Marine Arnaud1, Maud Loiselle1, Camille Vaganay2, Stéphanie Pons1, Emmanuel Letavernier3,4, Jordane Demonchy1, Sofiane Fodil1, Manal Nouacer1, Sandrine Placier3, Perrine Frère3, Eden Arrii1, Julien Lion1, Nuala Mooney1, Raphael Itzykson2,5, Chakib Djediat6, Alexandre Puissant2, Lara Zafrani7,8. 1. Human Immunology and Immunopathology, Institut National de la Santé et de la Recherche Médicale (INSERM) U 976, University of Paris Cité, Paris, France. 2. INSERM UMR 944, Saint Louis Hospital, University of Paris Cité, Paris, France. 3. INSERM UMR S 1155, Sorbonne University, Paris, France. 4. Multidisciplinary Functional Explorations Department, Assistance Publique des Hôpitaux de Paris, Tenon Hospital, Paris, France. 5. Department of Hematology, Assistance Publique des Hôpitaux de Paris, Saint Louis Hospital, Paris, France. 6. Electron Microscopy Department, UMR 7245, Museum National D'Histoire Naturelle, Paris, France. 7. Human Immunology and Immunopathology, Institut National de la Santé et de la Recherche Médicale (INSERM) U 976, University of Paris Cité, Paris, France lara.zafrani@aphp.fr. 8. Medical Intensive Care Unit, Assistance Publique des Hôpitaux de Paris, Saint Louis Hospital, Paris, France.
Abstract
BACKGROUND: The pathophysiology of AKI during tumor lysis syndrome (TLS) is not well understood due to the paucity of data. We aimed to decipher crystal-dependent and crystal-independent mechanisms of TLS-induced AKI. METHODS: Crystalluria, plasma cytokine levels, and extracellular histones levels were measured in two cohorts of patients with TLS. We developed a model of TLS in syngeneic mice with acute myeloid leukemia, and analyzed ultrastructural changes in kidneys and endothelial permeability using intravital confocal microscopy. In parallel, we studied the endothelial toxicity of extracellular histones in vitro. RESULTS: The study provides the first evidence that previously described crystal-dependent mechanisms are insufficient to explain TLS-induced AKI. Extracellular histones that are released in huge amounts during TLS caused profound endothelial alterations in the mouse model. The mechanisms of histone-mediated damage implicates endothelial cell activation mediated by Toll-like receptor 4. Heparin inhibits extracellular histones and mitigates endothelial dysfunction during TLS. CONCLUSION: This study sheds new light on the pathophysiology of TLS-induced AKI and suggests that extracellular histones may constitute a novel target for therapeutic intervention in TLS when endothelial dysfunction occurs.
BACKGROUND: The pathophysiology of AKI during tumor lysis syndrome (TLS) is not well understood due to the paucity of data. We aimed to decipher crystal-dependent and crystal-independent mechanisms of TLS-induced AKI. METHODS: Crystalluria, plasma cytokine levels, and extracellular histones levels were measured in two cohorts of patients with TLS. We developed a model of TLS in syngeneic mice with acute myeloid leukemia, and analyzed ultrastructural changes in kidneys and endothelial permeability using intravital confocal microscopy. In parallel, we studied the endothelial toxicity of extracellular histones in vitro. RESULTS: The study provides the first evidence that previously described crystal-dependent mechanisms are insufficient to explain TLS-induced AKI. Extracellular histones that are released in huge amounts during TLS caused profound endothelial alterations in the mouse model. The mechanisms of histone-mediated damage implicates endothelial cell activation mediated by Toll-like receptor 4. Heparin inhibits extracellular histones and mitigates endothelial dysfunction during TLS. CONCLUSION: This study sheds new light on the pathophysiology of TLS-induced AKI and suggests that extracellular histones may constitute a novel target for therapeutic intervention in TLS when endothelial dysfunction occurs.
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