Intravenous Glu-plasminogen attenuates cholesterol crystal embolism-induced thrombotic angiopathy, acute kidney injury and kidney infarction. Issue 1 (14th September 2022)

• Record Type: Journal Article
• Authors: Lyubenov, Lyuben; Shi, Chongxu; Zhao, Danyang; Yang, Luying; Lei, Yutian; Mammadova-Bach, Elmina; de Chiara, Letizia; Semeraro, Roberto; Landini, Samuela; Romagnani, Paola; Vörg, Elena; Devarapu, Satish K; Welz, Ricarda; Kiessig, Stephan T; Anders, Hans-Joachim
• Is Part Of: Nephrology dialysis transplantation. Volume 38:Issue 1(2023)
• Page Start: 93
• Page End: 105
• Publication Date: 2022-09-14
• Subjects: atheroembolism -- fibrinolysis -- renal failure -- thrombotic microangiopathy; Nephrology -- Periodicals; Hemodialysis -- Periodicals; Kidneys -- Transplantation -- Periodicals; Hemodialysis; Kidneys -- Transplantation; Nephrology; Periodicals; 616.61
• DOI: 10.1093/ndt/gfac273
• Languages: English
• ISSNs: 0931-0509

Abstract

ABSTRACT: Background: 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. Methods: We induced CC embolism by injecting CC into the left kidney artery of C57BL/6J mice. The primary endpoint was glomerular filtration rate (GFR). Results: Starting as early as 2 h 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 18 h, i.e. AKI, and progressive ischaemic kidney necrosis developing between 12–48 h after CC injection. Human plasma Glu-Plg extracts injected intravenously 4 h 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 (0.6 mg/kg) had only a transient protective effect on microvascular occlusions lasting for a few hours without a sustained protective effect on AKI at 18–48 h or cortical necrosis, while 1.5 mg/kg were fully protective. Importantly, no bleeding complications occurred. Conclusions: 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. Graphical Abstract: