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Journal Articles Journal of the American Society of Nephrology Year : 2022

Tumor Lysis Syndrome and AKI: Beyond Crystal Mechanisms

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Maud Loiselle
  • Function : Author
Camille Vaganay
  • Function : Author
Stéphanie Pons
Emmanuel Letavernier
  • Function : Author
Jordane Demonchy
Sofiane Fodil
  • Function : Author
Manal Nouacer
  • Function : Author
Sandrine Placier
  • Function : Author
Perrine Frère
Eden Arrii
  • Function : Author
Julien Lion
  • Function : Author
Nuala Mooney
Raphael Itzykson
Chakib Djediat
  • Function : Author
Alexandre Puissant
Lara Zafrani
  • Function : Author

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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Dates and versions

hal-03662530 , version 1 (09-05-2022)

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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, 2022, pp.ASN.2021070997. ⟨10.1681/ASN.2021070997⟩. ⟨hal-03662530⟩

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