Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2023
Intravenous Glu-plasminogen attenuates cholesterol crystal embolism-induced thrombotic angiopathy, acute kidney injury and kidney infarction.
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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
Аннотация
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.
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.