasculitis, Artery, MESH: Pandemics, medicine.medical_specialty, infection and infectious agents - viral, pediatrics, Adolescent, infectious disease, diagnostic techniques and imaging: ultrasound, complication, recipient selection, Anastomosis, MESH: Constriction, Pathologic, medicine, Humans, MESH: Arteries, Pandemics, Dialysis, Retrospective Studies, MESH: Adolescent, Transplantation, MESH: Humans, business.industry, Arterial stenosis, COVID-19, MESH: Retrospective Studies, MESH: Kidney, medicine.disease, Kidney Transplantation, MESH: Male, Surgery, Stenosis, business, Complication, MESH: Female
Abstract: International audience; Graft artery stenosis can have a significant short- and long-term negative impact on renal graft function. From the beginning of the COVID-19 pandemic, we noticed an unusual number of graft arterial anomalies following kidney transplant (KTx) in children. Nine children received a KTx at our center between February and July 2020, eight boys and one girl, of median age of 10 years. Seven presented Doppler features suggesting arterial stenosis, with an unusual extensive pattern. For comparison, over the previous 5-year period, persistent spectral Doppler arterial anomalies (focal anastomotic stenoses) following KTx were seen in 5% of children at our center. We retrospectively evidenced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in five of seven children with arterial stenosis. The remaining two patients had received a graft from a deceased adolescent donor with a positive serology at D0. These data led us to suspect immune postviral graft vasculitis, triggered by SARS-CoV-2. Because the diagnosis of COVID-19 is challenging in children, we recommend pretransplant monitoring of graft recipients and their parents by monthly RT-PCR and serology. We suggest balancing the risk of postviral graft vasculitis against the risk of prolonged dialysis when considering transplantation in a child during the pandemic.
Published: 2021
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48. Rare Collagenous Heterozygote Variants in Children With IgA Nephropathy

Author: Marion Rabant, Alexandra Cambier, Julien Hogan, Laurent Mesnard, Olivia Boyer, Michel Peuchmaur, Tim Ulinski, Renato C. Monteiro, Thomas Robert, Hôpital Robert Debré Paris, Hôpital Robert Debré, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Des Maladies Rénales Rares aux Maladies Fréquentes, Remodelage et Réparation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-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), Service de néphrologie et pédiatrie générale [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Urgences néphrologiques et transplantation rénale [CHU Tenon], CHU Tenon [AP-HP], Institut des Sciences du Calcul et des Données (ISCD), Sorbonne Université (SU), HAL-SU, Gestionnaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre de recherche du CHU Sainte-Justine [Montreal], Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), 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), Urgences néphrologiques et transplantation rénale [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: medicine.medical_specialty, 030232 urology & nephrology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 030204 cardiovascular system & hematology, urologic and male genital diseases, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Gastroenterology, Nephropathy, COL4A3 variants, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, 0302 clinical medicine, children, Clinical Research, Internal medicine, medicine, Alport syndrome, Phenocopy, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Proteinuria, Molecular pathology, business.industry, Oxford classification, Glomerulosclerosis, immunosuppressive treatment, Glomerulonephritis, IgA nephropathy, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Nephrology, Medical genetics, medicine.symptom, business
Abstract: Introduction Childhood IgA nephropathy (cIgAN) is a primary glomerulonephritis clinically characterized by microscopic hematuria and proteinuria, the presence of which may potentially overlap with Alport syndrome. Interestingly, earlier studies suggested that familial IgAN could be linked to the chromosome 2q36 region, also the coding region for collagen type 4 alpha 3/4 (COL4A3/A4). Methods To investigate a possible relationship or phenocopy between Alport syndrome and cIgAN, COL4A3, COL4A4, and COL4A5 exons were sequenced in 36 cIgAN patients. Clinical data and treatment were collected retrospectively. COL4A3/A4/A5 variants were classified according to American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) guidelines. Results Four of 36 cIgAN patients were affected by ACMG class 4/5 COL4A3 heterozygous variants (COL4A3-cIgAN). We found no COL4A4 or COL4A5 variant. Despite having rare and deleterious COL4A3 variants, 3 of 4 COL4A3-cIgAN children developed clinical and biologic features of active IgAN rather than Alport syndrome. Response to intensive immunosuppressive treatment was favorable, leading to a reduction of endocapillary and extracapillary proliferation lesions. High levels of immune immunoglobulin G and A (IgG/IgA) complexes, reduction of proteinuria, and gradual stabilization of estimated glomerular filtration rate (eGFR) argued against Alport syndrome. Nevertheless, COL4A3-cIgAN patients seemed predisposed to a more serious IgAN presentation compared with the non‒COL4A3-cIgAN group, with more glomerulosclerosis and a lower eGFR over time. One of the 4 patients underwent kidney transplant with subsequent IgAN recurrence. Conclusions Predisposition factors for developing serious cIgAN flare-up should be considered for cIgAN with COL4A3 pathologic heterozygous variants. COL4A3 variants, usually responsible for Alport syndrome in adults, should not automatically exclude an immunosuppressive regimen in cIgAN. Moreover, evidence of an ACMG class 4/5 COL4A3 variant in early-stage cIgAN could be a helpful tool for stratifying severity of cIgAN beyond the Oxford classification., Graphical abstract
Published: 2021
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49. BiallelicNPR1loss of function variants are responsible for neonatal systemic hypertension

Author: Yline Capri, Theresa Kwon, Olivia Boyer, Lucas Bourmance, Noe Testa, Véronique Baudouin, Ronan Bonnefoy, Anne Couderc, Chakib Meziane, Elisabeth Tournier-Lasserve, Laurence Heidet, and Judith Melki
Subjects: Genetics, Genetics (clinical)
Abstract: BackgroundEarly-onset isolated systemic hypertension is a rare condition of unknown genetic origin. Renovascular, renal parenchymal diseases or aortic coarctation are the most common causes of secondary systemic hypertension in younger children and neonates. We investigated the genetic bases of early-onset isolated systemic hypertension.MethodsWhole-exome sequencing (WES) was followed by variant filtering and Sanger sequencing for validation and familial segregation of selected variants in a large consanguineous family. mRNA expression was performed to evaluate the impact of the predicted pathogenic variant on gene expression. WES or Sanger sequencing was performed in additional unrelated affected individuals.ResultsIn one consanguineous family with four children presenting with isolated neonatal-onset systemic hypertension, we identified homozygous stop–gain variant in theNPR1gene (NM_000906.4:c.1159C>T (p.Arg387Ter)) in the affected individuals. This variant leads to a dramatic reduction of NPR1 RNA levels.NPR1gene analysis of additional families allowed the identification of another family with two affected children carrying homozygous frameshift variant inNPR1(NM_000906.4:c.175del (p.Val59TrpfsTer8)).ConclusionWe show for the first time that biallelic loss of function ofNPR1is responsible for isolated neonatal-onset systemic hypertension in humans, which represents a new autosomal recessive genetic cause of infantile systemic hypertension or cardiogenic shock. This is consistent with studies reporting early-onset systemic hypertension and sudden death in Npr1-deficient mice.NPR1gene analysis should be therefore investigated in infants with early-onset systemic hypertension with or without cardiogenic shock of unknown origin.
Published: 2023
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50. A rare cause of transitory hematuria and urinary tract dysfunction in children: Answers

Author: Guillaume Dorval, Laureline Berteloot, Luca Pio, Olivia Boyer, and Thomas Blanc
Subjects: Nephrology, medicine.medical_specialty, Pediatrics, business.industry, Urinary system, Acute kidney failure, medicine.disease, Enuresis, Internal medicine, Pediatrics, Perinatology and Child Health, Medicine, medicine.symptom, business
Published: 2021
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