Kidney Week

Abstract: TH-OR001

Extracellular DNA Drives Cholesterol Crystal Embolism-Related Tissue Injury

Session Information

• AKI: New Players and New Mechanisms
  October 25, 2018 | Location: 6D, San Diego Convention Center
  Abstract Time: 04:30 PM - 04:42 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Shi, Chongxu, Klinikum der Universität München, Munich, Germany

Chongxu Shi, PhD

• Mulay, Shrikant R., Klinikum der Universität München, Munich, Germany

Shrikant R. Mulay,

• Klinkhammer, Barbara Mara, RWTH University Aachen, Aachen, Germany

Barbara Mara Klinkhammer,

• Liapis, Helen, Pathology and Immunology School of Medicine, Washington University, Washington, Washington, United States

Helen Liapis,

• Boor, Peter, RWTH University Aachen, Aachen, Germany

Peter Boor,

• Anders, Hans J., Klinikum der Universität München, Munich, Germany

Hans J. Anders,

Background

Cholesterol crystal (CC) embolism may be an under recognized cause of acute kidney injury (AKI), especially of catheter intervention- or major surgery- related AKI. Little is known about the pathophysiology of CC embolism-related for the lack of animal models.

Methods

Injecting CC into the left renal artery of C57BL/6N, Mlkl-/- and CypD-/- mice, transcutaneous measurement of GFR after CC injection 24h, quantify renal tubular and endothelial cell injury, crystal clot formation inside arteries, quantify the occlusion of renal arteries of varies sizes. Neutrophil depletion and DNase I interventions were used on mice before CC injection, all experiments same as descripted before.

Results

CC injection to mice caused a sudden drop in glomerular filtration rate (GFR) associated CC embolism and crystal clot formation leading to either partial CC or complete occlusion of numerous interlobar arcuate, and interlobular arteries documented by histology and 3D reconstructions of vascular contrast micro-CT scans. 24h after CC injection partial obstruction was associated with ischemic necrosis of respective tubular S3 segments, while complete obstruction caused large territorial infarction. Such infarcts were surrounded by massive neutrophil infiltrates apparently also derived from vessels of the renal capsule (rim sign). Necroptosis and mitochondrial permeability transition-related regulated necrosis are known to drive post-ischemic AKI but lack of Mlkl, CypD or both had no effect on GFR loss or infarct size probably because crystal clot obstruction remained unaffected. Crystal clots stained positive for platelets, neutrophils, fibrin, and DNA. While neutrophil depletion only partially attenuated GFR loss and infarct size recombinant DNAse I was fully protective as it reduced the number of complete vascular occlusion. In vitro studies revealed that CC induce membrane rupture and DNA release from endothelial cells, neutrophils, and platelets and that CC-induced activation of platelets induces neutrophil extracellular traps formation. CC embolism was found in 446 of 92,000 diagnostic kidney biopsies (0.5%).

Conclusion

CC embolism activates numerous cell types to release DNA, which is a central component of crystal clot formation, vascular occlusion, and kidney infarct-related AKI.

Funding

• Other U.S. Government Support