Endothelial injury is closely related to osteopontin and TNF receptor-mediated inflammation in end-stage renal disease
Introduction
In atherosclerotic lesions, the expression of thrombomodulin (TM), a cell membrane glycoprotein, has been demonstrated on the surface of endothelium, intimal and medial smooth muscle cells (SMC) and macrophages. The expression of TM in SMC depended on lesion type and patient age [1]. A soluble form of TM (sTM) is released from endothelial cells in response to endothelial damage [2], or TNFα-stimulated inflammatory settings [3]. TNFα was previously shown to display cytotoxic effects on microvascular endothelium [4], whereas serum TM has been correlated with measures of microvascular dysfunction [5]. Transgenic mice with endothelial TNFα expression, designed to represent chronic endothelial activation, developed inflammation which improved after exogenous sTM treatment [6]. The Atherosis Risk in Communities (ARIC) study revealed that incidence of coronary heart disease in healthy individuals was inversely correlated with sTM [7]. It was suggested that anti-coagulant function of TM, as a cofactor of protein C, and modulation of thrombin activity may be responsible for this protective effect. Conversely, incidence of carotid atherosclerosis was higher in the group characterized by higher sTM quintiles, which might reflect a compensatory, physiological response to endothelial dysfunction and inflammation [7]. Results of the Hoorn study indicate that endothelial dysfunction contributes to cardiovascular (CV) mortality, even in mild renal insufficiency [8]. Indeed, a recent meta-analysis has shown that endothelial function tests are able to significantly predict CV events [9]. In patients with a history of vascular incidents, higher sTM levels have been associated with increased mortality [10]. Elevated sTM in hemodialysis (HD) patients was found to rapidly decline after kidney transplantation, reflecting restoration of the endothelial function [11]. The aim of this study was to assess correlations of sTM with various parameters of cardiovascular and renal pathology in patients with end stage renal disease. In a cross-sectional analysis, we investigated a wide panel of novel biomarkers implicated in cardiovascular comorbidity and chronic kidney disease.
Section snippets
Methods
Eighty patients in stage 5 CKD were consecutively recruited using a convenience sample from the Department of Nephrology, Jagiellonian University Medical College. Patients qualified for hemodialysis (HD) (n = 30) and undergoing HD (n = 50) were included. Following medical examination, blood samples were collected for the panel of laboratory investigations. In patients requiring surgical creation of arteriovenous fistula (AVF) for HD access, radial artery samples were collected for
Pre-dialysis and haemodialysis patient characteristics
The patients did not differ with respect to sex, age, main comorbidities and cardiovascular risk factors. However, serum creatinine concentrations were higher among those under HD, as were the concentrations of the studied inflammatory markers, inorganic phosphate, FGF-23, OPG, OPN and OC. Of note, sTM concentrations were also significantly higher in patients treated with HD (Table 1).
Serum thrombomodulin and traditional cardiovascular risk factors
sTM did not differ between patients with and without diabetes (p = 0.6), hypertension (p = 0.8), hyperlipidemia
Discussion
The salient finding of the present study is that inflammatory and mineralization cytokines TNFR2 and OPN independently predict sTM concentrations. Moreover, medial radial artery calcifications (RAC) closely correlate with sTM levels.
To our knowledge, this is the first study to investigate the relationship between sTM and an extensive panel of novel inflammatory, tissue remodeling and mineral/bone biomarkers in the setting of pre-dialysis and HD.
Previous studies reported that among other
Ethics approval and consent to participate
The study is in accordance with the Declaration of Helsinki and was approved by the Bioethics Committee of the Jagiellonian University. All patients signed an informed consent for participation prior to their inclusion into the study.
Disclosure statement
The manuscript has not been published elsewhere.
Funding
The study was supported by unrestricted grant from the Jagiellonian University Medical College, Cracow, Poland (number K/ZDS/000597).
Authors’ contributions
KB and KK conceived the study, were the major participants in its design, coordination, interpretation of results and statistical analysis, they also prepared draft manuscript. MG carried out histological examinations. PD performed statistical analysis. KW, DF and MK participated in the design of the study. JAL participated in data analysis and in preparation of the final manuscript version. MAK and WS participated in study design and coordination. All authors were involved in data collection,
Declaration of Competing Interest
The authors declare that they have no competing interests.
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