Assessment of Thrombotic and Bleeding Tendency in Two Mouse Models of Chronic Kidney Disease: Adenine-Diet and 5/6th Nephrectomy.

Stéphane Burtey,Roxane Darbousset,Camélia Makhloufi,Ziad A Massy,Nathalie Mckay,Laurence Panicot-Dubois,Stéphane Poitevin,Christophe Dubois,Lydie Crescence

doi:10.1055/s-0040-1705138

Abstract

The coexistence of bleeding and thrombosis in patients with chronic kidney disease (CKD) is frequent and poorly understood. Mouse models are essential to understand complications of CKD and to develop new therapeutic approaches improving the health of patients. We evaluated the hemostasis in two models of renal insufficiency: adenine-diet and 5/6th nephrectomy (5/6Nx). Compared with 5/6Nx mice, mice fed with 0.25% adenine had more severe renal insufficiency and so higher levels of prothrombotic uremic toxins like indoxyl sulfate. More severe renal inflammation and fibrosis were observed in the adenine group, as demonstrated by histological and reverse transcription quantitative polymerase chain reaction experiments. Liver fibrinogen γ chain expression and level of plasma fibrinogen were increased only in adenine mice. In both CKD mouse models, tissue factor (TF) expression was increased in kidney and aorta extracts. Immunochemistry analysis of kidney sections showed that TF is localized in the vascular walls. Thrombin–antithrombin complexes were significantly increased in plasma from both adenine and 5/6Nx mice. Tail bleeding time increased significantly only in adenine mice, whereas platelet count was not significant altered. Finally, results obtained by intravital microscopy after laser-induced endothelial injury showed impaired platelet function in adenine mice and an increase in fibrin generation in 5/6Nx mice. To summarize, adenine diet causes a more severe renal insufficiency compared with 5/6Nx. The TF upregulation and the hypercoagulable state were observed in both CKD models. Bleeding tendency was observed only in the adenine model of CKD that recapitulates the whole spectrum of hemostasis abnormalities observed in advanced human CKD.

Highlights

It is well known that the incidence of cardiovascular events increases in patients with chronic kidney disease (CKD).1 CKD patients exhibit many abnormalities in their hemostatic response that may account for their increased risk of both bleeding and thrombotic events.2 The early stages of CKD are dominated by disturbances resulting likely in increased risk of myocardial infarction, peripheral arterial disease, stroke, and venous thromboembolism
In 5/6Nx mice, its concentration is closed to CKD stage 4.7 These findings are consistent with renal impairment in both CKD models and demonstrated that CKD is more severe with the adenine diet in comparison to the surgical model of 5/6Nx
CKD is responsible for a thrombotic predisposition and a bleeding diathesis18 that are associated with significant cardiovascular morbidity, severe hemorrhages, and mortality

Summary

Introduction

It is well known that the incidence of cardiovascular events increases in patients with chronic kidney disease (CKD). CKD patients exhibit many abnormalities in their hemostatic response that may account for their increased risk of both bleeding and thrombotic events. The early stages of CKD are dominated by disturbances resulting likely in increased risk of myocardial infarction, peripheral arterial disease, stroke, and venous thromboembolism. CKD patients exhibit many abnormalities in their hemostatic response that may account for their increased risk of both bleeding and thrombotic events.. In patients with advanced CKD, the procoagulant state persists, and in addition, uremia is strongly associated with platelet dysfunction leading to an increased risk of hemorrhagic events.. Recent studies strengthen an independent role of CKD in thrombosis by identifying uremiaspecific prothrombotic risk factors.. We and other have previously demonstrated the prothrombotic role of indolic uremic solutes indoxyl sulfate (IS) and indole-3 acetic acid. These indolic compounds induce tissue factor (TF) in both the endothelial cells and vascular smooth muscle cells (vSMCs).. Several prothrombotic hemostatic mediators are elevated, including fibrinogen, soluble thrombomodulin, soluble TF, thrombin–antithrombin TAT complex, von Willebrand factor, Factor VIII, and C-reactive protein (CRP). The generalized inflammatory state, the endothelial dysfunction, and possibly poor clearance of some of the thrombotic mediators may account for this derangement.

Methods

Results

Conclusion