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Kidney Week

Abstract: SA-OR010

A Novel Targeting Strategy That Can Prevent Cholesterol Crystal Embolism-Induced AKI and Kidney Infarction

Session Information

Category: Acute Kidney Injury

  • 102 AKI: Clinical, Outcomes, and Trials

Authors

  • Shi, Chongxu, Klinikum der Universitat Munchen, Muenchen, Germany
  • Kim, Tehyung, Klinikum der Universitat Munchen, Muenchen, Germany
  • Steiger, Stefanie, Klinikum der Universitat Munchen, Muenchen, Germany
  • Klinkhammer, Barbara Mara, RWTH University Aachen, Aachen, Germany
  • Boor, Peter, RWTH University Aachen, Aachen, Germany
  • Anders, Hans J., Klinikum der Universitat Munchen, Muenchen, Germany
Background

Cholesterol crystal embolism(CCE) is a life-threatening complication of advanced atherosclerosis and often missed as a cause of AKI. Due to the lack of a suitable animal model, little is known about the pathophysiology of CCE.

Methods

We injected the left kidney of C57/BL6 mice with cholesterol crystals(CC). Primary endpoint: GFR. Secondary endpoints: infarct size, kidney injury, vascular injury, vascular occlusions, territorial hypoperfusion and perifocal edema(3D imaging: MRI and microCT). 2D and 3D in vitro studies CC with neutrophils, platelets, and endothelial cells.

Results

CC injection induced CCE in interlobar, arcuate, and interlobular arteries(A). Not CC alone but CC-induced clots obstructed arteries and caused a tight dose-dependent GFR decline(B), i.e. CCE-related AKI, while infarct size showed a higher variability(C). Deficiency of Mlkl protected mice from kidney infarction but not AKI, suggesting only targeting crystal clots but not kidney infarct may prevent AKI. Crystal clots were made of fibrin, neutrophils, platelets, and extracellular DNA. Fibrinolysis with rtPA and recombinant DNase all reduced arterial occlusions, GFR loss, and infarct size. For DNase the window-of-opportunity was 3h after CCE. To maximize the renoprotective effect in a clinically potentially feasible manner we tested a single prophylactic dose of necrostatin-1s before CCE and gave DNase 3h after CCE, which entirely prevented AKI and kidney infarction(D, E). In vitro, CC activated platelets, triggered NETs formation, and killed endothelial cells(F). All these mechanisms lead to the DNA release into extracellular space.

Conclusion

CCE induces kidney infarction but AKI develops independently from infarction due to obstruction of pre-glomerular vessels. Not CC but CC-induced clots lead to vascular obstruction. The extracellular DNA as a critical component in CC-induced clots. The window-of-opportunity for DNase therapy is 3h. A 2-step dual targeting strategy can entirely prevent AKI and infarction.