Intravenous Glu-plasminogen attenuates cholesterol crystal embolism-induced thrombotic angiopathy, acute kidney injury and kidney infarction.

Abstract

Cholesterol crystal (CC) embolism causes acute kidney injury (AKI) and ischaemic cortical necrosis associated with high mortality. We speculated that sustaining the fibrinolytic system with Glu-plasminogen (Glu-Plg) could be a safe way to attenuate AKI and prevent ischaemic infarction upon CC embolism. We induced CC embolism by injecting CC into the left kidney artery of C57BL/6J mice. The primary endpoint was glomerular filtration rate (GFR). Starting as early as 2h after CC embolism, thrombotic angiopathy progressed gradually in the interlobular, arcuate and interlobar arteries. This was associated with a decrease of GFR reaching a peak at 18h, i.e. AKI, and progressive ischaemic kidney necrosis developing between 12-48h after CC injection. Human plasma Glu-Plg extracts injected intravenously 4h after CC embolism attenuated thrombotic angiopathy, GFR loss as well as ischaemic necrosis in a dose-dependent manner. No bleeding complications occurred after Glu-Plg injection. Injection of an intermediate dose (0.6mg/kg) had only a transient protective effect on microvascular occlusions lasting for a few hours without a sustained protective effect on AKI at 18-48h or cortical necrosis, while 1.5mg/kg were fully protective. Importantly, no bleeding complications occurred. These results provide the first experimental evidence that Glu-Plg could be an innovative therapeutic strategy to attenuate thrombotic angiopathy, AKI, kidney necrosis and potentially other clinical manifestations of CC embolism syndrome.