The relationship between sclerostin and carotid artery atherosclerosis in patients with stages 3-5 chronic kidney disease

doi:10.21203/rs.2.13024/v1

Download PDF

Research article

The relationship between sclerostin and carotid artery atherosclerosis in patients with stages 3-5 chronic kidney disease

https://doi.org/10.21203/rs.2.13024/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 26 May, 2020

Read the published version in International Urology and Nephrology →

Version 1

posted

You are reading this latest preprint version

Background: Sclerotin is an antagonist of the Wnt-β-catenin pathway, may play an important role in the pathophysiology of artery atherosclerosis. Previously, we reported that sclerostin was closely related to carotid atherosclerosis and the long-term outcomes of hemodialysis patients. Here, we aimed to investigate the associations of sclerostin with renal function and carotid artery atherosclerosis in non-dialysis patients with chronic kidney disease in stages 3–5 (CKD 3–5ND). Methods: A total of 140 patients with CKD 3–5ND were enrolled in this cross-sectional study. The Chronic Kidney Disease Epidemiology Collaboration Equation (CKD-EPI) was used to estimate glomerular filtration rate (eGFR). Carotid artery atherosclerotic plaques were identified by B-mode Doppler ultrasound. Blood samples were collected to assess serum sclerostin. Unconditional logistic regression analysis was used to assess risk factors for carotid atherosclerotic plaques. Results: The median eGFR and serum sclerostin were 24.9 mL/min/1.73m 2 (interquartile range: 10.0 to 40.3 mL/min/1.73m 2 ) and 46.76 pmol/L (interquartile range: 30.18 to 67.56 pmol/L) , respectively. Carotid atherosclerotic plaques were detected in 104 subjects (74.3%). There was a negative association between sclerostin and eGFR (r = -0.214, p = 0.011). Unconditional logistic regression revealed that sclerostin was an independent factor that was significantly related to the presence of carotid plaques, with odds ratio (OR) of 1.026 (1.003, 1.051). Conclusions: Patients with CKD 3–5ND showed a gradual increase in serum sclerostin with declining renal function, and sclerostin is an independent correlate for carotid atherosclerosis.

atherosclerosis

chronic kidney disease

renal function

sclerostin

Wnt pathway

The prevalence of cardiovascular disease (CVD) in patients with chronic kidney disease (CKD) is much higher than that in the general population [1, 2]. Numerous findings have suggested that the Wnt/β-catenin signaling pathway plays an important role in the pathophysiology of atherosclerosis [3-5]. The Wnt-β-catenin signaling pathway is an important player in bone remodeling, and is involved in osteoblast proliferation, differentiation and bone formation [6, 7]. Dysregulation of the Wnt-β-catenin pathway also plays a crucial role in chronic kidney disease–mineral bone disorder (CKD-MBD) [6]. Sclerotin is a product of the SOST gene. This glycoprotein is an antagonist of the Wnt-β-catenin pathway and is predominantly secreted by osteoblasts, and plays a powerful anti-anabolic role in the formation of bone [6]. In mice, inactivating mutations in the SOST gene lead to increased bone mass [8], while activating mutations result in bone loss [9].In addition, monoclonal antibodies raised against sclerostin have been used in postmenopausal women with osteoporosis, resulting in a dose-dependent increase in bone mineral density [10].

In a previous study, Pelletier et al. found that the levels of serum sclerostin were significantly higher in CKD patients than in the general population, and started to increase during CKD stage 3 [11]. However, the specific mechanisms underlying the elevation of sclerostin in CKD remain poorly understood, but are thought to be related to renal retention [12] and/or enhanced production by osteocytes [13]. The exact role of increased sclerostin in the induction or prevention of anomalies in bone turnover in

CKD patients, still remains poorly understood.

Sclerostin has been detected on the surface of mineralized osteoblast-like cells in vitro and in the calcified aortic valve tissue of patients undergoing hemodialysis (HD) [14, 15]. More recently, Leto et al. detected sclerostin in carotid atherosclerotic plaques by immunohistochemistry [16]. Clinical studies have also observed a correlation between serum sclerostin levels and atherosclerosis in obese and diabetic patients [17, 18]. Our previous research has also shown that serum sclerostin is closely related to atherosclerosis and the long-term survival of HD patients [19]. Consequently, we speculated that sclerostin also plays an important role in the pathophysiology of atherosclerosis. Few existing study has attempted to investigate the correlation between serum sclerostin level and atherosclerosis in non-dialysis patients with chronic kidney disease (CKD-ND) [20]; interestingly, the conclusions from this work were not consistent with those from studies investigating patients undergoing HD [19, 21]. Therefore, the present study aimed to analyze the relationship between sclerostin and atherosclerosis in non-dialysis patients with chronic kidney disease in stages 3–5 (CKD 3–5ND).

Study population

A total of 140 patients aged ≥18 years with CKD 3–5ND were enrolled as study subjects between February 2015 and October 2016. Patients under systemic immunosuppressive medication and those with active cancer disease, malignant hematological disorders, acute renal failure, active liver disease, fractures, and/or acute and chronic infections were excluded from the study.

A detailed medical history, including age, gender, height, weight and the causes of CKD (chronic glomerulonephritis, hypertensive renal disease, diabetic nephropathy, chronic interstitial nephritis, polycystic kidney disease, autoimmune diseases or other diseases) were collected. We also acquired information relating to medical history, smoking (Patients who had quit smoking for more than 5 years were classified as non-smokers), diabetes mellitus (DM), and hypertension (including primary and renal hypertension).

The study was approved by the local ethics committee of Beijing Hospital (Number: 2014BJYYEC-058-01), and written informed consent was obtained from all patients.

Kidney Function Measurement

Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration Equation (CKD-EPI), as shown below:

eGFR=175× Scr^-1.154× age^-0.203(× 0.742, if female).

eGFR data were then used to classify patients into different CKD stage groupings, as follows: stage 3 (eGFR: 30–60 mL/min/1.73 m²), stage 4 (eGFR: 15–30 mL/min/1.73 m²) and stage 5 (eGFR: <15 mL/min/1.73 m²).

Biochemical parameters

Venous blood samples were taken in a fasting state, and serum creatinine levels were measured by the enzymatic isotope dilution mass spectrometry (IDMS) traceable standardized method (Roche Cobas C501 Biochemical Analyzer, Roche Diagnostics, Mannheim, Germany) in our biochemical laboratory. The serum levels of uric acid, total serum calcium, phosphate, albumin, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), alkaline phosphatasev(ALP), high-sensitivity C-reactive protein (hs-CRP), intact parathyroid hormone (iPTH) and hemoglobin were determined according to the standard laboratory methods at the hospital’s central laboratory. All serum samples were then stored at -80°C until to October 2016, an enzyme-linked immunosorbent assay (ELISA) kit (Biomedica, Austria) was used to determine the serum levels of sclerostin. Simultaneously, 18 patients with normal renal function (11 males, 7 females, mean age 59.9 years) were recruited as the control group, with a median sclerostin level of 36.31 (26.29, 43.60) pmol/L.

B-mode and Doppler ultrasound of the common carotid arteries

B-mode and Doppler ultrasound of the common carotid arteries was performed at baseline. An atherosclerotic plaque was defined as a focal structure that encroached into the arterial lumen by at least 0.5 mm or 50% of the surrounding intima-media thickness (IMT) value, or that has a thickness >1.5 mm, as measured from the media-adventitia interface to the intima-lumen interface [22]. The sonographer looked for the presence of plaques by scanning the common carotid artery, the bifurcation of the carotid artery, the proximal internal carotid artery and the external carotid artery segment, in both a longitudinal and cross-sectional manner [23]. The carotid arteries were detected bilaterally using color Doppler ultrasound at a frequency of 5–10 MHz (model IU-22; Philips, Netherlands) by an experienced sonographer, with each measurement repeated twice.

Statistical analyses

Statistical analyses were performed with SPSS 20.0 software (version 20.0, IBM Corp., Armonk, NY, USA). The normality of raw data was determined by the Kolmogorov-Smirnov test. Normally distributed continuous variables were expressed as mean ± standard deviation (SD), and non-normally distributed continuous variables as median with 25^th and 75^th percentiles. Differences between groups were compared using the Student’s t test or the Mann-Whitney U test, depending upon whether the data were normally distributed or not. Categorical data were expressed as percentages and assessed using the chi-square test. Spearman’s method was used to investigate the correlation between sclerostin and other parameters. Finally, risk factors for carotid atherosclerotic plaques were assessed by unconditional logistic regression. P < 0.05 was considered to indicate statistical significance.

Baseline patient characteristics

The demographic and clinical characteristics of the study cohort are shown in Table 1. A total of 140 subjects (age range, 25–81 years) were enrolled, including 60 patients with DM (44.3%). Of these patients, the causes of CKD were chronic glomerulonephritis (n = 41, 29.3%), hypertensive renal disease (n = 39, 27.9%), diabetic nephropathy (n = 33, 23.6%), chronic interstitial nephritis (n = 15, 10.7%), polycystic kidney disease (n = 3, 2.1%), autoimmune diseases (n = 2, 1.4%) and other diseases (n = 7, 5.0%). There were 58, 36 and 46 patients in CKD stages 3 (41.4%), 4 (25.7%) and 5 (32.9%), respectively.

The median eGFR was 24.9 mL/min/1.73m², and the median serum sclerostin concentration was 46.76 pmol/L. Carotid atherosclerotic plaques were detected in 104 subjects (74.3%). Males had significantly higher serum sclerostin levels compared with females (57.26 vs. 43.05 pmol/L; median, p < 0.001). While patients with a history of smoking (59.08 vs. 45.93 pmol/L; median, p = 0.063) and hypertension (47.75 vs. 34.41 pmol/L; median, p = 0.056) tended to have higher sclerostin levels compared with those without. Sclerostin levels were comparable between patients with and without DM (47.28 vs. 45.75 pmol/L; median, p = 0.273).

Relationships between serum sclerostin and both renal function and bone and mineral metabolism markers

With the deterioration of renal function, levels of serum sclerostin gradually increased. Spearman correlation analysis showed that serum sclerostin was negatively correlated with eGFR (r = -0.214, P = 0.011), and the sclerostin level in patients with CKD stage 5 was significantly higher than that in patients with CKD stage 3 (42.53 vs. 52.64 ng/mL, median, p = 0.048), but the levels were comparable in patients with CKD stage 3 and 4 (42.53 vs. 44.11 ng/mL, p = 0.741) and in patients with CKD stage 4 and 5 (44.11 vs. 52.64 ng/mL, p = 0.115), as shown in Figure 1. Spearman correlation analysis showed that serum sclerostin was negatively correlated with calcium (r = -0.225, P = 0.007), but positively correlated with phosphorus (r = 0.185, P = 0.028). There were no significant correlations between serum sclerostin and iPTH, hs-CRP or alkaline phosphatase.

Differences between the characteristics of the high and low sclerostin groups

The subjects (n = 140) were divided into two groups according to the median sclerostin levels (46.76pmol/L, “high” and “low” groups), as in previous studies [19]. The subjects in the high group showed a higher proportion of male patients (p = 0.042) and higher levels of serum phosphate (p = 0.002), and lower levels of eGFR (p = 0.020), serum total calcium (p = 0.007), hemoglobin (p = 0.008) and ALP (p = 0.034). (Table 1).

Comparisons between patients with and without atherosclerotic plaques

Subjects were divided into two groups according to whether they had carotid atherosclerotic plaques or not: a plaque group (n = 104) and a non-plaque group (n = 36). The plaque group had higher levels of serum sclerostin (P = 0.013), as shown in Figure 2. Moreover, the plaque group was significantly older (P < 0.001) and had a higher prevalence of hypertension (P = 0.007) and DM (P < 0.001), compared with the non-plaque group. (Table 2).

Factors related to carotid atherosclerotic plaques

Unconditional logistic regression analysis was used to analyze the related factors for carotid atherosclerotic plaques, and age, body mass index (BMI), DM, hypertension, eGFR and sclerostin (p < 0.05) were used as independent variables, and the presence of carotid atherosclerotic plaques was used as the dependent variable. This analysis showed that age, BMI, DM and sclerostin were independent factors that were significantly related to the presence of carotid plaques, with odds ratios (ORs) of 1.136 (1.082, 1.192), 1.170 (1.000, 1.369), 3.372 (1.020, 11.142) and 1.026 (1.003,1.051), respectively (Table 3).

This study found a strong negative relationship between serum sclerostin levels and renal function, and identified independent associations between serum sclerostin levels and carotid plaques in patients with CKD 3–5ND. While the increase in sclerostin levels with declining renal function has been well described in previous studies [11, 24], the specific mechanisms underlying elevated serum sclerostin levels in CKD patients have not yet been fully elucidated. In a previous study, Cejka et al. observed that urinary sclerostin excretion increased with decreasing eGFR, and noted that higher sclerostin levels in CKD patients were not related to a decline in renal function [25]. In a recent study, Graciolli et al. reported that the percentage of sclerostin-positive osteocytes in CKD patients was significantly higher when compared with a control group (38% in a group of patients with stage 2 – 3 CKD, 26% in patients with stage 4 CKD and 5.3% in the control group), and noted that the higher sclerostin levels in CKD patients may be partly derived from increased production by osteocytes [13]. In another study, Brandenburg et al. detected the expression of sclerostin by immunohistochemistry in calcified aortic valves in HD patients, they also found that serum sclerostin levels were closely associated with calcifying vasculature [15]. These authors went on to speculate that sclerostin may partly originate from an extra-skeletal source [15].

Atherosclerotic plaque formation is a complex process that involves vascular calcification, inflammation, endothelial dysfunction, and the proliferation and migration of vascular smooth muscle cells (VSMCs) [3]. Numerous studies have demonstrated that the Wnt-β-catenin pathway plays an important role in the pathophysiological process of atherosclerosis, and in the regulation of endothelial inflammation [26], mesenchymal stem cell differentiation [27, 28], and the proliferation, migration and survival of VSMCs [4]. The Wnt protein is also known to promote the adhesion of monocytes to endothelial cells [29]. Other research showed that missense mutations in the low-density lipoprotein (LDL) receptor-related proteins 6 (LRP6, a receptor of the Wnt ligand) were associated with the increased incidence of early-onset coronary artery disease, hypertension, high-serum LDL and DM [30]. Sclerotin is a soluble antagonist of the Wnt-β-catenin pathway, and interrupts this pathway by interfering with the extracellular binding of the Wnt ligand to the transmembrane receptor complex [6]. Leto et al. investigated sclerostin expression in atherosclerotic plaques, and found that levels of sclerostin were significantly increased in the media compared with the intima, and in vascular smooth muscle cells compared with infiltrating macrophages [16]. In another study, Krishna et al. observed that sclerostin may play a protective role in maintaining aortic homeostasis by inhibiting inflammation and degradation of the extracellular matrix [31]. The same authors also found that both the transgenic introduction of human sclerostin, and the administration of recombinant mouse sclerostin into apolipoprotein E-deficient mice, inhibited angiotensin II-induced aneurysm formation and atherosclerosis [31]. In the present study, we also found that sclerostin was independently associated with atherosclerotic plaques, and our previous publication reported a similar conclusion for HD patients [19]. Collectively, these findings suggest that sclerostin may play an important role in the process of atherosclerosis. We hypothesize that sclerostin may inhibit the process of atherosclerosis by inhibiting the Wnt pathway, and that the production of sclerostin by atherosclerotic plaques may act as a negative feedback protective mechanism against the development of atherosclerotic plaques. Consequently, the more severe the atherosclerosis, the more sclerostin is secreted. Further studies are now required to determine the exact role of sclerostin in atherosclerosis, and the precise involvement of the Wnt-β-catenin axis in this process.

iPTH is a well-known inhibitor of sclerostin expression in osteocytes. Rodent studies, and recent clinical studies in patients with DM and primary hyperparathyroidism, have reported a negative relationship between serum iPTH and sclerostin [32]. However, in the present study, we did not observe a significant correlation between iPTH and sclerostin in CKD patients prior to dialysis, which is similar to the results reported previously by Pelletier et al.[11] and Morena et al.[24]. In the present study, the suppressive effect may be masked by the low levels of iPTH in the early stages of CKD and in elderly CKD patients. In advanced CKD patients, both sclerostin and iPTH levels are known to increase; this suggests that osteocytes may become resistant to the suppressive effect of iPTH. Furthermore, there are other factors known to directly or indirectly regulate sclerostin, such as phosphorus and fibroblast growth factor 23 (FGF23) in CKD [33, 34]. It is also possible that sclerostin may be upregulated by other unknown regulators under uremic conditions.

This study had several limitations that need to be considered. First, this was a cross-sectional study with a relatively small sample size; we were unable to provide clear evidence of any causality between sclerostin and atherosclerosis. In addition, our study only involved a single center in China; this limits the generalizability of the findings to other ethnicities. Furthermore, our dataset lacked histopathological data from atherosclerotic plaques.

In conclusion, our results indicated that sclerostin increased with the deterioration of renal function in patients with CKD 3–5ND, and that sclerostin plays a crucial role in the development of atherosclerosis. Sclerostin may therefore represent an early warning indicator of atherosclerosis and mortality in patients with CKD.

ALP, alkaline phosphatase; BMI, body mass index; CKD, Chronic Kidney Disease; CKD-EPI, Chronic Kidney Disease-Epidemiology Collaboration Equation; CKD-MBD, chronic kidney disease–mineral bone disorder; CKD-ND, non-dialysis patients with chronic kidney disease; CVD, cardiovascular disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; ELISA, enzyme-linked immunosorbent assay; FGF23, fibroblast growth factor; HD, hemodialysis; HDL-C, high-density lipoprotein cholesterol; Hs-CRP, high-sensitivity C-reactive protein; IDMS, isotope dilution mass spectrometry; IMT, intima-media thicknesses; iPTH, intact parathyroid hormone; LDL-C, low-density lipoprotein cholesterol; LRP6, low-density lipoprotein receptor-related proteins 6; OR, odds ratio; SD, standard deviation; VSMCs, vascular smooth muscle cells.

Ethics approval and consent to participate

The study was performed in accordance with the Declaration of Helsinki and was approved by the local ethics committee of Beijing Hospital (Ethical approval number: 2014BJYYEC-058-01). Written informed consent was obtained from all patients.

Consent for publication

Written informed consent was obtained from all patients.

Availability of data and material

All data generated or analyzed during this study are included in this article. The original dataset is available as Supplementary Material.

Competing interests

The authors declare that they have no competing interests.

Funding

This study was supported by the Ministry of Science and Technology of the People’s Republic of China (No. 2017ZX09304026). The funding body had no role in study design, data collection, data interpretation, or manuscript writing.

Authors' contributions

BZ designed the experiments, performed the experiments, collected the data, performed the formal analysis and wrote the manuscript. AC designed the experiments, performed the experiments, collected the data, performed the formal analysis. HW, JC, YS and LX performed the experiments and collected the data. YM designed the experiments and reviewed/edited the manuscript.

Acknowledgements

Not applicable.

Moody WE, Edwards NC, Chue CD, Ferro CJ, Townend JN. Arterial disease in chronic kidney disease. Heart. 2013; 99:365-72.
Mafham M, Emberson J, Landray MJ, Wen CP, Baigent C. Estimated glomerular filtration rate and the risk of major vascular events and all-cause mortality: a meta-analysis. PLoS One. 2011; 6:e25920.
Marinou K, Christodoulides C, Antoniades C, Koutsilieris M. Wnt signaling in cardiovascular physiology. Trends Endocrinol Metab. 2012; 23:628-36.
Mill C, George SJ. Wnt signalling in smooth muscle cells and its role in cardiovascular disorders. Cardiovasc Res. 2012; 95:233-40.
Dejana E. The role of wnt signaling in physiological and pathological angiogenesis. Circ Res. 2010; 107:943-52.
Brandenburg VM, D'Haese P, Deck A, Mekahli D, Meijers B, Neven E, et al. From skeletal to cardiovascular disease in 12 steps-the evolution of sclerostin as a major player in CKD-MBD. Pediatr Nephrol. 2016; 31:195-206.
Monroe DG, McGee-Lawrence ME, Oursler MJ, Westendorf JJ. Update on Wnt signaling in bone cell biology and bone disease. Gene. 2012; 492:1-18.
Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D'Agostin D, et al. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res. 2008; 23:860-9.
Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. 2003; 22:6267-6276.
McClung MR, Grauer A, Boonen S, Bolognese MA, Brown JP, Diez-Perez A, et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med. 2014; 370:412-20.
Pelletier S, Dubourg L, Carlier MC, Hadj-Aissa A, Fouque D. The relation between renal function and serum sclerostin in adult patients with CKD. Clin J Am Soc Nephrol. 2013; 8:819-23.
Bonani M, Rodriguez D, Fehr T, Mohebbi N, Brockmann J, Blum M, et al. Sclerostin blood levels before and after kidney transplantation. Kidney Blood Press Res. 2014; 39:230-9.
Graciolli FG, Neves KR, Barreto F, Barreto DV, Dos Reis LM, Canziani ME, et al. The complexity of chronic kidney disease-mineral and bone disorder across stages of chronic kidney disease. Kidney Int. 2017; 91:1436-46.
Zhu D, Mackenzie NC, Millan JL, Farquharson C, MacRae VE. The appearance and modulation of osteocyte marker expression during calcification of vascular smooth muscle cells. PLoS One. 2011; 6:e19595.
Brandenburg VM, Kramann R, Koos R, Krüger T, Schurgers L, Mühlenbruch G, et al. Relationship between sclerostin and cardiovascular calcification in hemodialysis patients: a cross-sectional study. BMC Nephrol. 2013; 14:219.
Leto G, D'Onofrio L, Lucantoni F, Zampetti S, Campagna G, Foffi C, et al. Sclerostin is expressed in the atherosclerotic plaques of patients who undergoing carotid endarterectomy. Diabetes Metab Res Rev. 2019; 35:e3069.
Saadeldin MK, Elshaer SS, Emara IA, Maged M, Abdel-Aziz AK. Serum sclerostin and irisin as predictive markers for atherosclerosis in Egyptian type II diabetic female patients: A case control study. PLoS One. 2018; 13:e0206761.
Popovic DS, Mitrovic M, Tomic-Naglic D, Icin T, Bajkin I, Vukovic B, et al. The Wnt/beta-catenin Signalling Pathway Inhibitor Sclerostin is a Biomarker for Early Atherosclerosis in Obesity. Curr Neurovasc Res. 2017; 14:200-6.
Chen A, Sun Y, Cui J, Zhao B, Wang H, Chen X, et al. Associations of sclerostin with carotid artery atherosclerosis and all-cause mortality in Chinese patients undergoing maintenance hemodialysis. BMC Nephrol, 2018; 19:264.
Figurek A, Spasovski G. Is serum sclerostin a marker of atherosclerosis in patients with chronic kidney disease-mineral and bone disorder? Int Urol Nephrol. 2018; 50:1863-70.
Kirkpantur A, Balci M, Turkvatan A, Afsar B. Independent association between serum sclerostin levels and carotid artery atherosclerosis in prevalent haemodialysis patients. Clin Kidney J. 2015; 8:737-43.
Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Desvarieux M, et al. Mannheim intima-media thickness consensus. Cerebrovasc Dis. 2004; 18:346–9.
Touboul PJ, Hernández-Hernández R, Küçükoğlu S, Woo KS, Vicaut E, Labreuche J, et al. Carotid artery intima media thickness, plaque and framingham cardiovascular score in Asia, Africa/Middle East and Latin America: the PARC-AALA Study. Int J Cardiovasc Imaging. 2007; 23:557–67.
Morena M, Jaussent I, Dupuy AM, Bargnoux AS, Kuster N, Chenine L, et al. Osteoprotegerin and sclerostin in chronic kidney disease prior to dialysis: potential partners in vascular calcifications. Nephrol Dial Transplant. 2015; 30:1345-56.
Cejka D, Marculescu R, Kozakowski N,Plischke M, Reiter T, Gessl A, et al. Renal elimination of sclerostin increases with declining kidney function. J Clin Endocrinol Metab. 2014; 99:248-55.
Kim J, Kim J, Kim DW, Ha Y, Ihm MH, Kim H, et al. Wnt5a induces endothelial inflammation via beta-catenin-independent signaling. J Immunol. 2010; 185:1274-82.
Abedin M, Tintut Y, Demer LL. Vascular calcification: mechanisms and clinical ramifications. Arterioscler Thromb Vasc Biol. 2004; 24:1161-70.
Abedin M, Tintut Y, Demer LL. Mesenchymal stem cells and the artery wall. Circ Res. 2004; 95:671-6.
Lee DK, Nathan Grantham R, Trachte AL, Trachte AL, Mannion JD, Wilson CL. Activation of the canonical Wnt/beta-catenin pathway enhances monocyte adhesion to endothelial cells. Biochem Biophys Res Commun. 2006; 347:109-16.
Mani A, Radhakrishnan J, Wang H, Mani A, Mani MA, Nelson-Williams C, et al. LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science. 2007; 315:1278-82.
Krishna SM, Seto SW, Jose RJ,Li J, Morton SK, Biros E, et al. Wnt Signaling Pathway Inhibitor Sclerostin Inhibits Angiotensin II-Induced Aortic Aneurysm and Atherosclerosis. Arterioscler Thromb Vasc Biol. 2017; 37:553-66.
Drake MT, Khosla S. Hormonal and systemic regulation of sclerostin. Bone. 2017; 96:8-17.
Carrillo-Lopez N, Panizo S, Alonso-Montes C, Román-García P, Rodríguez I, Martínez-Salgado C, et al. Direct inhibition of osteoblastic Wnt pathway by fibroblast growth factor 23 contributes to bone loss in chronic kidney disease. Kidney Int. 2016; 90:77-89.
Bisson SK, Ung RV, Mac-Way F. Role of the Wnt/beta-Catenin Pathway in Renal Osteodystrophy. Int J Endocrinol. 2018; 2018:5893514.

Table 1. Demographic and clinical characteristics of the patients involved in this study along with comparisons between patients in the high and low sclerostin groups.

Variable	All patients n =140	Sclerostin < 46.76 pmol/L n = 70	Sclerostin > 46.76 pmol/L n = 70	P value
Age, years	64 (51, 73)	64 (49, 74)	64 (52, 73)	0.995
Male, n (%)	72, (51.4%)	27, (38.6%)	45, (64.3%)	0.002
Diabetes, n (%)	60, (44.3%)	29, (41.4%)	31, (44.3%)	0.733
Hypertension, n (%)	120, (85.7%)	57, (81.4%)	63, (90.0%)	0.147
Atherosclerotic plaque, n (%)	104, (74.3%)	50, (71.4%)	54, (77.1%)	0.439
Smoker, n (%)	38, (27.1%)	16, (22.9%)	22, (31.4%)	0.254
BMI, (kg/m²)	24.82 ± 3.91	25.00 ± 3.46	24.65 ± 4.33	0.601
Systolic BP, (mmHg)	130（130, 150）	133（130, 150）	130（130, 150）	0.594
Diastolic BP, (mmHg)	80（70, 86）	80（70, 90）	80（70, 80）	0.266
eGFR, mL/min/1.73 m²	24.9 (10.0, 40.3)	26.8 (14.3, 44.3)	22.0（8.0, 36.8）	0.020
Hemoglobin, g/L	110 ± 25	115 ± 23	104 ± 26	0.008
Albumin, g/L	40 (37, 43)	41 (38, 43)	40 (36, 42)	0.050
Phosphate, mmol/L	1.37 (1.17, 1.68)	1.32 (1.18, 1.52)	1.45 (1.16, 1.82)	0.042
iPTH, pg/mL	85 (47, 189)	79 (45, 179)	103 (50, 207)	0.161
Alkaline phosphatase, U/L	75 (59, 92)	81 (59, 97)	67 (59, 83)	0.034
Calcium, mmol/L	2.23 (2.10, 2.34)	2.28 (2.16, 2.34)	2.18 (2.00, 2.32)	0.007
Uric acid, umol/L	442 ± 126	424 ± 117	460 ± 133	0.086
Cholesterol, mmol/L	4.31 ± 0.95	4.37 ± 0.98	4.25 ± 0.93	0.429
LDL-C, mmol/L	2.54 ± 0.75	2.56 ± 0.71	2.52 ± 0.78	0.738
HDL-C, mmol/L	1.08 (0.91, 1.28)	1.13 (0.91, 1.35)	1.07 (0.91, 1.25)	0.528
hs-CRP, mg/dl	1.84 (0.85, 4.67)	1.84 (0.61, 4.13)	1.82 (0.86, 6.94)	0.250

Normally distributed variables are shown as mean ± standard deviation; non-normally distributed variables are shown as medians (with 25 and 75% interquartile ranges in parentheses). BMI, body mass index; eGFR, estimated glomerular filtration rate; iPTH, intact parathyroid hormone; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein.

Table 2. Comparisons between patients with and without atherosclerotic plaques.

Variable	Patients with plaques n = 104	Patients without plaques n = 36	P value
Age, years	67.0 (61.0, 74.0)	44.5 (35.3, 55.3)	< 0.001
Male, n (%)	58, (55.8%)	14, (38.9%)	0.081
Diabetes, n (%)	54, (51.9%)	6, (16.7%)	< 0.001
Hypertension, n (%)	94, (90.4%)	26, (72.2%)	0.007
Smoker, n (%)	32, (30.8%)	6, (16.7%)	0.101
BMI, (kg/m²)	25.35 ± 3.72	23.31 ± 4.11	0.007
Systolic BP, (mmHg)	130（130, 150）	137（130, 150）	0.896
eGFR, mL/min/1.73 m²	11.8 (27.0, 40.7)	5.6（18.3, 38.0）	0.069
Hemoglobin, g/L	113 ± 23	101 ± 27	0.013
Albumin, g/L	41 (38, 43)	40 (37, 43)	0.517
Phosphate, mmol/L	1.37 (1.11, 1.60)	1.39 (1.19, 1.92)	0.107
iPTH, pg/mL	77.9 (46.0, 172.3)	114.5 (58.0, 243.8)	0.037
Alkaline phosphatase, U/L	75 (59, 93)	74 (57, 91)	0.543
Calcium, mmol/L	2.26 (2.13, 2.34)	2.17 (1.97, 2.33)	0.144
Uric acid, umol/L	418.8 ± 107.3	509.7 ± 150.8	0.002
Cholesterol, mmol/L	4.26 ± 0.94	4.46 ± 0.99	0.265
LDL-C, mmol/L	2.51 ± 0.75	2.64 ± 0.75	0.379
HDL-C, mmol/L	1.07 (0.92, 1.28)	1.13 (0.89, 1.35)	0.894
hs-CRP, mg/dl	1.80 (0.83, 5.07)	2.02 (1.20, 3.73)	0.635
Sclerostin, (pmol/L)	47.66 (32.60, 72.91)	42.62 (26.20- 55.50)	0.010

Table 3. Factors related to carotid atherosclerotic plaques.

Variable	Coefficient(r) or β	P	OR (OR 95% CI)
Age (per year)	0.127	< 0.001	1.136 (1.082, 1.192)
BMI, (kg/m²)	0.157	0.049	1.170 (1.000, 1.369)
Diabetes (Y versus N)	1.125	0.046	3.372 (1.020, 11.142)
Sclerostin (1 pmol/L)	0.026	0.029	1.026 (1.003, 1.051)

BMI, body mass index; OR, Odds ratios; CI, confidence interval.

Additionalfile1.xlsx

Download PDF

Journal Publication

published 26 May, 2020

Read the published version in International Urology and Nephrology →

Version 1

posted

You are reading this latest preprint version

The relationship between sclerostin and carotid artery atherosclerosis in patients with stages 3-5 chronic kidney disease

Status:

Journal Publication

Version 1

Abstract

Figures

BACKGROUND

Methods

Results

Discussion

Conclusions

Abbreviations

Declarations

References

Tables

Supplementary Files

Status:

Journal Publication

Version 1