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Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis

  • Author Footnotes
    17 These authors contributed equally to this study.
    Idris Boudhabhay
    Footnotes
    17 These authors contributed equally to this study.
    Affiliations
    Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris, Paris, France
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  • Author Footnotes
    17 These authors contributed equally to this study.
    Victoria Poillerat
    Footnotes
    17 These authors contributed equally to this study.
    Affiliations
    Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris, Paris, France
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  • Author Footnotes
    17 These authors contributed equally to this study.
    Anne Grunenwald
    Footnotes
    17 These authors contributed equally to this study.
    Affiliations
    Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris, Paris, France
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  • Carine Torset
    Affiliations
    Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris, Paris, France
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  • Juliette Leon
    Affiliations
    Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris, Paris, France
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  • Marie V. Daugan
    Affiliations
    Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris, Paris, France
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  • Francesca Lucibello
    Affiliations
    Institut National de la Santé et de la Recherche Médicale U932, Paris Sciences et Lettres University, Institut Curie, Paris, France
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  • Khalil El Karoui
    Affiliations
    Service de Néphrologie et Transplantation Rénale, Hôpital Henri Mondor, Assistance Publique - Hôpitaux de Paris, Créteil, Paris, France
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  • Amandine Ydee
    Affiliations
    Pathology Department, Lille University Hospital (Centre Hospitalier Universitaire), Pathology Institute, Institut National de la Santé et de la Recherche Médicale UMR-S1172 Lille, JPARC-Jean-Pierre Aubert Research Center, Team “Mucins, Epithelial Differentiation and Carcinogenesis,” Lille University, Centre Hospitalier Universitaire Lille, Lille, France
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  • Sophie Chauvet
    Affiliations
    Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris, Paris, France

    Department of Nephrology, Georges Pompidou European Hospital, Paris, France
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  • Patrick Girardie
    Affiliations
    Intensive Care Department, Université de Lille, Centre Hospitalier Universitaire Lille, Lille, France
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  • Steven Sacks
    Affiliations
    Medical Research Council Centre for Transplantation, Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, London, UK
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  • Conrad A. Farrar
    Affiliations
    Medical Research Council Centre for Transplantation, Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, London, UK
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  • Peter Garred
    Affiliations
    Laboratory of Molecular Medicine, Department of Clinical Immunology, University of Copenhagen, Copenhagen, Denmark
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  • Romain Berthaud
    Affiliations
    Department of Pediatric Nephrology, Necker Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
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  • Moglie Le Quintrec
    Affiliations
    Department of Nephrology and Kidney Transplantation, Centre Hospitalier Universitaire de Montpellier, Montpellier, France
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  • Marion Rabant
    Affiliations
    Department of Pathology, Necker Hospital, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France
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  • Pascale de Lonlay
    Affiliations
    Reference Centre for Metabolic Diseases, Necker–Enfants Malades Hospital, Imagine Institute, Université Paris-Descartes, Assistance Publique - Hôpitaux de Paris, Paris, France
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  • Caroline Rambaud
    Affiliations
    Service Médecine Légale, Hôpital Raymond Poincaré, Assistance Publique - Hôpitaux de Paris, Garches, France
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  • Viviane Gnemmi
    Affiliations
    Pathology Department, Lille University Hospital (Centre Hospitalier Universitaire), Pathology Institute, Institut National de la Santé et de la Recherche Médicale UMR-S1172 Lille, JPARC-Jean-Pierre Aubert Research Center, Team “Mucins, Epithelial Differentiation and Carcinogenesis,” Lille University, Centre Hospitalier Universitaire Lille, Lille, France
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  • Veronique Fremeaux-Bacchi
    Affiliations
    Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris, Paris, France

    Laboratory of Immunology, Hôpital Européen Georges Pompidou, Assistance Publique - Hôpitaux de Paris, Paris, France
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  • Marie Frimat
    Affiliations
    University of Lille, U995-LIRIC-Lille Inflammation Research International Center, Lille, France

    Department of Nephrology, Lille University Hospital, Centre Hospitalier Universitaire, Lille, France
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  • Lubka T. Roumenina
    Correspondence
    Correspondence: Lubka T. Roumenina, Cordeliers Research Center, INSERM UMRS 1138, 15 rue de l’Ecole de Medecine, 75006 Paris, France.
    Affiliations
    Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris, Paris, France
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  • Author Footnotes
    17 These authors contributed equally to this study.
Published:October 30, 2020DOI:https://doi.org/10.1016/j.kint.2020.09.033
      Rhabdomyolysis is a life-threatening condition caused by skeletal muscle damage with acute kidney injury being the main complication dramatically worsening the prognosis. Specific treatment for rhabdomyolysis-induced acute kidney injury is lacking and the mechanisms of the injury are unclear. To clarify this, we studied intra-kidney complement activation (C3d and C5b-9 deposits) in tubules and vessels of patients and mice with rhabdomyolysis-induced acute kidney injury. The lectin complement pathway was found to be activated in the kidney, likely via an abnormal pattern of Fut2-dependent cell fucosylation, recognized by the pattern recognition molecule collectin-11 and this proceeded in a C4-independent, bypass manner. Concomitantly, myoglobin-derived heme activated the alternative pathway. Complement deposition and acute kidney injury were attenuated by pre-treatment with the heme scavenger hemopexin. This indicates that complement was activated in a unique double-trigger mechanism, via the alternative and lectin pathways. The direct pathological role of complement was demonstrated by the preservation of kidney function in C3 knockout mice after the induction of rhabdomyolysis. The transcriptomic signature for rhabdomyolysis-induced acute kidney injury included a strong inflammatory and apoptotic component, which were C3/complement-dependent, as they were normalized in C3 knockout mice. The intra-kidney macrophage population expressed a complement-sensitive phenotype, overexpressing CD11b and C5aR1. Thus, our results demonstrate a direct pathological role of heme and complement in rhabdomyolysis-induced acute kidney injury. Hence, heme scavenging and complement inhibition represent promising therapeutic strategies.

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