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Kidney Week

Abstract: PO0215

Platelets vs. Neutrophils as Therapeutic Targets in Cholesterol Embolism-Related Arterial Occlusion, Kidney Infarction, and AKI

Session Information

  • AKI Mechanisms - 2
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Shi, Chongxu, Medizinische Klinik und Poliklinik IV, AG Klinische Biochemie, Klinikum der Universität München, Munchen, Bayern, Germany
  • Anders, Hans J., Medizinische Klinik und Poliklinik IV, AG Klinische Biochemie, Klinikum der Universität München, Munchen, Bayern, Germany
Background

Cholesterol crystal embolism (CCE), a life-threatening complication, is a consequence of the rupture of atheromatous plaques in patients with advanced atherosclerosis. CCE often missed as a cause of AKI. We hypothesized that platelet contributes to CCE-related artery occlusion leading to AKI and kidney infarction.

Methods

C57/BL6 mice were injected with various doses of cholesterol crystals (CC) to induce CCE in kidney. Primary endpoint: GFR. Secondary endpoints: infarct size, vascular occlusions. 3D MRI and μCT. In vitro studies CC with neutrophils, platelets, endothelial cells.

Results

At 24h, MRI and μCT showed perifocal edema around ischemic lesion and vascular rarefication in CCE kidney. CC-induced clots causing a dose-dependent GFR loss and infarct size. Immunostainings revealed crystal clots contained fibrin, platelets, ecDNA, neutrophils. To study the role of platelets in this process, we treated mice with platelet antagonist clopidogrel. At 24h, clopidogrel completely protected mice from intravascular obstructions, GFR loss, and kidney infarction. In contrast, neutrophil depletion significantly decreased kidney infarction but not arterial obstructions or GFR loss. Maybe because mononuclear cells had partially replaced neutrophils within clots and ecDNA was still present. DNase I treatment also significantly reduced the percentage of ecDNA positive clots, occluded arterial, GFR loss, infarct size. In vitro studies show, CC induced ATP secretion and enhanced fibrinogen release from platelet granules which promotes fibrin clot formation. DNase I can strongly inhibit ATP secretion, fibrin formation, also normalized collagen-driven platelet aggregation.

Conclusion

In summary, not CC itself but the CC-induced fibrin clots obstructed peripheral arteries causing tissue infarction and organ failure. Platelets and ecDNA are central for crystal clots formation. Hence, crystal clots represent the primary target for therapeutic interventions. Among the possible molecular targets in thrombosis, especially enhancing fibrinolysis or inhibiting platelet purinergic signaling could reduce arterial occlusions, infarction, and organ failure. DNase I could have a synergistic effect on CC induced clot formation in mice and might be a prophylactic/therapeutic approach in human patients with a risk for procedure-related CC embolism.

Funding

  • Government Support - Non-U.S.