91 results on '"Magen, D."'
Search Results
2. Efficacité et sécurité du Lumasiran chez les patients atteints d’hyperoxalurie primaire de type 1 : analyse à 24 mois de l’essai ILLUMINATE-A
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Sionniere, J., primary, Lieske, J., additional, Groothoff, J., additional, Frishberg, Y., additional, Sellier-Leclerc, A.L., additional, Shasha-Lavsky, H., additional, Saland, J., additional, Hayes, W., additional, Magen, D., additional, and Hulton, S.A., additional
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- 2022
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3. Efficacité et sécurité du Lumasiran chez les nourrissons et les jeunes enfants atteints d’hyperoxalurie primaire de type 1 : analyse à 12 mois de l’essai de phase 3 ILLUMINATE-B
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Tranvouez, C., primary, Michael, M., additional, Hayes, W., additional, Sas, D., additional, Magen, D., additional, Lavsky, H.S., additional, Sellier-Leclerc, A.L., additional, Hogan, J., additional, Ngo, T., additional, and Frishberg, Y., additional
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- 2022
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4. Lumasiran chez les patients atteints d'hyperoxalurie primaire de type 1 (HP1) avec une fonction rénale altérée: données de l'analyse à 6 mois de l'essai de phases 3 ILLUMINATE-C
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UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, Sionniere, J, Groothoff, JW, Michael, Mini, Shasha-Lavsky, H, Lieske, JC, Frishberg, Y, Simkova, E, Sellier-Leclerc, AL, Devresse, Arnaud, Magen, D, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, Sionniere, J, Groothoff, JW, Michael, Mini, Shasha-Lavsky, H, Lieske, JC, Frishberg, Y, Simkova, E, Sellier-Leclerc, AL, Devresse, Arnaud, and Magen, D
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- 2022
5. Lumasiran for Advanced Primary Hyperoxaluria Type 1: Phase 3 ILLUMINATE-C Trial
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Michael, M., Groothoff, J. W., Shasha-Lavsky, H., Lieske, J. C., Frishberg, Y., Simkova, E., Sellier-Leclerc, A. L., Devresse, A., Guebre-Egziabher, F., Bakkaloglu, S. A., Mourani, C., Saqan, R., Singer, R., Willey, R., Habtemariam, B., Gansner, J. M., Bhan, I., Mcgregor, T., Magen, D., Paediatric Nephrology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ARD - Amsterdam Reproduction and Development, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, CarMeN, laboratoire, Texas Children's Hospital [Houston, USA], Baylor College of Medicine (BCM), Baylor University, Emma Children’s Hospital, Amsterdam UMC - Amsterdam University Medical Center, Galilee Medical Center [Nahariya, Israel], Bar-Ilan University [Israël], Mayo Clinic [Rochester], Shaare Zedek Medical Center [Jerusalem, Israel], Al Jalila Children's Specialty Hospital, Filières Maladies Rares ORKID et ERK-Net, Centre d'Investigation Clinique [Bron] (CIC1407), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupement Hospitalier Est [Bron], Cliniques Universitaires Saint-Luc [Bruxelles], Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Gazi University, Hôpital Hôtel Dieu de France [Beirut, Lebanon] (2HDF), Jordan University of Science and Technology [Irbid, Jordan] (JUST), Canberra Health Services [Garran, ACT, Australia] (CHS), Alnylam Pharmaceuticals [Cambridge, MA, USA], and Rambam Health Care Campus [Haifa, Israel]
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Adult ,Male ,RNA interference (RNAi) ,safety ,Lumasiran ,urinary oxalate (UOx) ,Adolescent ,[SDV]Life Sciences [q-bio] ,kidney disease ,efficacy ,Young Adult ,nephrocalcinosis ,glycolate ,pharmacodynamics ,Humans ,Child ,Hyperoxaluria ,Oxalates ,systemic oxalosis ,hemodialysis ,cardiac dysfunction ,phase 3 clinical trial ,Infant, Newborn ,Infant ,Middle Aged ,adverse events ,primary hyperoxaluria type 1 (PH1) ,[SDV] Life Sciences [q-bio] ,plasma oxalate (POx) ,anti-drug antibodies ,pediatric ,Nephrology ,Child, Preschool ,Hyperoxaluria, Primary ,Female ,Kidney Diseases ,pharmacokinetics - Abstract
Rationale & Objective: Lumasiran reduces urinary and plasma oxalate (POx) in patients with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. ILLUMINATE-C evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of lumasiran in patients with PH1 and advanced kidney disease. Study Design: Phase 3, open-label, single-arm trial. Setting & Participants: Multinational study; enrolled patients with PH1 of all ages, estimated glomerular filtration rate ≤45 mL/min/1.73 m2 (if age ≥12 months) or increased serum creatinine level (if age
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- 2023
6. Lumasiran chez les patients atteints d'hyperoxalurie primaire de type 1 (HP1) avec une fonction rénale altérée: données de l'analyse à 6 mois de l'essai de phases 3 ILLUMINATE-C
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Sionniere, J, Groothoff, JW, Michael, Mini, Shasha-Lavsky, H, Lieske, JC, Frishberg, Y, Simkova, E, Sellier-Leclerc, AL, Devresse, Arnaud, Magen, D, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, and UCL - (SLuc) Service de néphrologie
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- 2022
7. POS-438 Long-term Treatment With Lumasiran: Results From the Phase 2 Open-Label Extension Study
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Magen, D., primary, Groothoff, J., additional, Hulton, S.A., additional, Harambat, J., additional, Hogan, J., additional, Sellier-Leclerc, A.L., additional, Hayes, W., additional, Coenen, M., additional, Ngo, T., additional, Gansner, J., additional, and Frishberg, Y., additional
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- 2022
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8. Supplement to: A loss-of-function mutation in NaPi-IIa and renal Fanconiʼs syndrome
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Magen, D, Berger, L, and Coady, M J
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- 2010
9. Plasmapheresis in a very young infant with atypical hemolytic uremic syndrome
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Magen, D., Oliven, A., Shechter, Yael, Elhasid, Ronit, Bar-Joseph, G., and Zelikovic, Israel
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- 2001
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10. ILLUMINATE-A, une étude de phase 3 du lumasiran, un ARNi thérapeutique expérimental, chez les enfants et les adultes atteints d’hyperoxalurie primaire de type 1
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Garrelfs, S., primary, Frishberg, Y., additional, Hulton, S., additional, Koren, M., additional, O’Riordan, W., additional, Cochat, P., additional, Deschenes, G., additional, Shasha-Lavsky, H., additional, Saland, J., additional, van’t Hoff, W., additional, Fuster, D., additional, Magen, D., additional, Moochhala, S., additional, Schalk, G., additional, Simkova, E., additional, Groothoff, J., additional, Sas, D., additional, Meliambro, K., additional, Lu, J., additional, Garg, P., additional, Gansner, J., additional, McGregor, T., additional, and Lieske, J., additional
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- 2020
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11. MPGN type I induced by granulocyte colony stimulating factor
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Magen, D., Mandel, Hana, Berant, Moshe, Ben-Izhak, Ofer, and Zelikovic, Israel
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- 2002
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12. SUN-325 SAFETY AND EFFICACY OF LUMASIRAN, AN INVESTIGATIONAL RNA INTERFERENCE (RNAi) THERAPEUTIC, IN ADULT AND PEDIATRIC PATIENTS WITH PRIMARY HYPEROXALURIA TYPE 1
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van't Hoff, W., primary, Cochat, P., additional, Groothoff, J., additional, Harambat, J., additional, Frishberg, Y., additional, Hulton, S., additional, Magen, D., additional, Hoppe, B., additional, Lieske, J., additional, Milliner, D.S., additional, and Deschenes, G., additional
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- 2019
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13. A safety and efficacy study of lumasiran, an investigational RNA interference (RNAi) therapeutic, in adult and pediatric patients with primary hyperoxaluria type 1
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Frishberg, Y., primary, Deschenes, G., additional, Cochat, P., additional, Magen, D., additional, Groothoff, J., additional, Hulton, S.A., additional, Harambat, J., additional, Van’t Hoff, W., additional, Hoppe, B., additional, Lieske, J.C., additional, McGregor, T.L., additional, Tamimi, N., additional, Haslett, P., additional, Talamudupula, S., additional, Erbe, D.V., additional, and Milliner, D.S., additional
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- 2019
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14. P3.11-16 Comparative Analysis of Health-Care Resources and Economic Costs of Lung Cancer Patients Treated Medically or Surgically in Catalunya
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Guirao, A., primary, Molins, L., additional, Guzman, R., additional, Cleries, M., additional, Vela, E., additional, Magen, D., additional, Sanchez, D., additional, Boada, M., additional, Espinas, J.A., additional, Borras, J.M., additional, Argimon, J.M., additional, and Agusti, A., additional
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- 2018
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15. 301 - A safety and efficacy study of lumasiran, an investigational RNA interference (RNAi) therapeutic, in adult and pediatric patients with primary hyperoxaluria type 1
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Frishberg, Y., Deschenes, G., Cochat, P., Magen, D., Groothoff, J., Hulton, S.A., Harambat, J., Van’t Hoff, W., Hoppe, B., Lieske, J.C., McGregor, T.L., Tamimi, N., Haslett, P., Talamudupula, S., Erbe, D.V., and Milliner, D.S.
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- 2019
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16. An infant with polydactyly and renal anomalies: early diagnosis of a rare syndrome
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Magen, D., primary
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- 2002
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17. Isoniazid-induced crescentic glomerulonephritis in a child with a positive tuberculin skin test.
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Brik, Riva, Magen, Daniella, Ben-Yzhak, Ofer, Grin, Jacob, Brik, R, Magen, D, Ben-Yzhak, O, and Grin, J
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- 1998
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18. Genetic disorders of renal phosphate transport.
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Magen D, Zelikovic I, Skorecki K, Magen, Daniella, Zelikovic, Israel, and Skorecki, Karl
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- 2010
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19. Apparent mineralocorticoid excess in Israel: a case series and literature review.
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Lebel A, Ben Shalom E, Mokatern R, Halevy R, Zehavi Y, and Magen D
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- Humans, Israel epidemiology, Male, Female, Retrospective Studies, Child, Child, Preschool, 11-beta-Hydroxysteroid Dehydrogenase Type 2 genetics, Adolescent, Renal Insufficiency, Chronic epidemiology, Renal Insufficiency, Chronic therapy, Mutation, Hypertension epidemiology, Hypokalemia, Adult, Mineralocorticoid Excess Syndrome, Apparent genetics, Mineralocorticoid Excess Syndrome, Apparent diagnosis
- Abstract
Background and Objective: Apparent mineralocorticoid excess (AME) syndrome is an ultra-rare autosomal-recessive tubulopathy, caused by mutations in HSD11B2, leading to excessive activation of the kidney mineralocorticoid receptor, and characterized by early-onset low-renin hypertension, hypokalemia, and risk of chronic kidney disease (CKD). To date, most reports included few patients, and none described patients from Israel. We aimed to describe AME patients from Israel and to review the relevant literature., Design: Retrospective cohort study., Methods: Clinical, laboratory, and molecular data from patients' records were collected., Results: Five patients presented at early childhood with normal estimated glomerular filtration rate (eGFR), while 2 patients presented during late childhood with CKD. Molecular analysis revealed 2 novel homozygous mutations in HSD11B2. All patients presented with severe hypertension and hypokalemia. While all patients developed nephrocalcinosis, only 1 showed hypercalciuria. All individuals were managed with potassium supplements, mineralocorticoid receptor antagonists, and various antihypertensive medications. One patient survived cardiac arrest secondary to severe hyperkalemia. At last follow-up, those 5 patients who presented early exhibited normal eGFR and near-normal blood pressure, but 2 have hypertension complications. The 2 patients who presented with CKD progressed to end-stage kidney disease (ESKD) necessitating dialysis and kidney transplantation., Conclusions: In this 11-year follow-up report of 2 Israeli families with AME, patients who presented early maintained long-term normal kidney function, while those who presented late progressed to ESKD. Nevertheless, despite early diagnosis and management, AME is commonly associated with serious complications of the disease or its treatment., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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20. Efficacy and Safety of Lumasiran in Patients With Primary Hyperoxaluria Type 1: Results from a Phase III Clinical Trial.
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Saland JM, Lieske JC, Groothoff JW, Frishberg Y, Shasha-Lavsky H, Magen D, Moochhala SH, Simkova E, Coenen M, Hayes W, Hogan J, Sellier-Leclerc AL, Willey R, Gansner JM, and Hulton SA
- Abstract
Introduction: Patients with primary hyperoxaluria type 1 (PH1), a genetic disorder associated with hepatic oxalate overproduction, frequently experience recurrent kidney stones and worsening kidney function. Lumasiran is indicated for the treatment of PH1 to lower urinary and plasma oxalate (POx)., Methods: ILLUMINATE-A (NCT03681184) is a phase III trial in patients aged ≥6 years with PH1 and estimated glomerular filtration rate (eGFR) ≥30 ml/min per 1.73 m
2 . A 6-month double-blind placebo-controlled period is followed by an extension period (≤54 months; all patients receive lumasiran). We report interim data through month 36., Results: Of 39 patients enrolled, 24 of 26 (lumasiran/lumasiran group) and 13 of 13 (placebo/lumasiran group) entered and continue in the extension period. At month 36, in the lumasiran/lumasiran group (36 months of lumasiran treatment) and placebo/lumasiran group (30 months of lumasiran treatment), mean 24-hour urinary oxalate (UOx) reductions from baseline were 63% and 58%, respectively; 76% and 92% of patients reached a 24-hour UOx excretion ≤1.5× the upper limit of normal (ULN). eGFR remained stable. Kidney stone event rates decreased from 2.31 (95% confidence interval: 1.88-2.84) per person-year (PY) during the 12 months before consent to 0.60 (0.46-0.77) per PY during lumasiran treatment. Medullary nephrocalcinosis generally remained stable or improved; approximately one-third of patients (both groups) improved to complete resolution. The most common lumasiran-related adverse events (AEs) were mild, transient injection-site reactions., Conclusion: In patients with PH1, longer-term lumasiran treatment led to sustained reduction in UOx excretion, with an acceptable safety profile and encouraging clinical outcomes.See for Video Abstract., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)- Published
- 2024
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21. Moral clarity at WHO needs to be clearer.
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Beyar R, Blazer S, Breuer E, Carmi R, Ciechanover A, Clarfield AM, Glick S, Magen D, Manor O, Paltiel O, and Skorecki K
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- Humans, World Health Organization, Morals, Stress, Psychological
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- 2024
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22. Protocolized polyoma BK viral load monitoring and high-dose immunoglobulin treatment in children after kidney transplant.
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Pollack S, Plonsky-Toder M, Tibi R, Yakubov R, Libinson-Zebegret I, and Magen D
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Background: BKPyV virus nephropathy (BKPyVAN) is diagnosed in 5%-16% of pediatric renal transplant recipients (PRTR) and preceded by BKPyV-viruria and DNAemia. Despite the risk of irreversible transplant damage associated with BKPyVAN, evidence-based consensus guidelines for BKPyVAN prevention are still lacking. In this retrospective study, we examined the safety and efficacy of high-dose intravenous immunoglobulin (HD-IVIG) therapy for prevention of BKPyVAN in PRTR with significant BKPyV-viruria/DNAemia., Methods: Between January 2013 and December 2022, all PRTR under our care underwent routine urine and blood testing for BKPyV viral load, using specific polymerase chain reaction (PCR). BKPyV DNAemia, with <10
3 copies/mL, with BKPyV viruria <107 copies/mL, with no evidence of BKPyVAN, were managed with 50% dose reduction of mycophenolate mofetil (MMF). Patients showing no decline in BKPyV viral load within two months of MMF dose reduction were managed with HD-IVIG (2 g/kg)., Results: Seventy patients were recruited during a ten-year period and 31/70 patients (44%) demonstrated significant post-transplantation BKPyV-viruria/DNAemia, while 13/31 (42%) patients were unresponsive to MMF dose reduction, and were administered HD-IVIG. Of these, 12/13 (92%) patients achieved BKPyV viral clearance within six months from completion of HD-IVIG therapy and 1/13 patient (8%) was unresponsive to HD-IVIG therapy, showing increased BKPyV viral load. There were no major adverse events associated with HD-IVIG, and none of our patients developed BKPyVAN during the study period., Conclusions: Prophylactic HD-IVIG therapy in PRTR with significant BKPyV-viruria/DNAemia unresponsive to MMF dose reduction is safe and might be effective in preventing BKPyVAN. Our findings remain to be established by large-scale prospective studies., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)- Published
- 2023
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23. Innate Immunity and CKD: Is There a Significant Association?
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Plonsky-Toder M, Magen D, and Pollack S
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- Humans, Renal Dialysis adverse effects, Immunity, Innate, Inflammation complications, Renal Insufficiency, Chronic complications, Cardiovascular Diseases complications, Atherosclerosis complications
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Chronic kidney disease (CKD) constitutes a worldwide epidemic, affecting approximately 10% of the global population, and imposes significant medical, psychological, and financial burdens on society. Individuals with CKD often face elevated morbidity and mortality rates, mainly due to premature cardiovascular events. Chronic inflammation has been shown to play a significant role in the progression of CKD, as well as in the acceleration of CKD-related complications, including atherosclerosis, cardiovascular disease (CVD), protein-energy wasting, and the aging process. Over the past two decades, a substantial body of evidence has emerged, identifying chronic inflammation as a central element of the uremic phenotype. Chronic inflammation has been shown to play a significant role in the progression of CKD, as well as in the acceleration of CKD-related complications in dialysis patients, including atherosclerosis, CVD, protein-energy wasting, and the aging process. Remarkably, chronic inflammation also impacts patients with CKD who have not yet required renal replacement therapy. While extensive research has been conducted on the involvement of both the adaptive and innate immune systems in the pathogenesis of CKD-related complications, this wealth of data has not yet yielded well-established, effective treatments to counteract this ongoing pathological process. In the following review, we will examine the established components of the innate immune system known to be activated in CKD and provide an overview of the current therapeutic approaches designed to mitigate CKD-related chronic inflammation.
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- 2023
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24. Diagnostic Utility of Exome Sequencing Among Israeli Children With Kidney Failure.
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Ben-Moshe Y, Shlomovitz O, Atias-Varon D, Haskin O, Ben-Shalom E, Shasha Lavsky H, Volovelsky O, Mane S, Ben-Ruby D, Chowers G, Skorecki K, Borovitz Y, Kagan M, Mor N, Khavkin Y, Tzvi-Behr S, Pollack S, Toder MP, Geylis M, Schnapp A, Becker-Cohen R, Weissman I, Schreiber R, Davidovits M, Frishberg Y, Magen D, Barel O, and Vivante A
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Introduction: Genetic etiologies are estimated to account for a large portion of chronic kidney diseases (CKD) in children. However, data are lacking regarding the true prevalence of monogenic etiologies stemming from an unselected population screen of children with advanced CKD., Methods: We conducted a national multicenter prospective study of all Israeli pediatric dialysis units to provide comprehensive "real-world" evidence for the genetic basis of childhood kidney failure in Israel. We performed exome sequencing and assessed the genetic diagnostic yield., Results: Between 2019 and 2022, we recruited approximately 88% ( n = 79) of the children on dialysis from all 6 Israeli pediatric dialysis units. We identified genetic etiologies in 36 of 79 (45%) participants. The most common subgroup of diagnostic variants was in congenital anomalies of the kidney and urinary tract causing genes (e.g., EYA1 , HNF1B , PAX2 , COL4A1, and NFIA ) which together explain 28% of all monogenic etiologies. This was followed by mutations in genes causing renal cystic ciliopathies (e.g., NPHP1 , NPHP4 , PKHD1 , and BBS9 ), steroid-resistant nephrotic syndrome (e.g., LAGE3 , NPHS1 , NPHS2 , LMX1B , and SMARCAL1 ) and tubulopathies (e.g., CTNS and AQP2 ). The genetic diagnostic yield was higher among Arabs compared to Jewish individuals (55% vs. 29%) and in children from consanguineous compared to nonconsanguineous families (63% vs. 29%). In 5 participants (14%) with genetic diagnoses, the molecular diagnosis did not correspond with the pre-exome diagnosis. Genetic diagnosis has a potential influence on clinical management in 27 of 36 participants (75%)., Conclusion: Exome sequencing in an unbiased Israeli nationwide dialysis-treated kidney failure pediatric cohort resulted in a genetic diagnostic yield of 45% and can often affect clinical decision making., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)
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- 2023
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25. Efficacy and safety of lumasiran for infants and young children with primary hyperoxaluria type 1: 12-month analysis of the phase 3 ILLUMINATE-B trial.
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Hayes W, Sas DJ, Magen D, Shasha-Lavsky H, Michael M, Sellier-Leclerc AL, Hogan J, Ngo T, Sweetser MT, Gansner JM, McGregor TL, and Frishberg Y
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- Child, Child, Preschool, Humans, Infant, Oxalates adverse effects, Hyperoxaluria, Primary complications, Hyperoxaluria, Primary drug therapy, Kidney Calculi etiology
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Background: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease that causes progressive kidney damage and systemic oxalosis due to hepatic overproduction of oxalate. Lumasiran demonstrated efficacy and safety in the 6-month primary analysis period of the phase 3, multinational, open-label, single-arm ILLUMINATE-B study of infants and children < 6 years old with PH1 (ClinicalTrials.gov: NCT03905694 (4/1/2019); EudraCT: 2018-004,014-17 (10/12/2018)). Outcomes in the ILLUMINATE-B extension period (EP) for patients who completed ≥ 12 months on study are reported here., Methods: Of the 18 patients enrolled in the 6-month primary analysis period, all entered the EP and completed ≥ 6 additional months of lumasiran treatment (median (range) duration of total exposure, 17.8 (12.7-20.5) months)., Results: Lumasiran treatment was previously reported to reduce spot urinary oxalate:creatinine ratio by 72% at month 6, which was maintained at 72% at month 12; mean month 12 reductions in prespecified weight subgroups were 89%, 68%, and 71% for patients weighing < 10 kg, 10 to < 20 kg, and ≥ 20 kg, respectively. The mean reduction from baseline in plasma oxalate level was reported to be 32% at month 6, and this improved to 47% at month 12. Additional improvements were also seen in nephrocalcinosis grade, and kidney stone event rates remained low. The most common lumasiran-related adverse events were mild, transient injection-site reactions (3 patients (17%))., Conclusions: Lumasiran treatment provided sustained reductions in urinary and plasma oxalate through month 12 across all weight subgroups, with an acceptable safety profile, in infants and young children with PH1. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s).)
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- 2023
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26. Dialysis in Israeli Children between 1990 and 2020: Trends and International Comparisons.
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Regev-Epstein LC, Frishberg Y, Davidovits M, Landau D, Magen D, Weismann I, Stern-Zimmer M, Beckerman P, Keinan-Boker L, Calderon-Margalit R, and Vivante A
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- Humans, Child, Israel epidemiology, Cohort Studies, Ethnicity, Renal Dialysis, Renal Insufficiency
- Abstract
Background: Childhood kidney failure is a rare condition with worldwide clinical variability. We used a nationwide multicenter analysis to study the pretransplant course of the entire Israeli pediatric kidney failure population over 30 years., Methods: In this nationwide, population-based, historical cohort study, we analyzed medical and demographic data of all children treated with KRT and reported to the Israeli kidney failure registry in 1990-2020. Statistical analysis was performed with incidence rate corrected for age, ethnicity, and calendar year, using the appropriate age-related general population as denominator., Results: During the last 30 years, childhood incidence of kidney failure decreased. Average incidence in 2015-2019 was 9.1 cases per million age-related population (pmarp). Arab and Druze children exhibited higher kidney failure incidence rates than Jewish children (18.4 versus 7.0 cases pmarp for minorities versus Jews). The most common kidney failure etiologies among Arab and Jewish children were congenital anomalies of the kidney and urinary tract (approximately 27%), followed by cystic kidney diseases among Arab children (13%) and glomerulonephritis among Jewish children (16%). The most common etiology among Druze children was primary hyperoxaluria type 1 (33%). Israel's national health insurance provides access to primary health care to all citizens. Accordingly, waiting time for deceased-donor transplantation was equal between all ethnicities. Living-donor kidney transplantation rates among minority populations remained low in comparison with Jews over the entire study period. Although all patient groups demonstrated improvement in survival, overall survival rates were mainly etiology dependent., Conclusions: In Israel, Arab and Druze children had a higher incidence of kidney failure, a unique etiological distribution, and a lower rate of living-donor kidney transplantations compared with Jewish children., (Copyright © 2023 by the American Society of Nephrology.)
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- 2023
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27. Reduced Electroretinogram Responses in Morphologically Normal Retina in Patients with Primary Hyperoxaluria Type 1.
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Naaman E, Malul N, Safuri S, Bar N, Pollack S, Magen D, Leibu R, Perlman I, and Zayit-Soudry S
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Purpose: To describe ocular findings in individuals with primary hyperoxaluria type 1 (PH1), focusing on the correlations between retinal anatomy and retinal function. To characterize the retinal alterations that occur at different disease stages by evaluating individuals with diverse degrees of renal impairment associated with PH1., Design: A cross-sectional study., Participants: Patients diagnosed with PH1 based on clinical criteria and genetic testing, treated in the Pediatric Nephrology Unit of the Ruth Children's Hospital, Rambam Health Care Campus, Haifa, Israel between 2013 and 2021., Methods: The ophthalmological assessment included a slit-lamp biomicroscopy of the anterior and posterior segment or indirect ophthalmoscopy. Electroretinography was employed for assessment of the retinal function, and retinal imaging included spectral-domain OCT and fundus autofluorescence. A systematic evaluation of the disease stage was based on clinical criteria including physical examination, purposeful imaging (X-ray, echocardiography, and US abdomen), and laboratory tests as needed., Main Outcome Measures: Anatomical and functional assessment of the retina in patients with PH1, and the relationship between retinal dysfunction and kidney impairment., Results: A total of 16 eyes were examined in the study of 8 children ranging in age from 4 to 19 years. Four eyes (25%) showed normal structural and functional retinal findings, 8 eyes (50%) presented functional impairment in the absence of pathological structural findings, and 4 eyes (25%) had advanced retinal damage that manifested as significant morphological and functional impairment. There was no direct relationship between the severity of the renal disease and the severity of the retinal phenotype., Conclusions: Subjects with PH1 present varying severity levels of the retinal phenotype, with possible discrepancy between the clinical retinal morphology and the retinal function noted on electroretinography. These findings raise questions about the molecular basis of the retinal manifestations in PH1. The presence of functional impairment in the absence of evident crystal deposition in the retina suggests that, in addition to oxalate crystal accumulation, other biomolecular processes may play a role in the development of retinopathy., (© 2023 Published by Elsevier Inc. on behalf of American Academy of Ophthalmology.)
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- 2023
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28. Acute hemodialysis therapy in neonates with inborn errors of metabolism.
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Eisenstein I, Pollack S, Hadash A, Eytan D, Attias O, Halberthal M, Ben-Ari J, Bar-Joseph G, Zelikovic I, Mandel H, Tal G, and Magen D
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- Ammonia, Child, Humans, Infant, Newborn, Leucine, Retrospective Studies, Urea, Metabolism, Inborn Errors complications, Metabolism, Inborn Errors therapy, Renal Dialysis adverse effects, Renal Dialysis methods
- Abstract
Background: Inborn errors of metabolism (IEM), including organic acidemias and urea cycle defects, are characterized by systemic accumulation of toxic metabolites with deleterious effect on the developing brain. While hemodialysis (HD) is most efficient in clearing IEM-induced metabolic toxins, data regarding its use during the neonatal period is scarce., Methods: We retrospectively summarize our experience with HD in 20 neonates with IEM-induced metabolic intoxication (seven with maple syrup urine disease, 13 with primary hyperammonia), over a 16-year period, between 2004 and 2020. All patients presented with IEM-induced neurologic deterioration at 48 h to 14 days post-delivery, and were managed with HD in a pediatric intensive care setting. HD was performed through an internal jugular acute double-lumen catheter (6.5-7.0 French), using an AK-200S (Gambro, Sweden) dialysis machine and tubing, with F3 or FXpaed (Fresenius, Germany) dialyzers., Results: Median (interquartile range) age and weight at presentation were 5 (3-8) days and 2830 (2725-3115) g, respectively. Two consecutive HD sessions decreased the mean leucine levels from 2281 ± 631 to 179 ± 91 μmol/L (92.1% reduction) in MSUD patients, and the mean ammonia levels from 955 ± 444 to 129 ± 55 μmol/L (86.5% reduction), in patients with hyperammonemia. HD was uneventful in all patients, and led to marked clinical improvement in 17 patients (85%). Three patients (15%) died during the neonatal period, and four died during long-term follow-up., Conclusions: Taken together, our results indicate that HD is safe, effective, and life-saving for most neonates with severe IEM-induced metabolic intoxication, when promptly performed by an experienced and multidisciplinary team. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)
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- 2022
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29. A Founder Mutation in EHD1 Presents with Tubular Proteinuria and Deafness.
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Issler N, Afonso S, Weissman I, Jordan K, Cebrian-Serrano A, Meindl K, Dahlke E, Tziridis K, Yan G, Robles-López JM, Tabernero L, Patel V, Kesselheim A, Klootwijk ED, Stanescu HC, Dumitriu S, Iancu D, Tekman M, Mozere M, Jaureguiberry G, Outtandy P, Russell C, Forst AL, Sterner C, Heinl ES, Othmen H, Tegtmeier I, Reichold M, Schiessl IM, Limm K, Oefner P, Witzgall R, Fu L, Theilig F, Schilling A, Shuster Biton E, Kalfon L, Fedida A, Arnon-Sheleg E, Ben Izhak O, Magen D, Anikster Y, Schulze H, Ziegler C, Lowe M, Davies B, Böckenhauer D, Kleta R, Falik Zaccai TC, and Warth R
- Subjects
- Adolescent, Adult, Animals, Child, Child, Preschool, Endocytosis, Humans, Kidney Tubules, Proximal metabolism, Low Density Lipoprotein Receptor-Related Protein-2 genetics, Low Density Lipoprotein Receptor-Related Protein-2 metabolism, Mice, Mutation, Proteinuria metabolism, Vesicular Transport Proteins genetics, Young Adult, Deafness genetics, Zebrafish metabolism
- Abstract
Background: The endocytic reabsorption of proteins in the proximal tubule requires a complex machinery and defects can lead to tubular proteinuria. The precise mechanisms of endocytosis and processing of receptors and cargo are incompletely understood. EHD1 belongs to a family of proteins presumably involved in the scission of intracellular vesicles and in ciliogenesis. However, the relevance of EHD1 in human tissues, in particular in the kidney, was unknown., Methods: Genetic techniques were used in patients with tubular proteinuria and deafness to identify the disease-causing gene. Diagnostic and functional studies were performed in patients and disease models to investigate the pathophysiology., Results: We identified six individuals (5-33 years) with proteinuria and a high-frequency hearing deficit associated with the homozygous missense variant c.1192C>T (p.R398W) in EHD1 . Proteinuria (0.7-2.1 g/d) consisted predominantly of low molecular weight proteins, reflecting impaired renal proximal tubular endocytosis of filtered proteins. Ehd1 knockout and Ehd1
R398W/R398W knockin mice also showed a high-frequency hearing deficit and impaired receptor-mediated endocytosis in proximal tubules, and a zebrafish model showed impaired ability to reabsorb low molecular weight dextran. Interestingly, ciliogenesis appeared unaffected in patients and mouse models. In silico structural analysis predicted a destabilizing effect of the R398W variant and possible inference with nucleotide binding leading to impaired EHD1 oligomerization and membrane remodeling ability., Conclusions: A homozygous missense variant of EHD1 causes a previously unrecognized autosomal recessive disorder characterized by sensorineural deafness and tubular proteinuria. Recessive EHD1 variants should be considered in individuals with hearing impairment, especially if tubular proteinuria is noted., (Copyright © 2022 by the American Society of Nephrology.)- Published
- 2022
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30. Phase 3 trial of lumasiran for primary hyperoxaluria type 1: A new RNAi therapeutic in infants and young children.
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Sas DJ, Magen D, Hayes W, Shasha-Lavsky H, Michael M, Schulte I, Sellier-Leclerc AL, Lu J, Seddighzadeh A, Habtemariam B, McGregor TL, Fujita KP, and Frishberg Y
- Subjects
- Child, Preschool, Humans, Infant, RNA Interference, RNA, Small Interfering, Hyperoxaluria, Primary complications, Hyperoxaluria, Primary genetics, Hyperoxaluria, Primary therapy, RNAi Therapeutics
- Abstract
Purpose: Primary hyperoxaluria type 1 (PH1) is a rare, progressive, genetic disease with limited treatment options. We report the efficacy and safety of lumasiran, an RNA interference therapeutic, in infants and young children with PH1., Methods: This single-arm, open-label, phase 3 study evaluated lumasiran in patients aged <6 years with PH1 and an estimated glomerular filtration rate >45 mL/min/1.73 m
2 , if aged ≥12 months, or normal serum creatinine, if aged <12 months. The primary end point was percent change in spot urinary oxalate to creatinine ratio (UOx:Cr) from baseline to month 6. Secondary end points included proportion of patients with urinary oxalate ≤1.5× upper limit of normal and change in plasma oxalate., Results: All patients (N = 18) completed the 6-month primary analysis period. Median age at consent was 50.1 months. Least-squares mean percent reduction in spot UOx:Cr was 72.0%. At month 6, 50% of patients (9/18) achieved spot UOx:Cr ≤1.5× upper limit of normal. Least-squares mean percent reduction in plasma oxalate was 31.7%. The most common treatment-related adverse events were transient, mild, injection-site reactions., Conclusion: Lumasiran showed rapid, sustained reduction in spot UOx:Cr and plasma oxalate and acceptable safety in patients aged <6 years with PH1, establishing RNA interference therapies as safe, effective treatment options for infants and young children., Competing Interests: Conflict of Interest David J. Sas reports grants and other support from Alnylam Pharmaceuticals and personal fees from Advicenne. Daniella Magen reports research funding, consultancy fees, and nonfinancial support from Alnylam Pharmaceuticals. Wesley Hayes reports travel and accommodation expenses from Alnylam Pharmaceuticals to attend an international investigators’ meeting. Hadas Shasha-Lavsky reports serving as a principal investigator for Alnylam Pharmaceuticals and receiving travel and accommodation expenses from Alnylam Pharmaceuticals to attend international investigators’ meetings. Mini Michael reports serving as a principal investigator for and receiving travel and accommodation expenses from Alnylam Pharmaceuticals to attend international investigators’ meetings. Anne-Laure Sellier-Leclerc reports consultancy fees from Alnylam Pharmaceuticals and Dicerna Pharmaceuticals and was principal investigator for research funded by OxThera. Ali Seddighzadeh reports previous employment by and shareholder of Alnylam Pharmaceuticals (currently employed by Apellis Pharmaceuticals). Jiandong Lu, Bahru Habtemariam, Tracy L. McGregor, and Kenji P. Fujita report previous employment by and shareholder of Alnylam Pharmaceuticals. Yaacov Frishberg reports consultancy fees from Alnylam Pharmaceuticals and membership in the safety review committee. All other authors declare no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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31. Relation of glomerular filtration to insulin resistance and related risk factors in obese children.
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Magen D, Halloun R, Galderisi A, Caprio S, and Weiss R
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- Adolescent, Body Mass Index, Child, Female, Humans, Kidney physiopathology, Male, Pediatric Obesity physiopathology, Risk Factors, Glomerular Filtration Rate physiology, Insulin Resistance physiology, Pediatric Obesity metabolism
- Abstract
Background and Objective: Childhood obesity is associated with later development of significant renal morbidity. We evaluated the impact of the degree of insulin sensitivity on estimated glomerular filtration rate (eGFR) and determined the factors associated with eGFR in obese children. We further tested the relation of eGFR to clinical outcomes such as blood pressure and microalbuminuria., Materials and Methods: We evaluated the relation of whole body insulin sensitivity and estimated glomerular filtration rate (eGFR) across the spectrum of obesity in children and adolescents. eGFR was calculated using the iCARE formula, which has been validated in obese children with varying glucose tolerance., Results: 1080 children and adolescents with overweight and obesity (701 females and 379 males) participated. Insulin sensitivity was a strongly negatively associated with (B = -2.72, p < 0.001) eGFR), even after adjustment for potential confounders. Male sex emerged to be significantly associated with eGFR with boys having greater values than girls (B = 18.82, p < 0.001). Age was a positively associated (B = 2.86, p < 0.001) with eGFR. Whole body and hepatic insulin sensitivity decreased across eGFR quartiles. Adjusted eGFR was tightly positively associated with systolic blood pressure (B = 0.09, p = 0.003) and negatively associated with the presence of microalbuminuria (B = -2.18, p = 0.04)., Conclusions: eGFR tends to increase with greater degrees of insulin resistance in children and adolescents representing hyperfiltration and is associated with cardiovascular risk factors. Longitudinal studies are needed to determine the natural history of childhood insulin resistance related hyperfiltration in regards to future kidney disease., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2022
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32. Randomized Clinical Trial on the Long-Term Efficacy and Safety of Lumasiran in Patients With Primary Hyperoxaluria Type 1.
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Hulton SA, Groothoff JW, Frishberg Y, Koren MJ, Overcash JS, Sellier-Leclerc AL, Shasha-Lavsky H, Saland JM, Hayes W, Magen D, Moochhala SH, Coenen M, Simkova E, Garrelfs SF, Sas DJ, Meliambro KA, Ngo T, Sweetser MT, Habtemariam BA, Gansner JM, McGregor TL, and Lieske JC
- Abstract
Introduction: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate, leading to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. In the 6-month double-blind period (DBP) of ILLUMINATE-A, a phase 3, randomized, placebo-controlled trial in patients with PH1 ≥6 years old, treatment with lumasiran, an RNA interference therapeutic, led to substantial reductions in urinary oxalate (UOx) levels., Methods: We report data to month 12 in the extension period (EP) of ILLUMINATE-A, including patients who continued lumasiran (lumasiran/lumasiran) or crossed over from placebo to lumasiran (placebo/lumasiran)., Results: In the lumasiran/lumasiran group ( n = 24), the reduction in 24-hour UOx level was sustained to month 12 (mean reduction from baseline, 66.9% at month 6; 64.1% at month 12). The placebo/lumasiran group ( n = 13) had a similar time course and magnitude of 24-hour UOx reduction (mean reduction, 57.3%) after 6 months of lumasiran. Kidney stone event rates seemed to be lower after 6 months of lumasiran in both groups compared with the 12 months before consent, and this reduction was maintained at month 12 in the lumasiran/lumasiran group. At study start, 71% of patients in the lumasiran/lumasiran group and 92% in the placebo/lumasiran group had nephrocalcinosis. Nephrocalcinosis grade improved after 6 months of lumasiran in the lumasiran/lumasiran and placebo/lumasiran groups (13% and 8% of patients, respectively). After an additional 6 months of lumasiran, 46% of patients had improvement in nephrocalcinosis grade within the lumasiran/lumasiran group. Estimated glomerular filtration rate (eGFR) remained stable during the course of lumasiran treatment. The most common adverse events (AEs) related to lumasiran were mild, transient injection-site reactions (ISRs)., Conclusion: Long-term lumasiran treatment enabled sustained lowering of UOx levels with acceptable safety and encouraging results on clinical outcomes., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)
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- 2021
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33. [INTRAVENOUS IMMUNOGLOBULIN TREATMENT TO PREVENT BK NEPHROPATHY IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS WITH BK VIRUS].
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Pollack S, Eisenstein I, Mukatren R, and Magen D
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- BK Virus, Child, Humans, Retrospective Studies, Immunoglobulins, Intravenous therapeutic use, Kidney Transplantation adverse effects, Polyomavirus Infections prevention & control, Tumor Virus Infections prevention & control
- Abstract
Aims: In this retrospective study we examined the safety and efficacy of high-dose intravenous immunoglobulin (HD-IVIG) therapy in preventing BKVN in pediatric renal transplant recipients with BK-viremia/viruria., Background: BK virus nephropathy (BKVN) is diagnosed in 5-16% of pediatric renal transplant recipients and is preceded by BK viremia/viruria. Despite irreversible renal damage associated with BKVN, there is a lack of evidence-based guidelines for preventive measures in patients with BK viremia/viruria., Methods: All pediatric renal transplant recipients under our care underwent routine testing for urine and blood BK virus, using the polymerase chain reaction (PCR) technique. Patients exhibiting BK-viruria < 107 copies/milliliter (ml) and/or BK-viremia<103 copies/ml without any evidence of BKVN, were managed with 50% dose reduction of the immunosuppressive drug mycophenolate mofetil (MMF). Absence of BK viral load decline within two months from MMF dose reduction was managed with HD-IVIG (at 2 grams/kg body weight)., Results: The study included 62 patients over a 6-year period; 31 patients (50%) showed BK-viremia/viruria; 13/31 patients (42%) suffered from significant and persistent BK-viremia/viruria, unresponsive to MMF dose reduction, and were managed with HD-IVIG; 12/13 (92%) showed significant BK viral load reduction within 6 months from HD-IVIG therapy. Except for transient headache, no patient exhibited major adverse effects to HD-IVIG therapy, and none developed overt BKVN during the study period., Conclusions: Preventive HD-IVIG therapy in pediatric renal transplant recipients with BK viremia/viruria unresponsive to MMF dose reduction is safe and effective in preventing the development of BKVN. Additional large-scale studies are necessary to establish our findings.
- Published
- 2021
34. A novel loss-of-function mutation in LACC1 underlies hereditary juvenile arthritis with extended intra-familial phenotypic heterogeneity.
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Butbul Aviel Y, Ofir A, Ben-Izhak O, Vlodavsky E, Karbian N, Brik R, Mevorach D, and Magen D
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- Adolescent, Adult, Arthritis, Juvenile pathology, CRISPR-Associated Protein 9, CRISPR-Cas Systems, Cytokines blood, Female, Flow Cytometry, Gene Editing, Humans, Immunoblotting, Male, Pedigree, Exome Sequencing, Young Adult, Arthritis, Juvenile genetics, Intracellular Signaling Peptides and Proteins genetics, Loss of Function Mutation genetics
- Abstract
Objective: To investigate phenotypic and molecular characteristics of a consanguineous family with autosomal-recessive, polyarticular, juvenile isiopathic arthriris (JIA) with extra-articular manifestations, including renal amyloidosis and Crohn's disease, associated with a novel homozygous truncating variant in LACC1., Methods: Whole exome sequencing (WES) or targeted Sanger verification were performed in 15 participants. LACC1 expression and cytokine array were analysed in patient-derived and CRISPR/Cas9-generated LACC1-knockout macrophages (Mϕ)., Results: A homozygous truncating variant (p.Glu348Ter) in LACC1 was identified in three affected and one asymptomatic family member, and predicted harmful by causing premature stop of the LACC1 protein sequences, and by absence from ethnically-matched controls and public variation databases. Expression studies in patient-derived macrophages (Mϕ) showed no endogenous p.Glu348Ter-LACC1 RNA transcription or protein expression, compatible with nonsense-mediated mRNA decay. WES analysis in the asymptomatic homozygous subject for p. Glu348Ter-LACC1 detected an exclusive heterozygous variant (p.Arg928Gln) in complement component C5. Further complement activity analysis suggested a protective role for the p.Arg928Gln-C5 variant as a phenotypic modifier of LACC1-associated disease. Finally, cytokine profile analysis indicated increased levels of pro-inflammatory cytokines in LACC1-disrupted as compared with wild-type Mϕ., Conclusions: Our findings reinforce the role of LACC1 disruption in autosomal-recessive JIA, extend the clinical spectrum and intra-familial heterogeneity of the disease-associated phenotype, indicate a modulatory effect of complement factor C5 on phenotypic severity, and suggest an inhibitory role for wild-type LACC1 on pro-inflammatory pathways., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2021
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35. Phase 1/2 Study of Lumasiran for Treatment of Primary Hyperoxaluria Type 1: A Placebo-Controlled Randomized Clinical Trial.
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Frishberg Y, Deschênes G, Groothoff JW, Hulton SA, Magen D, Harambat J, Van't Hoff WG, Lorch U, Milliner DS, Lieske JC, Haslett P, Garg PP, Vaishnaw AK, Talamudupula S, Lu J, Habtemariam BA, Erbe DV, McGregor TL, and Cochat P
- Subjects
- Adolescent, Adult, Child, Female, Glycolates blood, Humans, Hyperoxaluria, Primary blood, Hyperoxaluria, Primary urine, Male, RNA, Small Interfering adverse effects, Renal Agents adverse effects, Single-Blind Method, Young Adult, Hyperoxaluria, Primary drug therapy, Oxalates urine, RNA, Small Interfering pharmacokinetics, RNA, Small Interfering pharmacology, Renal Agents pharmacokinetics, Renal Agents pharmacology
- Abstract
Background and Objectives: In the rare disease primary hyperoxaluria type 1, overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an RNA interference therapeutic, suppresses glycolate oxidase, reducing hepatic oxalate production. The objective of this first-in-human, randomized, placebo-controlled trial was to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of lumasiran in healthy participants and patients with primary hyperoxaluria type 1., Design, Setting, Participants, & Measurements: This phase 1/2 study was conducted in two parts. In part A, healthy adults randomized 3:1 received a single subcutaneous dose of lumasiran or placebo in ascending dose groups (0.3-6 mg/kg). In part B, patients with primary hyperoxaluria type 1 randomized 3:1 received up to three doses of lumasiran or placebo in cohorts of 1 or 3 mg/kg monthly or 3 mg/kg quarterly. Patients initially assigned to placebo crossed over to lumasiran on day 85. The primary outcome was incidence of adverse events. Secondary outcomes included pharmacokinetic and pharmacodynamic parameters, including measures of oxalate in patients with primary hyperoxaluria type 1. Data were analyzed using descriptive statistics., Results: Thirty-two healthy participants and 20 adult and pediatric patients with primary hyperoxaluria type 1 were enrolled. Lumasiran had an acceptable safety profile, with no serious adverse events or study discontinuations attributed to treatment. In part A, increases in mean plasma glycolate concentration, a measure of target engagement, were observed in healthy participants. In part B, patients with primary hyperoxaluria type 1 had a mean maximal reduction from baseline of 75% across dosing cohorts in 24-hour urinary oxalate excretion. All patients achieved urinary oxalate levels ≤1.5 times the upper limit of normal., Conclusions: Lumasiran had an acceptable safety profile and reduced urinary oxalate excretion in all patients with primary hyperoxaluria type 1 to near-normal levels., Clinical Trial Registry Name and Registration Number: Study of Lumasiran in Healthy Adults and Patients with Primary Hyperoxaluria Type 1, NCT02706886., (Copyright © 2021 by the American Society of Nephrology.)
- Published
- 2021
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36. A Novel Homozygous In-Frame Deletion in Complement Factor 3 Underlies Early-Onset Autosomal Recessive Atypical Hemolytic Uremic Syndrome - Case Report.
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Pollack S, Eisenstein I, Mory A, Paperna T, Ofir A, Baris-Feldman H, Weiss K, Veszeli N, Csuka D, Shemer R, Glaser F, Prohászka Z, and Magen D
- Subjects
- Atypical Hemolytic Uremic Syndrome congenital, Atypical Hemolytic Uremic Syndrome etiology, Child, Preschool, Complement Activation, Complement Membrane Attack Complex, Genes, Recessive, Homozygote, Humans, Male, Exome Sequencing, Atypical Hemolytic Uremic Syndrome diagnosis, Atypical Hemolytic Uremic Syndrome genetics, Base Sequence genetics, Complement C3 genetics, Sequence Deletion
- Abstract
Background and Objectives: Atypical hemolytic uremic syndrome (aHUS) is mostly attributed to dysregulation of the alternative complement pathway (ACP) secondary to disease-causing variants in complement components or regulatory proteins. Hereditary aHUS due to C3 disruption is rare, usually caused by heterozygous activating mutations in the C3 gene, and transmitted as autosomal dominant traits. We studied the molecular basis of early-onset aHUS, associated with an unusual finding of a novel homozygous activating deletion in C3., Design Setting Participants & Measurements: A male neonate with eculizumab-responsive fulminant aHUS and C3 hypocomplementemia, and six of his healthy close relatives were investigated. Genetic analysis on genomic DNA was performed by exome sequencing of the patient, followed by targeted Sanger sequencing for variant detection in his close relatives. Complement components analysis using specific immunoassays was performed on frozen plasma samples from the patient and mother., Results: Exome sequencing revealed a novel homozygous variant in exon 26 of C3 (c.3322_3333del, p.Ile1108_Lys1111del), within the highly conserved thioester-containing domain (TED), fully segregating with the familial disease phenotype, as compatible with autosomal recessive inheritance. Complement profiling of the patient showed decreased C3 and FB levels, with elevated levels of the terminal membrane attack complex, while his healthy heterozygous mother showed intermediate levels of C3 consumption., Conclusions: Our findings represent the first description of aHUS secondary to a novel homozygous deletion in C3 with ensuing unbalanced C3 over-activation, highlighting a critical role for the disrupted C3-TED domain in the disease mechanism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pollack, Eisenstein, Mory, Paperna, Ofir, Baris-Feldman, Weiss, Veszeli, Csuka, Shemer, Glaser, Prohászka and Magen.)
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- 2021
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37. Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1.
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Garrelfs SF, Frishberg Y, Hulton SA, Koren MJ, O'Riordan WD, Cochat P, Deschênes G, Shasha-Lavsky H, Saland JM, Van't Hoff WG, Fuster DG, Magen D, Moochhala SH, Schalk G, Simkova E, Groothoff JW, Sas DJ, Meliambro KA, Lu J, Sweetser MT, Garg PP, Vaishnaw AK, Gansner JM, McGregor TL, and Lieske JC
- Subjects
- Adolescent, Adult, Child, Creatinine urine, Double-Blind Method, Female, Glomerular Filtration Rate, Humans, Hyperoxaluria, Primary blood, Hyperoxaluria, Primary complications, Hyperoxaluria, Primary urine, Kidney Calculi prevention & control, Male, Middle Aged, Oxalates blood, Oxalates metabolism, RNA, Small Interfering adverse effects, Young Adult, Hyperoxaluria, Primary drug therapy, Oxalates urine, RNA, Small Interfering therapeutic use, RNAi Therapeutics
- Abstract
Background: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate that leads to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an investigational RNA interference (RNAi) therapeutic agent, reduces hepatic oxalate production by targeting glycolate oxidase., Methods: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with PH1 who were 6 years of age or older to receive subcutaneous lumasiran or placebo for 6 months (with doses given at baseline and at months 1, 2, 3, and 6). The primary end point was the percent change in 24-hour urinary oxalate excretion from baseline to month 6 (mean percent change across months 3 through 6). Secondary end points included the percent change in the plasma oxalate level from baseline to month 6 (mean percent change across months 3 through 6) and the percentage of patients with 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6., Results: A total of 39 patients underwent randomization; 26 were assigned to the lumasiran group and 13 to the placebo group. The least-squares mean difference in the change in 24-hour urinary oxalate excretion (lumasiran minus placebo) was -53.5 percentage points (P<0.001), with a reduction in the lumasiran group of 65.4% and an effect seen as early as month 1. The between-group differences for all hierarchically tested secondary end points were significant. The difference in the percent change in the plasma oxalate level (lumasiran minus placebo) was -39.5 percentage points (P<0.001). In the lumasiran group, 84% of patients had 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6, as compared with 0% in the placebo group (P<0.001). Mild, transient injection-site reactions were reported in 38% of lumasiran-treated patients., Conclusions: Lumasiran reduced urinary oxalate excretion, the cause of progressive kidney failure in PH1. The majority of patients who received lumasiran had normal or near-normal levels after 6 months of treatment. (Funded by Alnylam Pharmaceuticals; ILLUMINATE-A ClinicalTrials.gov number, NCT03681184.)., (Copyright © 2021 Massachusetts Medical Society.)
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- 2021
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38. Follicular Eruption With Folliculotropic Lymphocytic Infiltrates Associated With Iatrogenic Immunosuppression: Report and Study of 3 Cases, and Review of the Literature.
- Author
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Avitan-Hersh E, Dias-Polak D, Ramon M, Sahar D, Magen D, Pollack S, and Bergman R
- Subjects
- Adolescent, Child, Humans, Iatrogenic Disease, Male, Exanthema immunology, Immunocompromised Host, Immunosuppressive Agents adverse effects
- Abstract
Background: Several cases of folliculotropic mycosis fungoides, associated with immunosuppressive therapy, including calcineurin inhibitors, have been reported in solid organ transplant patients. We have encountered 3 patients on immunosuppressive therapy who developed follicular eruptions with folliculocentric infiltrates of nonatypical lymphocytes., Objective: To characterize these follicular eruptions and review the literature., Methods: Three patients, aged 7-15 years, who were treated with systemic immunosuppressive therapy developed follicular eruptions characterized histopathologically by folliculocentric lymphocytic infiltrates. These were studied clinically, histopathologically, immunophenotypically, and molecularly for T-cell receptor (TCR) gene rearrangement., Results: All 3 cases were characterized histopathologically by folliculocentric infiltrates of nonatypical CD3 T lymphocytes with variable follicular exocytosis. Two cases also showed follicular mucinosis. Marked reduction in CD7 staining, and marked predominance of CD4 cells over CD8 cells was observed in all 3 cases. The TCR gene rearrangement studies were monoclonal in 2 cases. Oral calcineurin inhibitors (2 cyclosporine A and 1 tacrolimus) were part of the therapeutic regimen in all 3 patients. Their cessation along with local corticosteroid creams in 2 patients, and phototherapy with oral acitretin in one patient, was associated with complete clinical remission., Conclusions: Patients undergoing systemic immunosuppressive therapy that includes calcineurin inhibitors might develop follicular eruption with some immunophenotypical variations and a monoclonal TCR gene rearrangement but lack sufficient cytomorphological features of folliculotropic mycosis fungoides. Altering the immunosuppressive agent including calcineurin inhibitors may result in regression of the eruptions.
- Published
- 2020
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39. Induction of retinopathy by fibrillar oxalate assemblies.
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Zaguri D, Shaham-Niv S, Naaman E, Mimouni M, Magen D, Pollack S, Kreiser T, Leibu R, Rencus-Lazar S, Adler-Abramovich L, Perlman I, Gazit E, and Zayit-Soudry S
- Abstract
The formation of metabolite fibrillar assemblies represents a paradigm shift in the study of human metabolic disorders. Yet, direct clinical relevance has been attributed only to metabolite crystals. A notable example for metabolite crystallization is calcium oxalate crystals observed in various diseases, including primary hyperoxaluria. We unexpectedly observed retinal damage among young hyperoxaluria patients in the absence of crystals. Exploring the possible formation of alternative supramolecular organizations and their biological role, here we show that oxalate can form ordered fibrils with no associated calcium. These fibrils inflict intense retinal cytotoxicity in cultured cells. A rat model injected with oxalate fibrils recaptures patterns of retinal dysfunction observed in patients. Antibodies purified from hyperoxaluria patient sera recognize oxalate fibrils regardless of the presence of calcium. These findings highlight a new molecular basis for oxalate-associated disease, and to our knowledge provide the first direct clinical indication for the pathogenic role of metabolite fibrillar assemblies., (© 2020. The Author(s).)
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- 2020
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40. Biallelic DMXL2 mutations impair autophagy and cause Ohtahara syndrome with progressive course.
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Esposito A, Falace A, Wagner M, Gal M, Mei D, Conti V, Pisano T, Aprile D, Cerullo MS, De Fusco A, Giovedì S, Seibt A, Magen D, Polster T, Eran A, Stenton SL, Fiorillo C, Ravid S, Mayatepek E, Hafner H, Wortmann S, Levanon EY, Marini C, Mandel H, Benfenati F, Distelmaier F, Fassio A, and Guerrini R
- Subjects
- Brain diagnostic imaging, Child, Child, Preschool, Disease Progression, Electroencephalography, Female, Humans, Infant, Lysosomes physiology, Magnetic Resonance Imaging, Male, Mutation, Pedigree, Spasms, Infantile diagnostic imaging, Spasms, Infantile physiopathology, Exome Sequencing, Adaptor Proteins, Signal Transducing genetics, Autophagy genetics, Brain physiopathology, Nerve Tissue Proteins genetics, Spasms, Infantile genetics
- Abstract
Ohtahara syndrome, early infantile epileptic encephalopathy with a suppression burst EEG pattern, is an aetiologically heterogeneous condition starting in the first weeks or months of life with intractable seizures and profound developmental disability. Using whole exome sequencing, we identified biallelic DMXL2 mutations in three sibling pairs with Ohtahara syndrome, belonging to three unrelated families. Siblings in Family 1 were compound heterozygous for the c.5135C>T (p.Ala1712Val) missense substitution and the c.4478C>G (p.Ser1493*) nonsense substitution; in Family 2 were homozygous for the c.4478C>A (p.Ser1493*) nonsense substitution and in Family 3 were homozygous for the c.7518-1G>A (p.Trp2507Argfs*4) substitution. The severe developmental and epileptic encephalopathy manifested from the first day of life and was associated with deafness, mild peripheral polyneuropathy and dysmorphic features. Early brain MRI investigations in the first months of life revealed thin corpus callosum with brain hypomyelination in all. Follow-up MRI scans in three patients revealed progressive moderate brain shrinkage with leukoencephalopathy. Five patients died within the first 9 years of life and none achieved developmental, communicative or motor skills following birth. These clinical findings are consistent with a developmental brain disorder that begins in the prenatal brain, prevents neural connections from reaching the expected stages at birth, and follows a progressive course. DMXL2 is highly expressed in the brain and at synaptic terminals, regulates v-ATPase assembly and activity and participates in intracellular signalling pathways; however, its functional role is far from complete elucidation. Expression analysis in patient-derived skin fibroblasts demonstrated absence of the DMXL2 protein, revealing a loss of function phenotype. Patients' fibroblasts also exhibited an increased LysoTracker® signal associated with decreased endolysosomal markers and degradative processes. Defective endolysosomal homeostasis was accompanied by impaired autophagy, revealed by lower LC3II signal, accumulation of polyubiquitinated proteins, and autophagy receptor p62, with morphological alterations of the autolysosomal structures on electron microscopy. Altered lysosomal homeostasis and defective autophagy were recapitulated in Dmxl2-silenced mouse hippocampal neurons, which exhibited impaired neurite elongation and synaptic loss. Impaired lysosomal function and autophagy caused by biallelic DMXL2 mutations affect neuronal development and synapse formation and result in Ohtahara syndrome with profound developmental impairment and reduced life expectancy., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2019
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41. Defects in t 6 A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome.
- Author
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Arrondel C, Missoury S, Snoek R, Patat J, Menara G, Collinet B, Liger D, Durand D, Gribouval O, Boyer O, Buscara L, Martin G, Machuca E, Nevo F, Lescop E, Braun DA, Boschat AC, Sanquer S, Guerrera IC, Revy P, Parisot M, Masson C, Boddaert N, Charbit M, Decramer S, Novo R, Macher MA, Ranchin B, Bacchetta J, Laurent A, Collardeau-Frachon S, van Eerde AM, Hildebrandt F, Magen D, Antignac C, van Tilbeurgh H, and Mollet G
- Subjects
- Adenosine genetics, Child, Female, GTP-Binding Proteins chemistry, GTP-Binding Proteins metabolism, Humans, Intrinsically Disordered Proteins metabolism, Male, Multiprotein Complexes chemistry, Multiprotein Complexes genetics, Multiprotein Complexes metabolism, Mutation, Nuclear Proteins chemistry, Nuclear Proteins metabolism, RNA-Binding Proteins chemistry, RNA-Binding Proteins metabolism, Adenosine analogs & derivatives, GTP-Binding Proteins genetics, Hernia, Hiatal genetics, Intrinsically Disordered Proteins genetics, Microcephaly genetics, Nephrosis genetics, Nuclear Proteins genetics, RNA, Transfer genetics, RNA-Binding Proteins genetics
- Abstract
N
6 -threonyl-carbamoylation of adenosine 37 of ANN-type tRNAs (t6 A) is a universal modification essential for translational accuracy and efficiency. The t6 A pathway uses two sequentially acting enzymes, YRDC and OSGEP, the latter being a subunit of the multiprotein KEOPS complex. We recently identified mutations in genes encoding four out of the five KEOPS subunits in children with Galloway-Mowat syndrome (GAMOS), a clinically heterogeneous autosomal recessive disease characterized by early-onset steroid-resistant nephrotic syndrome and microcephaly. Here we show that mutations in YRDC cause an extremely severe form of GAMOS whereas mutations in GON7, encoding the fifth KEOPS subunit, lead to a milder form of the disease. The crystal structure of the GON7/LAGE3/OSGEP subcomplex shows that the intrinsically disordered GON7 protein becomes partially structured upon binding to LAGE3. The structure and cellular characterization of GON7 suggest its involvement in the cellular stability and quaternary arrangement of the KEOPS complex.- Published
- 2019
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42. Clinical Heterogeneity and Phenotypic Expansion of NaPi-IIa-Associated Disease.
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Demir K, Yildiz M, Bahat H, Goldman M, Hassan N, Tzur S, Ofir A, and Magen D
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- Endoplasmic Reticulum pathology, Exome genetics, Fanconi Anemia pathology, Gene Duplication, Haplotypes, Humans, Infant, Kidney Diseases complications, Male, Mutation genetics, Pedigree, Phenotype, Proteasome Endopeptidase Complex, Renal Insufficiency, Chronic pathology, Fanconi Syndrome genetics, Hypercalcemia genetics, Sodium-Phosphate Cotransporter Proteins, Type IIa genetics
- Abstract
Context: NaPi-IIa, encoded by SLC34A1, is a key phosphate transporter in the mammalian proximal tubule and plays a cardinal role in renal phosphate handling. NaPi-IIa impairment has been linked to various overlapping clinical syndromes, including hypophosphatemic nephrolithiasis with osteoporosis, renal Fanconi syndrome with chronic kidney disease, and, most recently, idiopathic infantile hypercalcemia and nephrocalcinosis., Objectives: We studied the molecular basis of idiopathic infantile hypercalcemia with partial proximal tubulopathy in two apparently unrelated patients of Israeli and Turkish descent., Design: Genetic analysis in two affected children and their close relatives was performed using whole-exome sequencing, followed by in vitro localization and trafficking analysis of mutant NaPi-IIa., Results: Mutation and haplotype analyses in both patients revealed a previously described homozygous loss-of-function inserted duplication (p.I154_V160dup) in NaPi-IIa, which is inherited identical-by-descent from a common ancestor. The shared mutation was originally reported by our team in two adult siblings with renal Fanconi syndrome, hypophosphatemic bone disease, and progressive renal failure who are family members of one of the infants reported herein. In vitro localization assays and biochemical analysis of p.I154_V160dup and of additional NaPi-IIa mutants harboring a trafficking defect indicate aberrant retention at the endoplasmic reticulum in an immature and underglycosylated state, leading to premature proteasomal degradation., Conclusions: Our findings expand the phenotypic spectrum of NaPi-IIa disruption, reinforce its link with proximal tubular impairment, enable longitudinal study of the natural history of the disease, and shed light on cellular pathways associated with loss of function and impaired trafficking of NaPi-IIa mutants., (Copyright © 2017 Endocrine Society)
- Published
- 2017
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43. [GENETIC DISORDERS OF RENAL PHOSPHATE HANDLING].
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Magen D
- Subjects
- Fibroblast Growth Factor-23, Genetic Markers genetics, Genetic Predisposition to Disease, Humans, Kidney, Kidney Tubules, Proximal, Parathyroid Hormone, Kidney Diseases genetics, Kidney Diseases metabolism, Phosphates metabolism
- Abstract
Introduction: Hereditary disorders of renal phosphate handling comprise a diverse group of genetic diseases, usually characterized by excessive urinary phosphate wasting and a negative phosphate balance. In the minority of cases, perturbations of renal phosphate handling are associated with excessive urinary phosphate reabsorption, leading to pathological hyperphosphatemia. Inorganic phosphate is an essential mineral in the human body, playing a crucial role in cellular metabolism and skeletal mineralization. Whole body phosphate balance is maintained by a highly controlled equilibrium between intestinal uptake, skeletal deposition and renal excretion. The human kidney plays a crucial role in phosphate homeostasis. The bulk filtered phosphate is reabsorbed in the renal proximal tubule by two specialized phosphate transporters, NaPi-IIa and NaPi-IIc. Phosphate balance is regulated by dietary phosphate intake, and by the action of the parathyroid hormone, vitamin D3 and fibroblast growth factor-23 (FGF-23). All these regulators exert their effect by modulating the activity of the proximal-tubular phosphate transporters, NaPi-IIa and NaPi-IIc. Based on the versatile molecular mechanism underlying various renal phosphate wasting disorders, these diseases can be divided into three main subgroups: (1) primary impairment of proximal tubular phosphate transporters; (2) disorders of FGF-23 metabolism; (3) generalized dysfunction of the proximal tubule, also known as renal Fanconi syndrome. The clinical similarity between various renal phosphate wasting disorders, combined with their rarity, pose a diagnostic and therapeutic challenge. Recent advancement in molecular biology has led to the identification of the genetic basis of many disorders in this group, has improved our understanding of underlying disease mechanisms, and enables accurate genetic diagnosis. Nevertheless, the current therapy of most renal phosphate wasting disorders is mainly supportive, with limited capacity to change their natural course.
- Published
- 2017
44. Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly.
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Braun DA, Rao J, Mollet G, Schapiro D, Daugeron MC, Tan W, Gribouval O, Boyer O, Revy P, Jobst-Schwan T, Schmidt JM, Lawson JA, Schanze D, Ashraf S, Ullmann JFP, Hoogstraten CA, Boddaert N, Collinet B, Martin G, Liger D, Lovric S, Furlano M, Guerrera IC, Sanchez-Ferras O, Hu JF, Boschat AC, Sanquer S, Menten B, Vergult S, De Rocker N, Airik M, Hermle T, Shril S, Widmeier E, Gee HY, Choi WI, Sadowski CE, Pabst WL, Warejko JK, Daga A, Basta T, Matejas V, Scharmann K, Kienast SD, Behnam B, Beeson B, Begtrup A, Bruce M, Ch'ng GS, Lin SP, Chang JH, Chen CH, Cho MT, Gaffney PM, Gipson PE, Hsu CH, Kari JA, Ke YY, Kiraly-Borri C, Lai WM, Lemyre E, Littlejohn RO, Masri A, Moghtaderi M, Nakamura K, Ozaltin F, Praet M, Prasad C, Prytula A, Roeder ER, Rump P, Schnur RE, Shiihara T, Sinha MD, Soliman NA, Soulami K, Sweetser DA, Tsai WH, Tsai JD, Topaloglu R, Vester U, Viskochil DH, Vatanavicharn N, Waxler JL, Wierenga KJ, Wolf MTF, Wong SN, Leidel SA, Truglio G, Dedon PC, Poduri A, Mane S, Lifton RP, Bouchard M, Kannu P, Chitayat D, Magen D, Callewaert B, van Tilbeurgh H, Zenker M, Antignac C, and Hildebrandt F
- Subjects
- Animals, Apoptosis genetics, CRISPR-Cas Systems, Carrier Proteins genetics, Cell Movement, Cytoskeleton ultrastructure, DNA Repair genetics, Endoplasmic Reticulum Stress genetics, Gene Knockout Techniques, Humans, Intracellular Signaling Peptides and Proteins deficiency, Intracellular Signaling Peptides and Proteins genetics, Metalloendopeptidases deficiency, Metalloendopeptidases genetics, Mice, Models, Molecular, Nephrotic Syndrome genetics, Nephrotic Syndrome pathology, Podocytes metabolism, Podocytes ultrastructure, Protein Conformation, Protein Serine-Threonine Kinases deficiency, Protein Serine-Threonine Kinases genetics, RNA Processing, Post-Transcriptional genetics, RNA, Transfer metabolism, Telomere Homeostasis genetics, Zebrafish, Zebrafish Proteins deficiency, Zebrafish Proteins genetics, Hernia, Hiatal genetics, Microcephaly genetics, Multiprotein Complexes genetics, Mutation, Nephrosis genetics
- Abstract
Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.
- Published
- 2017
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45. A Dominant Mutation in Nuclear Receptor Interacting Protein 1 Causes Urinary Tract Malformations via Dysregulation of Retinoic Acid Signaling.
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Vivante A, Mann N, Yonath H, Weiss AC, Getwan M, Kaminski MM, Bohnenpoll T, Teyssier C, Chen J, Shril S, van der Ven AT, Ityel H, Schmidt JM, Widmeier E, Bauer SB, Sanna-Cherchi S, Gharavi AG, Lu W, Magen D, Shukrun R, Lifton RP, Tasic V, Stanescu HC, Cavaillès V, Kleta R, Anikster Y, Dekel B, Kispert A, Lienkamp SS, and Hildebrandt F
- Subjects
- Animals, Mice, Nuclear Receptor Interacting Protein 1, Adaptor Proteins, Signal Transducing genetics, Mutation, Nuclear Proteins genetics, Signal Transduction genetics, Tretinoin physiology, Urinary Tract abnormalities
- Abstract
Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of CKD in the first three decades of life. However, for most patients with CAKUT, the causative mutation remains unknown. We identified a kindred with an autosomal dominant form of CAKUT. By whole-exome sequencing, we identified a heterozygous truncating mutation (c.279delG, p.Trp93fs*) of the nuclear receptor interacting protein 1 gene ( NRIP1 ) in all seven affected members. NRIP1 encodes a nuclear receptor transcriptional cofactor that directly interacts with the retinoic acid receptors (RARs) to modulate retinoic acid transcriptional activity. Unlike wild-type NRIP1, the altered NRIP1 protein did not translocate to the nucleus, did not interact with RAR α , and failed to inhibit retinoic acid-dependent transcriptional activity upon expression in HEK293 cells. Notably, we also showed that treatment with retinoic acid enhanced NRIP1 binding to RAR α RNA in situ hybridization confirmed Nrip1 expression in the developing urogenital system of the mouse. In explant cultures of embryonic kidney rudiments, retinoic acid stimulated Nrip1 expression, whereas a pan-RAR antagonist strongly reduced it. Furthermore, mice heterozygous for a null allele of Nrip1 showed a CAKUT-spectrum phenotype. Finally, expression and knockdown experiments in Xenopus laevis confirmed an evolutionarily conserved role for NRIP1 in renal development. These data indicate that dominant NRIP1 mutations can cause CAKUT by interference with retinoic acid transcriptional signaling, shedding light on the well documented association between abnormal vitamin A levels and renal malformations in humans, and suggest a possible gene-environment pathomechanism in this disease., (Copyright © 2017 by the American Society of Nephrology.)
- Published
- 2017
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46. Loss of CD55 in Eculizumab-Responsive Protein-Losing Enteropathy.
- Author
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Kurolap A, Eshach-Adiv O, Hershkovitz T, Paperna T, Mory A, Oz-Levi D, Zohar Y, Mandel H, Chezar J, Azoulay D, Peleg S, Half EE, Yahalom V, Finkel L, Weissbrod O, Geiger D, Tabib A, Shaoul R, Magen D, Bonstein L, Mevorach D, and Baris HN
- Subjects
- Child, Child, Preschool, Compassionate Use Trials, Complement Activation, Complement Membrane Attack Complex metabolism, Diarrhea etiology, Female, Humans, Male, Middle Aged, Pedigree, Sequence Analysis, DNA, Serum Albumin metabolism, Young Adult, Antibodies, Monoclonal, Humanized therapeutic use, CD55 Antigens genetics, Frameshift Mutation, Protein-Losing Enteropathies drug therapy, Protein-Losing Enteropathies genetics
- Published
- 2017
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47. APOL1-Mediated Cell Injury Involves Disruption of Conserved Trafficking Processes.
- Author
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Kruzel-Davila E, Shemer R, Ofir A, Bavli-Kertselli I, Darlyuk-Saadon I, Oren-Giladi P, Wasser WG, Magen D, Zaknoun E, Schuldiner M, Salzberg A, Kornitzer D, Marelja Z, Simons M, and Skorecki K
- Subjects
- Alleles, Animals, Apolipoprotein L1, Apolipoproteins genetics, Drosophila melanogaster cytology, Humans, Hydrogen-Ion Concentration, Lipoproteins, HDL genetics, Protein Transport, Saccharomyces cerevisiae cytology, Apolipoproteins metabolism, Apolipoproteins physiology, Cell Death physiology, Lipoproteins, HDL metabolism, Lipoproteins, HDL physiology
- Abstract
APOL1 harbors C-terminal sequence variants (G1 and G2), which account for much of the increased risk for kidney disease in sub-Saharan African ancestry populations. Expression of the risk variants has also been shown to cause injury to podocytes and other cell types, but the underlying mechanisms are not understood. We used Drosophila melanogaster and Saccharomyces cerevisiae to help clarify these mechanisms. Ubiquitous expression of the human APOL1 G1 and G2 disease risk alleles caused near-complete lethality in D. melanogaster , with no effect of the G0 nonrisk APOL1 allele, corresponding to the pattern of human disease risk. We also observed a congruent pattern of cellular damage with tissue-specific expression of APOL1. In particular, expression of APOL1 risk variants in D. melanogaster nephrocytes caused cell-autonomous accumulation of the endocytic tracer atrial natriuretic factor-red fluorescent protein at early stages and nephrocyte loss at later stages. We also observed differential toxicity of the APOL1 risk variants compared with the APOL1 nonrisk variants in S. cerevisiae , including impairment of vacuole acidification. Yeast strains defective in endosomal trafficking or organelle acidification but not those defective in autophagy displayed augmented APOL1 toxicity with all isoforms. This pattern of differential injury by the APOL1 risk alleles compared with the nonrisk alleles across evolutionarily divergent species is consistent with an impairment of conserved core intracellular endosomal trafficking processes. This finding should facilitate the identification of cell injury pathways and corresponding therapeutic targets of interest in these amenable experimental platforms., (Copyright © 2017 by the American Society of Nephrology.)
- Published
- 2017
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48. A novel homozygous splice site mutation in NALCN identified in siblings with cachexia, strabismus, severe intellectual disability, epilepsy and abnormal respiratory rhythm.
- Author
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Gal M, Magen D, Zahran Y, Ravid S, Eran A, Khayat M, Gafni C, Levanon EY, and Mandel H
- Subjects
- Animals, Cachexia pathology, Epilepsy genetics, Epilepsy pathology, Female, Homozygote, Humans, Infant, Intellectual Disability pathology, Ion Channels, Male, Membrane Proteins, Mice, Mice, Knockout, Mutation, Pedigree, RNA Splice Sites genetics, Seizures pathology, Siblings, Strabismus genetics, Strabismus pathology, Cachexia genetics, Intellectual Disability genetics, Seizures genetics, Sodium Channels genetics
- Abstract
We studied three siblings, born to consanguineous parents who presented with severe intellectual disability, cachexia, strabismus, seizures and episodes of abnormal respiratory rhythm. Whole exome sequencing led to identification of a novel homozygous splice site mutation, IVS29-1G > A in the NALCN gene, that resulted in aberrant transcript in the patients. NALCN encodes a voltage-independent cation channel, involved in regulation of neuronal excitability. Three homozygous mutations in the NALCN gene were previously identified in only eight patients with severe hypotonia, speech impairment, cognitive delay, constipation and Infantile-Neuroaxonal-dystrophy- like symptoms. Our patients broaden the clinical spectrum associated with recessive mutations in NALCN, featuring also disrupted respiratory rhythm mimicking homozygous Nalcn knockout mice., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)
- Published
- 2016
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49. Long-term hemodialysis therapy in neonates and infants with end-stage renal disease: a 16-year experience and outcome.
- Author
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Pollack S, Eisenstein I, Tarabeih M, Shasha-Lavski H, Magen D, and Zelikovic I
- Subjects
- Catheter-Related Infections etiology, Catheter-Related Infections mortality, Catheterization, Central Venous, Central Venous Catheters, Female, Humans, Infant, Infant, Newborn, Kidney Failure, Chronic mortality, Male, Renal Dialysis adverse effects, Survival Rate, Treatment Outcome, Kidney Failure, Chronic therapy, Renal Dialysis methods
- Abstract
Background: Peritoneal dialysis is the preferred mode of renal replacement therapy in infants with end-stage renal disease (ESRD). Hemodialysis (HD) is seldom used in neonates and infants due to the risk of major complications in the very young., Methods: Demographic, clinical, laboratory, and imaging data on all infants younger than 12 months with ESRD who received HD in our Pediatric Dialysis Unit between January 1997 and June 2013 were analyzed., Results: Eighteen infants (n = 6 male) with ESRD (median age 3 months; median weight 4.06 kg) received HD through a central venous catheter (CVC) for a total of 543 months (median duration per infant 16 months). Seven of the infants (39%) were neonates, and five (28%) had serious comorbidities. There were five episodes of CVC infection, which is a rate of 0.3/1000 CVC days. Median catheter survival time was 320 days. Most infants had good oral intake, and only four (22%) required a gastric tube; 14 (78%) infants displayed normal growth. Fourteen (78%) infants had hypertension, of whom four (22%) had severe cardiac complications; eight (44%) showed delayed psychomotor development. Eleven (61%) of the infants, including six (86%) of the neonates, survived. Five (28%) infants underwent renal transplantation; 10-year graft survival was 80%., Conclusions: Based on these results, long-term HD in neonates and infants with ESRD is technically feasible, can be implemented without major complications, carries a very low rate of CVC infection and malfunction, and results in adequate nutrition, good growth, as well as good kidney graft and patient survivals. Future efforts should aim to prevent hypertension and its cardiac sequelae, improve neurodevelopmental outcome, and lower mortality rate in these infants.
- Published
- 2016
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50. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with a loss-of-function mutation in CDK5.
- Author
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Magen D, Ofir A, Berger L, Goldsher D, Eran A, Katib N, Nijem Y, Vlodavsky E, Tzur S, Behar DM, Fellig Y, and Mandel H
- Subjects
- Base Sequence, Cells, Cultured, Cerebellum enzymology, Consanguinity, DNA Mutational Analysis, Developmental Disabilities enzymology, Developmental Disabilities genetics, Female, Genes, Recessive, Genetic Association Studies, Genetic Complementation Test, Homozygote, Humans, Infant, Infant, Newborn, Lissencephaly enzymology, Male, Mutation, Missense, Nervous System Malformations enzymology, Pedigree, Cerebellum abnormalities, Cyclin-Dependent Kinase 5 genetics, Lissencephaly genetics, Nervous System Malformations genetics
- Abstract
Lissencephaly comprises a heterogeneous group of developmental brain disorders of varying severity, involving abnormal cortical gyration. We studied a highly consanguineous Israeli Moslem family with a lethal form of autosomal recessive lissencephaly with cerebellar hypoplasia (LCH). Using microarray-based homozygosity mapping in the reported family, combined with whole exome sequencing in one affected infant, we identified a homozygous splice site mutation g.IVS8+1G>A in cyclin-dependent kinase 5 (CDK5), causing complete skipping of exon 8, and leading to a frame shift and premature stop codon (p.V162SfsX19). The mutation co-segregated with the disease phenotype in all 29 study participants (4 patients and 25 healthy relatives), and was not identified in 200 ethnically matched control chromosomes. The p.V162SfsX19 mutation causes lack of endogenous CDK5 expression in affected dermal fibroblasts and brain tissue at the mRNA and protein levels, consistent with nonsense-mediated mRNA decay. Functional analysis of the p.V162SfsX19 mutation, using a yeast complementation assay, showed loss-of-function of the mutant CDK5 gene product, thereby implicating its role in the pathogenesis of autosomal recessive LCH in the studied family.
- Published
- 2015
- Full Text
- View/download PDF
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