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6. Three years pilot of spinal muscular atrophy newborn screening turned into official program in Southern Belgium

Author

Boemer, François, Caberg, Jean-Hubert, Beckers, Pablo, Dideberg, Vinciane, di Fiore, Samantha, Bours, Vincent, Marie, Sandrine, Dewulf, Joseph, Marcelis, Lionel, Deconinck, Nicolas, Daron, Aurore, Blasco-Perez, Laura, Tizzano, Eduardo, Hiligsmann, Mickaël, Lombet, Jacques, Pereira, Tatiana, Lopez-Granados, Lucia, Shalchian-Tehran, Sarvnaz, van Assche, Véronique, Willems, Arabelle, Huybrechts, Sofie, Mast, Bénédicte, van Olden, Rudolf, Dangouloff, Tamara, and Servais, Laurent

Published
2021
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8. Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria

Author

Lucienne, Marie, primary, Gerlini, Raffaele, additional, Rathkolb, Birgit, additional, Calzada-Wack, Julia, additional, Forny, Patrick, additional, Wueest, Stephan, additional, Kaech, Andres, additional, Traversi, Florian, additional, Forny, Merima, additional, Bürer, Céline, additional, Aguilar-Pimentel, Antonio, additional, Irmler, Martin, additional, Beckers, Johannes, additional, Sauer, Sven, additional, Kölker, Stefan, additional, Dewulf, Joseph P, additional, Bommer, Guido T, additional, Hoces, Daniel, additional, Gailus-Durner, Valerie, additional, Fuchs, Helmut, additional, Rozman, Jan, additional, Froese, D Sean, additional, Baumgartner, Matthias R, additional, and de Angelis, Martin Hrabě, additional

Published
2023
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9. C2orf69 mutations disrupt mitochondrial function and cause a multisystem human disorder with recurring autoinflammation

Author

Lausberg, Eva, Gieftelmann, Sebastian, Dewulf, Joseph P., Wiame, Elsa, Holz, Anja, Salvarinova, Ramona, van Karnebeek, Clara D., Klemm, Patricia, Ohl, Kim, Mull, Michael, and Braunschweig, Till

Subjects
Gene mutations -- Research, Genetic research, Inflammation -- Genetic aspects -- Causes of, Metabolism, Inborn errors of -- Genetic aspects -- Causes of, Mitochondrial diseases -- Genetic aspects -- Causes of, Autoimmune diseases -- Genetic aspects -- Causes of, Health care industry
Abstract

BACKGROUND. Deciphering the function of the many genes previously classified as uncharacterized open reading frame (ORF) would complete our understanding of a cell's function and its pathophysiology. METHODS. Whole-exome sequencing, yeast 2-hybrid and transcriptome analyses, and molecular characterization were performed in this study to uncover the function of the C2orf69 gene. RESULTS. We identified loss-of-function mutations in the uncharacterized C2orf69 gene in 8 individuals with brain abnormalities involving hypomyelination and microcephaly, liver dysfunction, and recurrent autoinflammation. C2orf69 contains an N-terminal signal peptide that is required and sufficient for mitochondrial localization. Consistent with mitochondrial dysfunction, the patients showed signs of respiratory chain defects, and a CRISPR/Cas9-KO cell model of C2orf69 had similar respiratory chain defects. Patient-derived cells revealed alterations in immunological signaling pathways. Deposits of periodic acid-Schiff-positive (PAS-positive) material in tissues from affected individuals, together with decreased glycogen branching enzyme 1 (GBE1) activity, indicated an additional impact of C2orf69 on glycogen metabolism. CONCLUSIONS. Our study identifies C2orf69 as an important regulator of human mitochondrial function and suggests that this gene has additional influence on other metabolic pathways., Introduction Inborn errors of metabolism (IEMs) are a genetically heterogeneous group of more than 1000 diseases (1). They result from metabolic defects due to a deficiency of enzymes, membrane transporters, [...]

Published
2021
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10. Expanding the spectrum of clinical severity of AICA-ribosiduria: Report of two siblings with mild phenotype causedby a novel pathogenic variant in ATIC gene

Author

UCL - (SLuc) Service de biochimie médicale, Galli, Jessica, Valente, Enza Maria, Dewulf, Joseph P, Franzoni, Alessandra, Marie, Sandrine, Plumari, Massimo, Zanetti, Federica, Fazzi, Elisa, UCL - (SLuc) Service de biochimie médicale, Galli, Jessica, Valente, Enza Maria, Dewulf, Joseph P, Franzoni, Alessandra, Marie, Sandrine, Plumari, Massimo, Zanetti, Federica, and Fazzi, Elisa

Published
2023

11. Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria

Author

Lucienne, Marie, Gerlini, Raffaele, Rathkolb, Birgit, Calzada-Wack, Julia, Forny, Patrick, Wueest, Stephan, Kaech, Andres, Traversi, Florian, Forny, Merima, Bürer, Céline, Aguilar-Pimentel, Antonio, Irmler, Martin, Beckers, Johannes, Sauer, Sven, Kölker, Stefan, Dewulf, Joseph P, Bommer, Guido T, Hoces, Daniel, Gailus-Durner, Valerie, Fuchs, Helmut, Rozman, Jan, Froese, D Sean; https://orcid.org/0000-0003-1557-3517, Baumgartner, Matthias R, de Angelis, Martin Hrabě, Lucienne, Marie, Gerlini, Raffaele, Rathkolb, Birgit, Calzada-Wack, Julia, Forny, Patrick, Wueest, Stephan, Kaech, Andres, Traversi, Florian, Forny, Merima, Bürer, Céline, Aguilar-Pimentel, Antonio, Irmler, Martin, Beckers, Johannes, Sauer, Sven, Kölker, Stefan, Dewulf, Joseph P, Bommer, Guido T, Hoces, Daniel, Gailus-Durner, Valerie, Fuchs, Helmut, Rozman, Jan, Froese, D Sean; https://orcid.org/0000-0003-1557-3517, Baumgartner, Matthias R, and de Angelis, Martin Hrabě

Abstract

Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria, present unique challenges to energetic homeostasis by disrupting energy-producing pathways. To better understand global responses to energy shortage, we investigated a hemizygous mouse model of methylmalonyl-CoA mutase (Mmut)–type methylmalonic aciduria. We found Mmut mutant mice to have reduced appetite, energy expenditure and body mass compared with littermate controls, along with a relative reduction in lean mass but increase in fat mass. Brown adipose tissue showed a process of whitening, in line with lower body surface temperature and lesser ability to cope with cold challenge. Mutant mice had dysregulated plasma glucose, delayed glucose clearance and a lesser ability to regulate energy sources when switching from the fed to fasted state, while liver investigations indicated metabolite accumulation and altered expression of peroxisome proliferator–activated receptor and Fgf21-controlled pathways. Together, these shed light on the mechanisms and adaptations behind energy imbalance in methylmalonic aciduria and provide insight into metabolic responses to chronic energy shortage, which may have important implications for disease understanding and patient management.

Published
2023

14. HYGIEIA: HYpothesizing the Genesis of Infectious Diseases and Epidemics through an Integrated Systems Biology Approach

Author

Ward, Bradley, primary, Yombi, Jean Cyr, additional, Balligand, Jean-Luc, additional, Cani, Patrice D., additional, Collet, Jean-François, additional, de Greef, Julien, additional, Dewulf, Joseph P., additional, Gatto, Laurent, additional, Haufroid, Vincent, additional, Jodogne, Sébastien, additional, Kabamba, Benoît, additional, Pyr dit Ruys, Sébastien, additional, Vertommen, Didier, additional, Elens, Laure, additional, and Belkhir, Leïla, additional

Published
2022
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16. Multisystem involvement, defective lysosomes and impaired autophagy in a novel rat model of nephropathic cystinosis

Author

UCL - SSS/IREC/NEFR - Pôle de Néphrologie, Krohn, Patrick, Rega, Laura Rita, Harvent, Marianne, Festa, Beatrice Paola, Taranta, Anna, Luciani, Alessandro, Dewulf, Joseph P., Cremonesi, Alessio, Camassei, Francesca Diomedi, Hanson, James V M, Gerth-Kahlert, Christina, Emma, Francesco, Berquez, Marine, Devuyst, Olivier, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, Krohn, Patrick, Rega, Laura Rita, Harvent, Marianne, Festa, Beatrice Paola, Taranta, Anna, Luciani, Alessandro, Dewulf, Joseph P., Cremonesi, Alessio, Camassei, Francesca Diomedi, Hanson, James V M, Gerth-Kahlert, Christina, Emma, Francesco, Berquez, Marine, and Devuyst, Olivier

Published
2022

18. Disorders of purine biosynthesis metabolism.

Author

UCL - SSS/DDUV - Institut de Duve, UCL - (SLuc) Service de biochimie médicale, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Centre de malformations vasculaires congénitales, UCL - (SLuc) Centre de référence en lésions congénitales de la moëlle épinière, UCL - (SLuc) Centre de référence pour l'épilepsie réfractaire, UCL - (SLuc) Service de neurologie pédiatrique, Dewulf, Joseph P., Marie, Sandrine, Nassogne, Marie-Cécile, UCL - SSS/DDUV - Institut de Duve, UCL - (SLuc) Service de biochimie médicale, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Centre de malformations vasculaires congénitales, UCL - (SLuc) Centre de référence en lésions congénitales de la moëlle épinière, UCL - (SLuc) Centre de référence pour l'épilepsie réfractaire, UCL - (SLuc) Service de neurologie pédiatrique, Dewulf, Joseph P., Marie, Sandrine, and Nassogne, Marie-Cécile

Abstract

Purines are essential molecules that are components of vital biomolecules, such as nucleic acids, coenzymes, signaling molecules, as well as energy transfer molecules. The de novo biosynthesis pathway starts from phosphoribosylpyrophosphate (PRPP) and eventually leads to the synthesis of inosine monophosphate (IMP) by means of 10 sequential steps catalyzed by six different enzymes, three of which are bi-or tri-functional in nature. IMP is then converted into guanosine monophosphate (GMP) or adenosine monophosphate (AMP), which are further phosphorylated into nucleoside di- or tri-phosphates, such as GDP, GTP, ADP and ATP. This review provides an overview of inborn errors of metabolism pertaining to purine synthesis in humans, including either phosphoribosylpyrophosphate synthetase (PRS) overactivity or deficiency, as well as adenylosuccinate lyase (ADSL), 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), and adenylosuccinate synthetase (ADSS) deficiencies. ITPase deficiency is being described as well. The clinical spectrum of these disorders is broad, including neurological impairment, such as psychomotor retardation, epilepsy, hypotonia, or microcephaly; sensory involvement, such as deafness and visual disturbances; multiple malformations, as well as muscle presentations or consequences of hyperuricemia, such as gouty arthritis or kidney stones. Clinical signs are often nonspecific and, thus, overlooked. It is to be hoped that this is likely to be gradually overcome by using sensitive biochemical investigations and next-generation sequencing technologies.

Published
2021

19. C2orf69 mutations disrupt mitochondrial function and cause a multisystem human disorder with recurring autoinflammation

Author

UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, UCL - (SLuc) Service de biochimie médicale, Lausberg, Eva, Gießelmann, Sebastian, Dewulf, Joseph P., Wiame, Elsa, Holz, Anja, Salvarinova, Ramona, van Karnebeek, Clara D., Klemm, Patricia, Ohl, Kim, Mull, Michael, Braunschweig, Till, Weis, Joachim, Sommer, Clemens J., Demuth, Stephanie, Haase, Claudia, Stollbrink-Peschgens, Claudia, Debray, François-Guillaume, Libioulle, Cecile, Choukair, Daniela, Oommen, Prasad T., Borkhardt, Arndt, Surowy, Harald, Wieczorek, Dagmar, Wagner, Norbert, Meyer, Robert, Eggermann, Thomas, Begemann, Matthias, Van Schaftingen, Emile, Häusler, Martin, Tenbrock, Klaus, van den Heuvel, Lambert, Elbracht, Miriam, Kurth, Ingo, Kraft, Florian, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, UCL - (SLuc) Service de biochimie médicale, Lausberg, Eva, Gießelmann, Sebastian, Dewulf, Joseph P., Wiame, Elsa, Holz, Anja, Salvarinova, Ramona, van Karnebeek, Clara D., Klemm, Patricia, Ohl, Kim, Mull, Michael, Braunschweig, Till, Weis, Joachim, Sommer, Clemens J., Demuth, Stephanie, Haase, Claudia, Stollbrink-Peschgens, Claudia, Debray, François-Guillaume, Libioulle, Cecile, Choukair, Daniela, Oommen, Prasad T., Borkhardt, Arndt, Surowy, Harald, Wieczorek, Dagmar, Wagner, Norbert, Meyer, Robert, Eggermann, Thomas, Begemann, Matthias, Van Schaftingen, Emile, Häusler, Martin, Tenbrock, Klaus, van den Heuvel, Lambert, Elbracht, Miriam, Kurth, Ingo, and Kraft, Florian

Abstract

BACKGROUNDDeciphering the function of the many genes previously classified as uncharacterized open reading frame (ORF) would complete our understanding of a cell's function and its pathophysiology.METHODSWhole-exome sequencing, yeast 2-hybrid and transcriptome analyses, and molecular characterization were performed in this study to uncover the function of the C2orf69 gene.RESULTSWe identified loss-of-function mutations in the uncharacterized C2orf69 gene in 8 individuals with brain abnormalities involving hypomyelination and microcephaly, liver dysfunction, and recurrent autoinflammation. C2orf69 contains an N-terminal signal peptide that is required and sufficient for mitochondrial localization. Consistent with mitochondrial dysfunction, the patients showed signs of respiratory chain defects, and a CRISPR/Cas9-KO cell model of C2orf69 had similar respiratory chain defects. Patient-derived cells revealed alterations in immunological signaling pathways. Deposits of periodic acid-Schiff-positive (PAS-positive) material in tissues from affected individuals, together with decreased glycogen branching enzyme 1 (GBE1) activity, indicated an additional impact of C2orf69 on glycogen metabolism.CONCLUSIONSOur study identifies C2orf69 as an important regulator of human mitochondrial function and suggests that this gene has additional influence on other metabolic pathways.

Published
2021

20. A fortuitous but characteristic blood smear observation allowing a late diagnosis of MPS-VII

Author

UCL - (SLuc) Service de biochimie médicale, Goudji, Cedrick W., Schick, Tobias, Cherkaoui, Sara, Camaiani, Massimo, Dewulf, Joseph P., Nassogne, Marie-Cecile, Chevalier, Charles, UCL - (SLuc) Service de biochimie médicale, Goudji, Cedrick W., Schick, Tobias, Cherkaoui, Sara, Camaiani, Massimo, Dewulf, Joseph P., Nassogne, Marie-Cecile, and Chevalier, Charles

Published
2021

21. Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria

Author

Lucienne, Marie, Gerlini, Raffaele; https://orcid.org/0000-0003-0852-5621, Rathkolb, Birgit; https://orcid.org/0000-0003-1239-0547, Calzada-Wack, Julia; https://orcid.org/0000-0003-0816-9305, Forny, Patrick; https://orcid.org/0000-0003-1877-2976, Wueest, Stephan, Kaech, Andres; https://orcid.org/0000-0002-7035-9858, Traversi, Florian, Forny, Merima, Bürer, Céline, Aguilar-Pimentel, Antonio; https://orcid.org/0000-0002-4694-7107, Irmler, Martin; https://orcid.org/0000-0003-3169-479X, Beckers, Johannes, Sauer, Sven; https://orcid.org/0000-0001-9383-5311, Kölker, Stefan, Dewulf, Joseph P; https://orcid.org/0000-0001-7223-2706, Bommer, Guido T; https://orcid.org/0000-0001-6898-4884, Hoces, Daniel; https://orcid.org/0000-0002-1451-5166, Gailus-Durner, Valerie; https://orcid.org/0000-0002-6076-0111, Fuchs, Helmut; https://orcid.org/0000-0002-5143-2677, Rozman, Jan; https://orcid.org/0000-0002-8035-8904, Froese, D Sean; https://orcid.org/0000-0003-1557-3517, Baumgartner, Matthias R; https://orcid.org/0000-0002-9270-0826, de Angelis, Martin Hrabě; https://orcid.org/0000-0002-7898-2353, Lucienne, Marie, Gerlini, Raffaele; https://orcid.org/0000-0003-0852-5621, Rathkolb, Birgit; https://orcid.org/0000-0003-1239-0547, Calzada-Wack, Julia; https://orcid.org/0000-0003-0816-9305, Forny, Patrick; https://orcid.org/0000-0003-1877-2976, Wueest, Stephan, Kaech, Andres; https://orcid.org/0000-0002-7035-9858, Traversi, Florian, Forny, Merima, Bürer, Céline, Aguilar-Pimentel, Antonio; https://orcid.org/0000-0002-4694-7107, Irmler, Martin; https://orcid.org/0000-0003-3169-479X, Beckers, Johannes, Sauer, Sven; https://orcid.org/0000-0001-9383-5311, Kölker, Stefan, Dewulf, Joseph P; https://orcid.org/0000-0001-7223-2706, Bommer, Guido T; https://orcid.org/0000-0001-6898-4884, Hoces, Daniel; https://orcid.org/0000-0002-1451-5166, Gailus-Durner, Valerie; https://orcid.org/0000-0002-6076-0111, Fuchs, Helmut; https://orcid.org/0000-0002-5143-2677, Rozman, Jan; https://orcid.org/0000-0002-8035-8904, Froese, D Sean; https://orcid.org/0000-0003-1557-3517, Baumgartner, Matthias R; https://orcid.org/0000-0002-9270-0826, and de Angelis, Martin Hrabě; https://orcid.org/0000-0002-7898-2353

Abstract

Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria (MMAuria), present unique challenges to energetic homeostasis by disrupting energy producing pathways. To better understand global responses to energy shortage, we investigated a hemizygous mouse model of methylmalonyl-CoA mutase (Mmut) type MMAuria. We found Mmut mutant mice to have reduced appetite, energy expenditure and body mass compared to littermate controls, along with a relative reduction in lean mass but increase in fat mass. Brown adipose tissue showed a process of whitening, in line with lower body surface temperature and lesser ability to cope with cold challenge. Mutant mice had dysregulated plasma glucose, delayed glucose clearance and a lesser ability to regulate energy sources when switching from the fed to fasted state, while liver investigations indicated metabolite accumulation and altered expression of peroxisome proliferator-activated receptor and Fgf21-controlled pathways. Together, these indicate hypometabolism, energetic inflexibility and increased stores at the expense of active tissue as energy shortage consequences.

Published
2021

22. Ethylmalonyl-CoA decarboxylase (ECHDC1) prevents the synthesis of methyl- and ethyl-branched fatty acids

Author

UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, UCL - Faculté de médecine et médecine dentaire, Van Schaftingen, Emile, Leclercq, Isabelle, Veiga da Cunha, Maria, Bommer, Guido T., Vincent, Marie-Françoise, Rider, Mark, Linster, Carole, Van Veldhoven, Paul, Dewulf, Joseph P., UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, UCL - Faculté de médecine et médecine dentaire, Van Schaftingen, Emile, Leclercq, Isabelle, Veiga da Cunha, Maria, Bommer, Guido T., Vincent, Marie-Françoise, Rider, Mark, Linster, Carole, Van Veldhoven, Paul, and Dewulf, Joseph P.

Abstract

The purpose of the present thesis was to evaluate the function of ECHDC1, a cytosolic enzyme that decarboxylates ethylmalonyl-CoA (em-CoA) and to a lesser extent, methylmalonyl-CoA (mm-CoA). As reviewed in the Introduction, fatty acid synthase (FASN), a cytosolic enzyme, usually elongates acetyl-CoA by successive additions of malonyl-CoA to synthesize straight chain fatty acids (FAs). Less frequently, methyl-branched FAs can be synthesized by starting with CoA esters derived from branched-chain amino acids (replacing acetyl-CoA and forming iso and anteiso FAs), or by using mm-CoA instead of malonyl-CoA during the elongation. Cytosolic mmCoA is formed by a side-reaction of acetyl-CoA carboxylase (ACC) on propionyl-CoA. ACC also acts on butyryl-CoA, thereby forming em-CoA. Incorporation of em-CoA by FASN should lead to the formation of ethyl-branched FAs, but this formation has never been demonstrated. Our working hypothesis on the function of ECHDC1 was that by destroying the two side products of ACC, it would prevent the formation of branched-FAs. We first showed in the Results section that mammalian FASN is not only able to synthesize straight or methyl-branched FAs, but also ethyl-branched FAs. Yet, the catalytic activity observed with emCoA is very weak compared to those observed with malonyl-CoA and mm-CoA. Metabolomic analysis of ECHDC1 KO adipocytes revealed a several-fold increase in the amount of methyl-branched FAs, derived from propionate as shown by isotopic labeling. Feeding the KO cells with labeled ethylmalonate led to the formation of ethyl-branched FAs. Analysis of ECHDC1 KO mice confirmed an increase in the formation of methyl-branched FAs. Yet, the most striking observation was that this deficiency led to the appearance of ethyl-branched FAs in tissues. We also discovered a remarkable accumulation of medium chain ethyl-branched FAs. These species were found in liver mitochondria as CoA esters and were excreted in urine mainly as glycine and taurine, (MED - Sciences médicales) -- UCL, 2019

Published
2019

23. SARS-CoV-2 causes a specific dysfunction of the kidney proximal tubule

Author

Werion, Alexis, Belkhir, Leila, Perrot, Marie, Schmit, Gregory, Aydin, Selda, Chen, Zhiyong, Penaloza, Andrea, De Greef, Julien, Yildiz, Halil, Pothen, Lucie, Yombi, Jean Cyr, Dewulf, Joseph, Scohy, Anais, Gérard, Ludovic, Wittebole, Xavier, Laterre, Pierre-François, Miller, Sara E., Devuyst, Olivier, Jadoul, Michel, Morelle, Johann, Aboubakar, Frank, Acid, Souad, Amini, Nadia, Bailly, Sarah, Beauloye, Christophe, Castanares-Zapatero, Diego, Coche, Emmanuel, Collienne, Christine, Cornette, Pascale, De Brauwer, Isabelle, Dechamps, Mélanie, Dupriez, Florence, Froidure, Antoine, Garnir, Quentin, Gerber, Bernhard, Ghaye, Benoît, Gilard, Isabelle, Gohy, Sophie, Grégoire, Charles, Hantson, Philippe, Jacquet, Luc-Marie, Kabamba, Benoit, Kautbally, Shakeel, Lanthier, Nicolas, Larbaoui, Fatima, Liistro, Giuseppe, Maes, Frédéric, Montiel, Virginie, Mwenge, Benny, Pierard, Sophie, Pilette, Charles, Pouleur, Anne Catherine, Sogorb, Amaury, Starkel, Peter, Rodriguez-Villalobos, Hector, Thoma, Maximilien, Van Caeneghem, Olivier, and Vancraeynest, David

Abstract

Coronavirus disease 2019 (COVID-19) is commonly associated with kidney damage, and the angiotensin converting enzyme 2 (ACE2) receptor for SARS-CoV-2 is highly expressed in the proximal tubule cells. Whether patients with COVID-19 present specific manifestations of proximal tubule dysfunction remains unknown. To test this, we examined a cohort of 49 patients requiring hospitalization in a large academic hospital in Brussels, Belgium. There was evidence of proximal tubule dysfunction in a subset of patients with COVID-19, as attested by low-molecular-weight proteinuria (70-80%), neutral aminoaciduria (46%), and defective handling of uric acid (46%) or phosphate (19%). None of the patients had normoglycemic glucosuria. Proximal tubule dysfunction was independent of pre-existing comorbidities, glomerular proteinuria, nephrotoxic medications or viral load. At the structural level, kidneys from patients with COVID-19 showed prominent tubular injury, including in the initial part of the proximal tubule, with brush border loss, acute tubular necrosis, intraluminal debris, and a marked decrease in the expression of megalin in the brush border. Transmission electron microscopy identified particles resembling coronaviruses in vacuoles or cisternae of the endoplasmic reticulum in proximal tubule cells. Among features of proximal tubule dysfunction, hypouricemia with inappropriate uricosuria was independently associated with disease severity and with a significant increase in the risk of respiratory failure requiring invasive mechanical ventilation using Cox (adjusted hazard ratio 6.2, 95% CI 1.9-20.1) or competing risks (adjusted sub-distribution hazard ratio 12.1, 95% CI 2.7-55.4) survival models. Thus, our data establish that SARS-CoV-2 causes specific manifestations of proximal tubule dysfunction and provide novel insights into COVID-19 severity and outcome.

Published
2020
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