CC BY 4.0 · TH Open 2020; 04(02): e66-e76
DOI: 10.1055/s-0040-1705138
Original Article
Georg Thieme Verlag KG Stuttgart · New York

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

Camélia Makhloufi
1   Aix Marseille Univ, INSERM 1263, INRAE, C2VN, Marseille, France
,
Lydie Crescence
1   Aix Marseille Univ, INSERM 1263, INRAE, C2VN, Marseille, France
,
Roxane Darbousset
2   Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Nathalie McKay
1   Aix Marseille Univ, INSERM 1263, INRAE, C2VN, Marseille, France
,
Ziad A. Massy
3   Centre for Research in Epidemiology and Population Health (CESP), University Paris-Saclay, Villejuif, France
4   Department of Nephrology, Ambroise Paré University Hospital, Boulogne Billancourt/Paris, France
,
Christophe Dubois
1   Aix Marseille Univ, INSERM 1263, INRAE, C2VN, Marseille, France
,
Laurence Panicot-Dubois
1   Aix Marseille Univ, INSERM 1263, INRAE, C2VN, Marseille, France
,
Stéphane Burtey
1   Aix Marseille Univ, INSERM 1263, INRAE, C2VN, Marseille, France
5   Centre de Néphrologie et Transplantation Rénale, APHM, Marseille, France
,
Stéphane Poitevin
1   Aix Marseille Univ, INSERM 1263, INRAE, C2VN, Marseille, France
› Author Affiliations
Funding This work was supported by funding from the Aix-Marseille Université, the Institut National de la santé et de la Recherche médicale (INSERM), the European Uremic Toxins (EUTox) Work Group, and a grant from Fondation du Rein/FNAIR.
Further Information

Publication History

20 September 2019

27 January 2020

Publication Date:
16 April 2020 (online)

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.

Authors' Contribution

S.P. and S.B. designed the research, analyzed the data, and wrote the manuscript. C.M. performed the experiments, analyzed the data, and wrote the manuscript. L.C., R.D., and N.M.K. performed the experiments and analyzed the data. C.D., L.P.D., and Z.M. analyzed the data.


Supplementary Material