{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T15:45:38Z","timestamp":1793375138147,"version":"4.5.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","funder":[{"DOI":"10.13039\/100011096","name":"Jazz Pharmaceuticals","doi-asserted-by":"publisher","award":["ESICM"],"award-info":[{"award-number":["ESICM"]}],"id":[{"id":"10.13039\/100011096","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004690","name":"Basic Science Award, and Minist\u00e8re de la Sant\u00e9","doi-asserted-by":"publisher","award":["PHRC AOM 08235"],"award-info":[{"award-number":["PHRC AOM 08235"]}],"id":[{"id":"10.13039\/501100004690","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>\n                      The pathophysiology of AKI during tumor lysis syndrome (TLS) is not fully understood. We aimed to decipher crystal-dependent and crystal-independent mechanisms of TLS-induced AKI. Analyzing urine and blood from patients with TLS provided data on crystal-independent mechanisms of the pathogenesis of AKI during TLS. We also explored mechanisms of TLS-induced AKI\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      in a murine model of TLS (syngeneic mice with acute myeloid leukemia receiving chemotherapy). We found that extracellular histones released in huge amounts during TLS profoundly alter the endothelium. Nonanticoagulant heparin mitigated AKI in this model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic toggle=\"yes\">in vitro.<\/jats:italic>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.2021070997","type":"journal-article","created":{"date-parts":[[2022,5,6]],"date-time":"2022-05-06T15:42:26Z","timestamp":1651851746000},"page":"1154-1171","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":47,"title":["Tumor Lysis Syndrome and AKI: Beyond Crystal Mechanisms"],"prefix":"10.1681","volume":"33","author":[{"given":"Marine","family":"Arnaud","sequence":"first","affiliation":[{"name":"Human 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