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Article Dans Une Revue Journal of the American Society of Nephrology Année : 2022

Tumor Lysis Syndrome and AKI: Beyond Crystal Mechanisms

Maud Loiselle
  • Fonction : Auteur
Camille Vaganay
  • Fonction : Auteur
Stéphanie Pons
Emmanuel Letavernier
  • Fonction : Auteur
Jordane Demonchy
Sofiane Fodil
  • Fonction : Auteur
Manal Nouacer
  • Fonction : Auteur
Sandrine Placier
  • Fonction : Auteur
Perrine Frère
Eden Arrii
  • Fonction : Auteur
Julien Lion
  • Fonction : Auteur
Nuala Mooney
Raphael Itzykson
Chakib Djediat
  • Fonction : Auteur
  • PersonId : 1268475
Alexandre Puissant
Lara Zafrani
  • Fonction : Auteur

Résumé

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.

Dates et versions

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

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Citer

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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