Human Immunology and Immunopathology, Institut National de la Santé et de la Recherche Médicale (INSERM) U 976, University of Paris Cité, Paris, France.
INSERM UMR 944, Saint Louis Hospital, University of Paris Cité, Paris, France.
J Am Soc Nephrol. 2022 Jun;33(6):1154-1171. doi: 10.1681/ASN.2021070997. Epub 2022 May 6.
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.
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 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.
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.
由于数据有限，肿瘤溶解综合征（TLS）期间急性肾损伤（AKI）的病理生理学机制尚不清楚。我们旨在破译 TLS 诱导的 AKI 的晶体依赖性和晶体非依赖性机制。
我们在两批 TLS 患者中测量了结晶尿、血浆细胞因子水平和细胞外组蛋白水平。我们在急性髓系白血病的同种异体小鼠中建立了 TLS 模型，并使用活体共聚焦显微镜分析肾脏的超微结构变化和内皮通透性。同时，我们研究了细胞外组蛋白的内皮毒性。
该研究首次提供证据表明，先前描述的晶体依赖性机制不足以解释 TLS 诱导的 AKI。TLS 期间大量释放的细胞外组蛋白在小鼠模型中引起了严重的内皮改变。组蛋白介导损伤的机制涉及 Toll 样受体 4 介导的内皮细胞激活。肝素抑制细胞外组蛋白并减轻 TLS 期间的内皮功能障碍。
这项研究揭示了 TLS 诱导的 AKI 的病理生理学新机制，并表明细胞外组蛋白在发生内皮功能障碍时可能成为 TLS 治疗干预的新靶点。
