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

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 ? 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.

SUBMITTER: Makhloufi C

PROVIDER: S-EPMC7162676 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Makhloufi Camélia C Crescence Lydie L Darbousset Roxane R McKay Nathalie N Massy Ziad A ZA Dubois Christophe C Panicot-Dubois Laurence L Burtey Stéphane S Poitevin Stéphane S

TH open : companion journal to thrombosis and haemostasis 20200416 2

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 ...[more]

PMID: 32309772

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Project description:Preclinical animal models of chronic kidney disease (CKD) are critical to investigate the underlying mechanisms of disease and to evaluate the efficacy of novel therapeutics aimed to treat CKD-associated pathologies. The objective of the present study was to compare the adenine diet and 5/6 nephrectomy (Nx) CKD models in mice. Male and female 10-wk-old C57BL/6J mice (n = 5-9 mice/sex/group) were randomly allocated to CKD groups (0.2-0.15% adenine-supplemented diet or 5/6 Nx surgery) or the corresponding control groups (casein diet or sham surgery). Following the induction of CKD, the glomerular filtration rate was reduced to a similar level in both adenine and 5/6 Nx mice (adenine diet-fed male mice: 81.1 ± 41.9 µL/min vs. 5/6 Nx male mice: 160 ± 80.9 µL/min, P = 0.5875; adenine diet-fed female mice: 112.9 ± 32.4 µL/min vs. 5/6 Nx female mice: 107.0 ± 45.7 µL/min, P = 0.9995). Serum metabolomics analysis indicated that established uremic toxins were robustly elevated in both CKD models, although some differences were observed between CKD models (i.e., p-cresol sulfate). Dysregulated phosphate homeostasis was observed in the adenine model only, whereas Ca2+ homeostasis was disturbed in male mice with both CKD models. Compared with control mice, muscle mass and myofiber cross-sectional areas of the extensor digitorum longus and soleus muscles were ∼18-24% smaller in male CKD mice regardless of the model but were not different in female CKD mice (P > 0.05). Skeletal muscle mitochondrial respiratory function was significantly decreased (19-24%) in CKD mice in both models and sexes. These findings demonstrate that adenine diet and 5/6 Nx models of CKD have similar levels of renal dysfunction and skeletal myopathy. However, the adenine diet model demonstrated superior performance with regard to mortality (∼20-50% mortality for 5/6 Nx vs. 0% mortality for the adenine diet, P < 0.05 for both sexes) compared with the 5/6 Nx surgical model.NEW & NOTEWORTHY Numerous preclinical models of chronic kidney disease have been used to evaluate skeletal muscle pathology; however, direct comparisons of popular models are not available. In this study, we compared adenine-induced nephropathy and 5/6 nephrectomy models. Both models produced equivalent levels of muscle atrophy and mitochondrial impairment, but the adenine model exhibited lower mortality rates, higher consistency in uremic toxin levels, and dysregulated phosphate homeostasis compared with the 5/6 nephrectomy model.

Project description:BackgroundPrediction of thrombotic and bleeding risk is important to optimize antithrombotic therapy after percutaneous coronary intervention.Methods and resultsWe developed the prediction rules for thrombotic and bleeding events separately in Japanese patients. Derivation and validation cohorts consisted of 4778 patients from CREDO-Kyoto (Coronary Revascularization Demonstrating Outcome Study in Kyoto) registry cohort 2 and 4669 patients from RESET (Randomized Evaluation of Sirolimus-Eluting Versus Everolimus-Eluting Stent Trial) and NEXT (Nobori Biolimus-Eluting Versus Xience/Promus Everolimus-Eluting Stent Trial). Primary thrombotic and bleeding events were a composite of myocardial infarction, definite or probable stent thrombosis or ischemic stroke, and GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) moderate or severe bleeding. The prediction rule for thrombosis assigned 2 points for severe chronic kidney disease, atrial fibrillation, peripheral vascular disease, and anemia and 1 point for age ?75 years, heart failure, diabetes mellitus, and chronic total occlusion. The prediction rule for bleeding assigned 2 points for thrombocytopenia, severe chronic kidney disease, peripheral vascular disease, and heart failure and 1 point for prior myocardial infarction, malignancy, and atrial fibrillation. In derivation and validation cohorts, area under the curve was 0.68 and 0.64, respectively, for thrombosis and 0.66 and 0.66, respectively, for bleeding. In the validation cohort, a high thrombosis risk score (?4, n=682) was associated with higher 3-year incidence of thrombotic events than a score that was intermediate (2-3, n=1178) or low (0-1, n=2809) (7.6%, 3.7%, versus 2.4%, respectively; P<0.0001). A high bleeding risk score (?3, n=666) was associated with higher incidence of bleeding than scores that were intermediate (1-2, n=1802) or low (0, n=2201) (8.8%, 4.1%, versus 2.3%, respectively; P<0.0001). Among 682 patients at high thrombotic risk, only 39 (5.7%) had low bleeding risk, whereas 401 (58.8%) had high bleeding risk with very high incidence of bleeding (11.6%).ConclusionsCREDO-Kyoto thrombotic and bleeding risk scores demonstrated modest accuracy in stratifying thrombotic and bleeding risks; however, a large proportion of patients at high thrombotic risk also had high bleeding risk.

Project description:Sorting spikes from extracellular recording into clusters associated with distinct single units (putative neurons) is a fundamental step in analyzing neuronal populations. Such spike sorting is intrinsically unsupervised, as the number of neurons are not known a priori. Therefor, any spike sorting is an unsupervised learning problem that requires either of the two approaches: specification of a fixed value k for the number of clusters to seek, or generation of candidate partitions for several possible values of c, followed by selection of a best candidate based on various post-clustering validation criteria. In this paper, we investigate the first approach and evaluate the utility of several methods for providing lower dimensional visualization of the cluster structure and on subsequent spike clustering. We also introduce a visualization technique called improved visual assessment of cluster tendency (iVAT) to estimate possible cluster structures in data without the need for dimensionality reduction. Experimental results are conducted on two datasets with ground truth labels. In data with a relatively small number of clusters, iVAT is beneficial in estimating the number of clusters to inform the initialization of clustering algorithms. With larger numbers of clusters, iVAT gives a useful estimate of the coarse cluster structure but sometimes fails to indicate the presumptive number of clusters. We show that noise associated with recording extracellular neuronal potentials can disrupt computational clustering schemes, highlighting the benefit of probabilistic clustering models. Our results show that t-Distributed Stochastic Neighbor Embedding (t-SNE) provides representations of the data that yield more accurate visualization of potential cluster structure to inform the clustering stage. Moreover, The clusters obtained using t-SNE features were more reliable than the clusters obtained using the other methods, which indicates that t-SNE can potentially be used for both visualization and to extract features to be used by any clustering algorithm.

Dataset Information

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

Publications

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

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