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Journal articles

Tumor Lysis Syndrome and AKI: Beyond Crystal Mechanisms

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.
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https://hal-univ-paris.archives-ouvertes.fr/hal-03662530
Contributor : Marine Arnaud Connect in order to contact the contributor
Submitted on : Monday, May 9, 2022 - 1:50:20 PM
Last modification on : Wednesday, May 11, 2022 - 3:16:46 AM

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Marine Arnaud, Maud Loiselle, Camille Vaganay, Stéphanie Pons, Emmanuel Letavernier, et al.. Tumor Lysis Syndrome and AKI: Beyond Crystal Mechanisms. Journal of the American Society of Nephrology, American Society of Nephrology, 2022, pp.ASN.2021070997. ⟨10.1681/ASN.2021070997⟩. ⟨hal-03662530⟩

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