|Year : 2018 | Volume
| Issue : 4 | Page : 103-111
Relation of wnt-signaling antagonist sclerostin to valvular calcification and carotid intimal-medial thickness in hemodialysis patients
Ghada El-Said1, Mohamed AbdAlbary1, Ahmed Bahi1, Rash R Elzehry2, Ghada El-Kannishy1
1 Department of Mansoura Nephrology and Dialysis Unit(MNDU), Internal Medicine, Nephrology, Faculty of medicine, Mansoura University, Mansoura, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Mansoura Univertsity, Mansoura, Egypt
|Date of Submission||17-Jul-2018|
|Date of Acceptance||09-Aug-2018|
|Date of Web Publication||17-Dec-2018|
Dr. Ghada El-Said
Lecturer of Internal Medicine, Nephrology, Mansoura University Hospital
Source of Support: None, Conflict of Interest: None
Introduction Sclerostin (Scl) is a Wnt pathway antagonist and is considered to have a role in the bone-vascular axis in patients with chronic kidney disease. However, there is a paucity of data on the relation of circulating serum Scl and valvular calcifications (VCs) in chronic kidney disease and hemodialysis (HD) patients. The present study aimed to evaluate the relationship between serum Scl level and cardiac valve calcification (CVC) as well as carotid intimal-medial thickness (CIMT) in HD patients.
Patients and methods This cross-sectional study included 75 HD patients in Mansoura Nephrology and Dialysis Unit. Patients with age older than 75 years, rheumatic valvular disease, cardiomyopathy, prosthetic valves, ischemic heart disease, and carotid artery surgery were excluded. Echocardiogram calcification scores were used to assess the degree of aortic and mitral valve calcification. CIMT was measured using B-mode ultrasonography. Patients’ basic clinical and biochemical data were recorded. Serum Scl level was measured using commercially available enzyme-linked immunosorbent assay kits before HD sessions.
Results CIMT (>0.9 mm) was present in 68% of the patients. Double-valve calcification (aortic and mitral) was present in 72% of the patients and 21.3% of the patients had single-valve calcification. Serum Scl level was significantly higher in studied HD patients than normal healthy control (P=0.05). There was a significant negative correlation between serum Scl level and degree of cardiac valve calcification as well as with CIMT. Multiple linear regression analysis revealed that age was the strongest predictor for CIMT in HD patients.
Conclusion Cardiac valve calcification and increased CIMT were prevalent in HD patients. Serum Scl level was strongly related to both CVC and CIMT, and it may be considered as one of the calcification modulators in HD patients.
Keywords: cardiac valve calcification, carotid intimal-medial thickness calcification, hemodialysis, sclerostin
|How to cite this article:|
El-Said G, AbdAlbary M, Bahi A, Elzehry RR, El-Kannishy G. Relation of wnt-signaling antagonist sclerostin to valvular calcification and carotid intimal-medial thickness in hemodialysis patients. J Egypt Soc Nephrol Transplant 2018;18:103-11
|How to cite this URL:|
El-Said G, AbdAlbary M, Bahi A, Elzehry RR, El-Kannishy G. Relation of wnt-signaling antagonist sclerostin to valvular calcification and carotid intimal-medial thickness in hemodialysis patients. J Egypt Soc Nephrol Transplant [serial online] 2018 [cited 2019 Jan 20];18:103-11. Available from: http://www.jesnt.eg.net/text.asp?2018/18/4/103/247705
| Introduction|| |
Cardiovascular diseases (CVDs) are the most common cause of morbidity and mortality in patients with end-stage renal disease (ESRD) receiving hemodialysis (HD) . A previous study considered valvular calcification (VC) to be one of the most common risk factors in the pathogenesis of CVD in patients with ESRD . However, a recent study reported that there are different pathogenetic mechanisms of VC and was uncertain that this leads to cardiovascular events in the future .
For vascular smooth muscle cell-mediated calcification to occur, at least three key processes are required: an imbalance between calcification inhibitors and promoters, nidus formation, and osteochondrocytic differentiation ,. The Wnt canonical pathway is controlled tightly by several inhibitors, among which are Dickkopf-related protein 1 (DKK1) and sclerostin (Scl) . Scl levels in patients with ESRD reveal significant associations with the classical chronic kidney disease (CKD)-metabolic bone disease biomarkers of bone turnover such as parathyroid hormone (PTH) ,. Many studies have been done to assess the relation between Scl and VC in patients with CKD, but the results were inconsistent. Some studies have found positive associations ,, whereas others have found no association  or negative associations ,. Our study aimed to assess the relation between CVC, carotid intimal-medial thickness (CIMT), and serum Scl in patients with CKD on HD, which may be considered as a link between metabolic bone disease and VC in CKD.
| Patients and methods|| |
Our study was a cross-sectional study involving all patients with CKD on regular HD in Mansoura University Dialysis Unit during the period 2016-2017. Informed consent was obtained from all participants. The study was approved by Mansoura Faculty of Medicine Institutional Research Board. A total of 75 long-term HD patients were recruited. All patients were undergoing HD thrice a week, 4 h/session using bicarbonate-based dialysate with calcium concentrations of 1.5 mmol/l. The exclusion criteria were as follows: age younger than 18 or older than 75 years, HD duration less than 6 months, patients who had rheumatic valvular disease or underwent prosthetic valve replacement, cardiomyopathic patients with ejection fraction less than 40%, and patients who underwent carotid artery surgery. All patients were subjected to history taking, with stress on age; smoking status; HD duration; cause of ESRD, drug history and current treatment; associated comorbidities such as diabetes mellitus, hypertension, chronic liver disease and CVD; and surgical history especially previous renal transplantation and parathyroidectomy. Estimated glomerular filtration rates were calculated using the Modification of Diet in Renal Disease equation . Physical examination was done including ; measurement of weight , hight, waist , mid-arm circumference, and blood pressure, examination for edema of lower limb ,heart ,abdominal , and arteriovenous fistula examination.
Fasting blood samples were obtained before the mid-week dialysis sessions for measurement of biochemical data and serum Scl levels. We measured serum Scl in ten normal people as a comparative group of matched age and sex. Serum Scl levels were measured using a kit that uses a double-antibody sandwich enzyme-linked immunosorbent assay (SunRed ELISA Kit, Catalog No. 201-12-5418) by PeloBiotech GmbH (Planegg, Germany) (96 tests), with sensitivity of 0.175 ng/ml, and range of assay of 0.2–60 ng/ml. Biochemical data, including complete blood count, serum albumin, corrected serum calcium, phosphorus, intact PTH, serum iron, total iron-binding capacity, serum ferritin, total cholesterol, total triglycerides, high-density lipoprotein, and serum low-density lipoprotein-cholesterol concentration were calculated according to Friedewald et al. . Predialysis urea and postdialysis urea were recorded. Kt/v was calculated using Daugirdas formula .
An expert echocardiographer, who was unaware of the patients’ data, performed echocardiographic measurements according to the recommendations of the American Society of Echocardiography . Patients were examined before HD session lying in left lateral position in a semi-dark room. Two-dimensional assessment of the aortic valve and mitral valve was done using Medison SonoAce X6 device (Gyeonggi-do South Korea). Scoring of mitral calcification was done according to Wilkins calcification , and grading of aortic valve was done according to a previous study by Tenenbaum et al.  ([Table 1], as seen in [Figure 1]).
|Table 1 Grading of aortic valve calcification and mitral valve calcification|
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|Figure 1 Grades of Aortic Valve Calcification (AVC) and Mitral Valve Calcification(MVC) in some patients.|
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Common CIMT was measured using with B-mode ultrasonography using SonoScape A5 device (Guangdong, China) with a linear (superficial) probe. CIMT was measured before HD session by an expert radiologist who was blind to the patients’ clinical and laboratory data. The patients were asked to lie down in the supine position with their head tilted slightly toward the opposite of the examined side, and the probe was placed in the anterolateral position. Intima-media thickness is measured on each side from the posterior (far) wall of both right and left common carotid artery 10 mm below the carotid bifurcation. The CIMT measurement was obtained from five contiguous sites at 1-mm intervals, and the average of the five measurements was calculated on each side . Then mean CIMT was calculated from the average of right and left CIMT as seen in [Figure 2].
|Figure 2 Carotid Intimal Medial Thickness (CIMT) measurement in some patients.|
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Data were analyzed using IBM SPSS Statistics V 24 (IBM Co., Linux ,USA) for Windows. The normality of data was first tested with Shapiro–Wilk test. Qualitative data were presented by frequency tables (frequency and percentages). Quantitative variables were presented by central indices (mean±SD) for normally distributed variables and median (minimum–maximum) for non-normally distributed variables. Pearson’s correlation was used to correlate continuous normally distributed data, whereas Spearman correlation was used to correlate ordinal and non-normally distributed data. We compared non-normally distributed and ordinal variables between qualitative groups using Mann–Whitney U-test and Kruskal–Wallis H-test. Mean CIMT as a normally distributed variable was compared between qualitative groups with independent sample t-test and analysis of variance. For all aforementioned statistical tests, the results were considered significant when the probability of error is less than or equal to 5% (P≤0.05).
| Results|| |
The mean age was 46.32±15.67 years. Of the 75 patients included in the study, 41 (54.7%) patients were male and 34 (45.3%) patients were female. Most patients were nonsmokers [60 (80%) patients], 12 (15%) patients were ex-smokers, and only three (4%) patients were current smokers ([Table 2]).
Laboratory data of the current study revealed that the mean hemoglobin level was 9.35±1.59 g/dl. The transferrin saturation mean was 36.45±16.99%, and the median for serum ferritin levels was 640 ng/ml, with values ranging from 62 to 1992 ng/ml. The mean serum calcium level was 8.33±0.9 mg/dl, and the mean serum phosphorus level was 4.99±1.59 mg/dl. There was a wide range of intact PTH levels from 27 to 2000 ng/l, with median of 687 ng/l. The median for alkaline phosphatase was 146 IU/l, with values from 11 to 2151 IU/l.
Most patients had a normal lipid profile, with mean serum cholesterol of 147.83±48.27 mg/dl, mean triglyceride level of 112 (45–276) mg/dl, high-density lipoprotein of 26.080±9.84 mg/dl, and low-density lipoprotein of 96.16±44.38 mg/dl. The mean serum albumin level was 3.71±0.44 g/l. Serum Scl levels ranged from 2.1 to 60.4 ng/ml, with a median of 12.3 ng/ml ([Table 3]).
Serum Scl levels in HD patients were higher than a normal comparative group of matched age and sex ([Table 4]).
Of the 75 patients included in the study, five (6.7%) patients did not have calcification of aortic nor mitral valve when examined by echocardiography, whereas most of patients 54 (72%) had double-valve calcification and 16 (21.3%) patients had calcification in only one of the two valves ([Table 5]).
|Table 5 Prevalence of valvular calcification in the studied hemodialysis group|
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The CIMT was below or equal 0.9 mm in 24 (32%) patients when examined by carotid ultrasound and more than 0.9 mm in 51 (68%) patients ([Figure 3]). The mean for CIMT was 1.08±0.28 mm.
|Figure 3 CIMT among the studied group. CIMT, carotid intimal-medial thickness.|
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Although aortic valve calcification (AVC) had a highly significant negative correlation with serum Scl (r=−0.507, P≤0.0.001), mitral valve calcification (MVC) had a significant negative weaker correlation with serum Scl (r −0.351, P=0.002; [Figure 4], [Table 6]).
|Figure 4 Correlation between cardiac valve calcification (AVC and MVC) and sclerostin. There were significant negative correlations in both. AVC, aortic valve calcification; MVC, mitral valve calcification.|
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|Table 6 Correlation between valvular calcification, and carotid artery intima-media thickness with serum sclerostin and other parameters|
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There was a significant negative correlation between CIMT and serum Scl (r=−0.361 P=0.001; [Figure 5], [Table 6]).
|Figure 5 Correlation between sclerostin and carotid intimal-medial thickness (CIMT). There was a significant negative correlation.|
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In multiple linear regression, age was the only predictor for increased CIMT ([Table 7]).
|Table 7 Multiple linear regression analysis with carotid intimal-medial thickness as a dependent variable|
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| Discussion|| |
Most HD patients are affected by the coronary calcification  VC contributes to an extremely high cardiovascular morbidity and mortality in HD patients . Our study aimed to assess circulating levels of Scl in patients with ESRD receiving HD and their relation to aortic and MVC detected by echocardiography as well as CIMT measured by carotid ultrasonography. Serum Scl levels in our study was found to be higher in HD patients than in normal population. In accordance with the previous studies ,,, serum Scl level in the current study ranged from 2.1 to 60.4 ng/ml, with a median of 12.3 ng/ml.
KDIGO suggested that echocardiogram can be used to detect the VC in HD patients, as acceptable alternative to computed tomography-based imaging . Calcification in one valve (aortic or mitral) was documented in 21.3% of our HD patients, whereas most patients (72%) had double-valve calcification. The prevalence of VC in our patients group was higher than that reported by many studies ,. On the contrary, a higher prevalence of calcification (either vascular or valvular) was reported in a meta-analysis by Kanbay et al.  involving 12 studies investigating the relation of Scl levels and severity of calcification in ESRD on HD at 71–80%. In the study published by Ikee et al. , AVC was reported in 75.0% and MVC in 51.7% of studied patients (patients on HD). Di Lullo et al.  reported a higher prevalence of cardiac valve calcification. They evaluated VC by echocardiography in 100 patients with CKD before ESRD using the same Wilkins score as we used for MVC stratification; the study showed that all patients had AVC and 96% of them had MVC .
The CIMT in our study was more than 0.9 mm in 68% patients with a mean of 1.08±0.28 mm. However, CIMT ranged from 0.5 to 2.0 mm with a mean value of 0.93 in a study published by Ikee et al.  on HD patients. Patel et al.  reported higher values for CIMT. They studied the long-term outcome in HD patients over a period of 18 months and found the mean CIMT of 1.02 and 0.92 within the expired and the survived group, respectively. Furthermore, the median for CIMT according to Park et al.  was higher with a median of 1.2 mm with a range up to 2.50 mm. In contrary to previous reports, Ari et al.  found a mean CIMT of only 0.64 mm within their group of patients with ESRD. The age of the patients included in the study was ∼30 years . So, there is a wide variation of CIMT values in HD population in various studies, which may be attributed to differences in age, HD duration, and biochemical data in different groups.
In the past few years, many studies were published illustrating the relation between serum Scl and VC. Yet, the results may be confusing. In the current study, Scl had a significant negative correlation with AVC and MVC and as well as with CIMT. However, Brandenburg and his research group found no correlation between Scl levels and CVC and a positive correlation with AVC. They did ex-vivo analysis of 10 calcified aortic valves and found that Scl is locally produced in aortic valve tissue adjacent to areas of calcification, whereas no Scl was produced in noncalcified valves . Moreover, other studies found that there was a significant positive correlation between Scl and VC ,. This is in accordance with Pelletier et al.  who stated that for each 0.1 ng/ml rise in serum Scl, there was a 33% increase in abdominal aortic calcification risk.
On the contrary, many studies have been published proving a negative relationship between serum Scl levels and VC . In a systematic review and meta-analysis, Kanbay et al.  revealed a negative association between serum Scl and VC in eight of the 12 studies included and a positive association in only three studies, with one study that did not show a significant association . Mohamed et al.  reported that higher Scl levels were linked with better bone density, and lesser VC in HD Egyptian patients. Many studies also found a significant inverse association between Scl and VC ,.
Variations of patient groups regarding age, HD duration, comorbid conditions, the analytical differences of Scl assay (there is no standardized method), variable methods to detect VC (radiography vs. computed tomography), and discrepancy of the studied areas of calcification (cardiac valves, coronary arteries, and large arteries) all these may account for the conflicting results of the previous studies.
Whether Scl is a cause or a consequence of VC is yet to be determined . From a physiological point of view, Scl is a Wnt–β-catenin pathway inhibitor which decreases bone formation by inhibiting the osteoblasts differentiation and causing down-regulation of bone formation markers ,. It is now evident that VC follows a pathological pathway which is similar to physiologic bone process , so Scl is expected to act as an inhibitor to VC as well. On the contrary, the apparent positive association between VC and serum Scl levels may owe the compensatory action of Scl to counterbalance the VC process that results from other mechanisms . These two possible explanations may reconcile each other, and VC leads to increased Scl levels as a counter-regulatory mechanism. If this counter-regulatory mechanism suffices, Scl will be able to attenuate calcification process and higher Scl levels will be seen with lower VC. However, failure of this mechanism owing to other factors will result in higher Scl levels with higher VC . We can presume that Scl has made its way down the road from the bone to the CV field.
| Conclusion|| |
The current study concluded that serum Scl was higher in HD patients and had a significant negative correlation with cardiac valve calcification as well as CIMT. Age is the strongest determinant of CIMT in HD patients.
Study limitations and recommendations
We acknowledge several limitations of our study including the cross-sectional nature, which does not allow establishment of a causal relationship, and the relatively small number of patients. More studies are required to illustrate their relationship with larger number of patients. We must be sure about the exact effect of Scl on VC before using sclerostin antagonist as therapy for osteoporosis in patients with CKD.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]