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

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

doi:10.1016/j.kint.2020.07.019

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

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

Résultats de recherche: Contribution à un journal/une revue › Article › Revue par des pairs

Résumé

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.

langue originale	Anglais
Pages (de - à)	1296-1307
Nombre de pages	12
journal	Kidney international
Volume	98
Numéro de publication	5
Les DOIs	https://doi.org/10.1016/j.kint.2020.07.019
Etat de la publication	Publié - nov. 2020
Modification externe	Oui

Financement

JM is supported by the National Fund for Scientific Research (Brussels, Belgium), the Saint-Luc Foundation (Brussels, Belgium), the Clinical Research Fund at Cliniques universitaires Saint-Luc (Brussels, Belgium), and the Association pour l’Information et la Recherche sur les Maladies Rénales Génétiques (Brussels, Belgium). OD is supported by the European Reference Network for Rare Kidney Diseases (ERKNet)—project ID 739532 (Europe); the Cystinosis Research Foundation (USA); the NCCR Kidney.CH program ( Swiss National Science Foundation, Switzerland ); and the Swiss National Science Foundation : 310030-189044 (Switzerland). The funders had no role in study design, data collection, analysis, reporting, or the decision to submit for publication. We thank Yvette Cnops, Huguette Debaix, and Sebastien Druart for expert technical assistance; Cynthia S. Goldsmith (Centers for Disease Control and Prevention, Atlanta, GA, USA), Andres Kaech (University of Zurich, Zurich, Switzerland), Johannes Loffing (University of Zurich, Zurich, Switzerland), John Shelburne (Durham Veterans Administration Hospital, Durham, NC, USA), and Marie-Francoise Vincent (UCLouvain, Brussels, Belgium) for helpful discussions; and Caroline Bouzin and Arthur Colson for image acquisition and analysis. Imaging was performed at the IREC Imaging platform at UCLouvain (Brussels, Belgium), and with equipment maintained by the Center for Microscopy and Image Analysis, University of Zurich (Zurich, Switzerland). JM is supported by the National Fund for Scientific Research (Brussels, Belgium), the Saint-Luc Foundation (Brussels, Belgium), the Clinical Research Fund at Cliniques universitaires Saint-Luc (Brussels, Belgium), and the Association pour l'Information et la Recherche sur les Maladies Rénales Génétiques (Brussels, Belgium). OD is supported by the European Reference Network for Rare Kidney Diseases (ERKNet)—project ID 739532 (Europe); the Cystinosis Research Foundation (USA); the NCCR Kidney.CH program (Swiss National Science Foundation, Switzerland); and the Swiss National Science Foundation: 310030-189044 (Switzerland). The funders had no role in study design, data collection, analysis, reporting, or the decision to submit for publication. AW, OD, MJ, and JM designed the study; AW, LB, MP, AP, JDG, HY, LP, JCY, LG, XW, PFL, and JM took care of the patients; AW, MP, and JM collected clinical data; GS and SA performed postmortem examinations; JD, OD, and JM assessed and interpreted urine amino acids; AS performed and interpreted SARS-CoV-2 PCR; ZC, SEM, OD, and JM performed, supervised, and analyzed experiments; JM performed statistical analyses. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual's own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate.

Bailleurs de fonds	Numéro du bailleur de fonds
Association pour l'Information et la Recherche sur les Maladies Rénales Génétiques
Association pour l'Information et la Recherche sur les Maladies Rénales Génétiques
Durham Veterans Administration Hospital
NCCR Kidney.CH program
Cystinosis Research Foundation
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	310030-189044
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
Fonds de la Recherche Scientifique F.R.S.-FNRS
University of Zurich
Fondation Saint Luc
European Rare Kidney Disease Reference Network	739532
European Rare Kidney Disease Reference Network

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10.1016/j.kint.2020.07.019

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Werion, A., Belkhir, L., Perrot, M., Schmit, G., Aydin, S., Chen, Z., Penaloza, A., De Greef, J., Yildiz, H., Pothen, L., Yombi, J. C., Dewulf, J., Scohy, A., Gérard, L., Wittebole, X., Laterre, P. F., Miller, S. E., Devuyst, O., Jadoul, M., ... Vancraeynest, D. (2020). SARS-CoV-2 causes a specific dysfunction of the kidney proximal tubule. Kidney international, 98(5), 1296-1307. https://doi.org/10.1016/j.kint.2020.07.019

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title = "SARS-CoV-2 causes a specific dysfunction of the kidney proximal tubule",

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.",

keywords = "COVID-19, kidney, renal Fanconi syndrome, severe acute respiratory syndrome",

author = "Alexis Werion and Leila Belkhir and Marie Perrot and Gregory Schmit and Selda Aydin and Zhiyong Chen and Andrea Penaloza and \{De Greef\}, Julien and Halil Yildiz and Lucie Pothen and Yombi, \{Jean Cyr\} and Joseph Dewulf and Anais Scohy and Ludovic G{\'e}rard and Xavier Wittebole and Laterre, \{Pierre Fran{\c c}ois\} and Miller, \{Sara E.\} and Olivier Devuyst and Michel Jadoul and Johann Morelle and Frank Aboubakar and Souad Acid and Nadia Amini and Sarah Bailly and Christophe Beauloye and Diego Castanares-Zapatero and Emmanuel Coche and Christine Collienne and Pascale Cornette and \{De Brauwer\}, Isabelle and M{\'e}lanie Dechamps and Florence Dupriez and Antoine Froidure and Quentin Garnir and Bernhard Gerber and Beno{\^i}t Ghaye and Isabelle Gilard and Sophie Gohy and Charles Gr{\'e}goire and Philippe Hantson and Jacquet, \{Luc Marie\} and Benoit Kabamba and Shakeel Kautbally and Nicolas Lanthier and Fatima Larbaoui and Giuseppe Liistro and Fr{\'e}d{\'e}ric Maes and Virginie Montiel and Benny Mwenge and Sophie Pierard and Charles Pilette and Pouleur, \{Anne Catherine\} and Amaury Sogorb and Peter Starkel and Hector Rodriguez-Villalobos and Maximilien Thoma and \{Van Caeneghem\}, Olivier and David Vancraeynest",

note = "Publisher Copyright: {\textcopyright} 2020 International Society of Nephrology",

year = "2020",

month = nov,

doi = "10.1016/j.kint.2020.07.019",

language = "English",

volume = "98",

pages = "1296--1307",

journal = "Kidney international",

issn = "0085-2538",

publisher = "Elsevier",

number = "5",

}

Werion, A, Belkhir, L, Perrot, M, Schmit, G, Aydin, S, Chen, Z, Penaloza, A, De Greef, J, Yildiz, H, Pothen, L, Yombi, JC, Dewulf, J, Scohy, A, Gérard, L, Wittebole, X, Laterre, PF, Miller, SE, Devuyst, O, Jadoul, M, Morelle, J, Aboubakar, F, Acid, S, Amini, N, Bailly, S, Beauloye, C , Castanares-Zapatero, D, Coche, E, Collienne, C, Cornette, P, De Brauwer, I, Dechamps, M, Dupriez, F, Froidure, A, Garnir, Q, Gerber, B, Ghaye, B, Gilard, I, Gohy, S, Grégoire, C, Hantson, P, Jacquet, LM, Kabamba, B, Kautbally, S, Lanthier, N, Larbaoui, F, Liistro, G, Maes, F, Montiel, V, Mwenge, B, Pierard, S, Pilette, C, Pouleur, AC, Sogorb, A, Starkel, P, Rodriguez-Villalobos, H, Thoma, M, Van Caeneghem, O & Vancraeynest, D 2020, 'SARS-CoV-2 causes a specific dysfunction of the kidney proximal tubule', Kidney international, VOL. 98, Numéro 5, p. 1296-1307. https://doi.org/10.1016/j.kint.2020.07.019

TY - JOUR

T1 - SARS-CoV-2 causes a specific dysfunction of the kidney proximal tubule

AU - Werion, Alexis

AU - Belkhir, Leila

AU - Perrot, Marie

AU - Schmit, Gregory

AU - Aydin, Selda

AU - Chen, Zhiyong

AU - Penaloza, Andrea

AU - De Greef, Julien

AU - Yildiz, Halil

AU - Pothen, Lucie

AU - Yombi, Jean Cyr

AU - Dewulf, Joseph

AU - Scohy, Anais

AU - Gérard, Ludovic

AU - Wittebole, Xavier

AU - Laterre, Pierre François

AU - Miller, Sara E.

AU - Devuyst, Olivier

AU - Jadoul, Michel

AU - Morelle, Johann

AU - Aboubakar, Frank

AU - Acid, Souad

AU - Amini, Nadia

AU - Bailly, Sarah

AU - Beauloye, Christophe

AU - Castanares-Zapatero, Diego

AU - Coche, Emmanuel

AU - Collienne, Christine

AU - Cornette, Pascale

AU - De Brauwer, Isabelle

AU - Dechamps, Mélanie

AU - Dupriez, Florence

AU - Froidure, Antoine

AU - Garnir, Quentin

AU - Gerber, Bernhard

AU - Ghaye, Benoît

AU - Gilard, Isabelle

AU - Gohy, Sophie

AU - Grégoire, Charles

AU - Hantson, Philippe

AU - Jacquet, Luc Marie

AU - Kabamba, Benoit

AU - Kautbally, Shakeel

AU - Lanthier, Nicolas

AU - Larbaoui, Fatima

AU - Liistro, Giuseppe

AU - Maes, Frédéric

AU - Montiel, Virginie

AU - Mwenge, Benny

AU - Pierard, Sophie

AU - Pilette, Charles

AU - Pouleur, Anne Catherine

AU - Sogorb, Amaury

AU - Starkel, Peter

AU - Rodriguez-Villalobos, Hector

AU - Thoma, Maximilien

AU - Van Caeneghem, Olivier

AU - Vancraeynest, David

PY - 2020/11

Y1 - 2020/11

N2 - 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.

AB - 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.

KW - COVID-19

KW - kidney

KW - renal Fanconi syndrome

KW - severe acute respiratory syndrome

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U2 - 10.1016/j.kint.2020.07.019

DO - 10.1016/j.kint.2020.07.019

M3 - Article

C2 - 32791255

AN - SCOPUS:85092285936

SN - 0085-2538

VL - 98

SP - 1296

EP - 1307

JO - Kidney international

JF - Kidney international

IS - 5

ER -

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

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