|Year : 2016 | Volume
| Issue : 1 | Page : 46-54
Evaluation of coronary artery calcification using multislice computed tomography in patients on dialysis: association with fetuin-A and osteoprotegerin
Sherif Aziz Zaki1, Osama Hassan Shehata1, Akram A Deghedi2, Shehab Mohamed Sami3, Rehab H.M. Mersal1
1 Department of Internal Medicine, Faculty of Medicine, Alexandria University, Alexandria, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
3 Department of Radiodiagnosis, Faculty of Medicine, Alexandria University, Alexandria, Egypt
|Date of Submission||01-Dec-2015|
|Date of Acceptance||03-Jan-2016|
|Date of Web Publication||22-Jun-2016|
Rehab H.M. Mersal
Department of Internal Medicine, Faculty of Medicine, Alexandria Smouha District 7 Kamal Eldin Salah, Alexandria
Source of Support: None, Conflict of Interest: None
Cardiovascular disease is the leading cause of mortality in patients with end-stage renal disease (ESRD) and is attributed to a combination of traditional and nontraditional risk factors. In recent years, there has been an increasing recognition of a very high prevalence of cardiovascular calcification in the ESRD population, including patients receiving hemodialysis (HD) and peritoneal dialysis. The mechanism is multifactorial, including structural and functional abnormalities in the large vessels, disorders in calcium (Ca2+) and phosphate (P) metabolism, vascular smooth muscle cells changes, and regulatory markers such as fetuin-A and osteoprotegerin (OPG).
Aim of the work
The aim of the present study was to determine the utility of multislice computed tomography (MSCT) for the assessment of coronary artery calcifications (CACs) and to identify the potential risks for CAC, including calcification regulating proteins such as fetuin-A and OPG, among patients with ESRD on maintenance dialysis (HD and peritoneal dialysis).
Patients and methods
This study included 70 patients who were divided into four groups: 20 patients on continuous ambulatory peritoneal dialysis (CAPD), 10 patients with ESRD stage 4 and 5, 30 patients on HD (subdivided into three subgroups according to the duration of HD: for 1–5 years, for 5–10 years, and for more than 10 years), and 10 healthy controls. They were subjected to complete history-taking, thorough clinical examination, investigations including serum level of fetuin-A, serum level of OPG by using the enzyme-linked immunosorbent assay technique, as well as MSCT imaging using 128-detector scanners for the quantification of CAC (calcium scoring) by using the Agatston method.
There was a significant decrease in the serum level of fetuin-A in patients on HD compared with patients on CAPD, as well as in healthy controls. Moreover, there was a significant increase in the serum level of OPG in patients on HD compared with its level in CAPD patients as well as in healthy controls. The calcium scoring was significantly high in the HD group of patients (group IIa) (P = 0.032), with a low calcium score in CAPD patients group (group I) (P = 0.036) compared with healthy controls in group IV. CAC scoring was correlated positively and significantly with serum level of OPG in the total samples (r = 0.345* and P = 0.0270). On the other hand, it was negatively and significantly correlated with the serum level of fetuin-A in the total samples (r = −0.411* and P = 0.002).
Fetuin-A and OPG can be early and important markers of vascular calcifications in patients on dialysis; in addition, calcium scoring using MSCT provides a noninvasive method of assessment of the vascular calcification in these patients. Vascular calcification is more evident in patients on HD than in patients treated using CAPD; this can help in the selection of the modality of treatment of patients with ESRD, as well as early detection and prevention of cardiovascular (CVS) diseases in patients with ESRD treated with dialysis either HD or CAPD.
Keywords: Agatston calcium scoring, fetuin-A, osteoprotegerin, vascular calcifications
|How to cite this article:|
Zaki SA, Shehata OH, Deghedi AA, Sami SM, Mersal RH. Evaluation of coronary artery calcification using multislice computed tomography in patients on dialysis: association with fetuin-A and osteoprotegerin. Egypt J Obes Diabetes Endocrinol 2016;2:46-54
|How to cite this URL:|
Zaki SA, Shehata OH, Deghedi AA, Sami SM, Mersal RH. Evaluation of coronary artery calcification using multislice computed tomography in patients on dialysis: association with fetuin-A and osteoprotegerin. Egypt J Obes Diabetes Endocrinol [serial online] 2016 [cited 2020 Jul 9];2:46-54. Available from: http://www.ejode.eg.net/text.asp?2016/2/1/46/184398
| Introduction|| |
Patients with chronic kidney disease (CKD) experience up to 30-fold higher cardiovascular disease mortality than does the general population . This staggering outcome is only incompletely explained by such traditional risk factors as aging, smoking, diabetes, dyslipidemia, or hypertension ,. These traditional risk factors cannot completely account for the excessive prevalence of CKD , suggesting dialysis-specific risk factors that may contribute to hyperphosphatemia and elevations in the calcium × phosphorus product in patients with CKD-5 with increased mortality . In addition, studies have linked these disorders of mineral metabolism with vascular calcification in-vitro, in-vivo animal models, and in humans .
Vascular calcification is a common complication in uremia, due in part to disturbed mineral metabolism and the therapies used to control it , as well as due to a complex, active process of osteogenesis in vascular smooth muscle cells ,,. Furthermore, cardiovascular calcifications in patients with CKD are more prevalent, progressive, extensive, and severe compared with the non-CKD population. The prevalence of coronary artery calcification (CAC) has been reported to range from 40% to nearly 100% in patients on dialysis .
Vascular calcifications can result in a range of pathologies including calcemic uremic arteriolopathy (formerly termed calciphylaxis) and extraosseous soft tissue calcification; however, valvular and vascular calcifications are the most common and perhaps the most clinically significant manifestations .
Research efforts have expanded because of the contribution of vascular pathologies to understand the nature of extraosseous calcification that occurs in patients with CKD.
There are two major types of calcification affecting different layers of the artery :
- Atherosclerotic plaque, which occurs within the intimal layer of the arteries; arterial intimal calcification is seen in advanced atherosclerosis. Arterial intimal calcification has been shown to develop in older individuals and those with prolonged history of diabetes, hypertension, smoking, and other traditional risk factors .
- Monckeberg's sclerosis, which occurs in the medial wall (or tunica media).
Medial calcification is noninflammatory and increases vascular stiffness and reduces vascular compliance. This type of calcification is common in uremic patients, especially in young age.
Multiple inhibitors of vascular calcification are known. Local tissue inhibitors include matrix gla protein, pyrophosphates, osteopontin, fetuin-A, and osteoprotegerin (OPG) ,.
Fetuin-A [Heremans-Schmid glycoprotein (AHSG)] is an inhibitor of calcification. It is synthesized predominantly in the liver and is abundant in serum at levels of 0.5–1.0 g/l. The transcription and synthesis of fetuin-A are downregulated during inflammation; therefore, fetuin-A represents a reverse acute phase reactant. Low levels of fetuin-A in patients with CKD are associated with arterial calcification, calciphylaxis, vascular smooth muscle cells apoptosis, and mortality. Fetuin-A binds to both calcium and phosphate in the serum, forming small 'calciparticles', which are presumably removed through the reticuloendothelial system; therefore, fetuin-A acts in host defense to clean the blood of unwanted calcium and phosphate ,.
OPG is a regulatory factor produced by bone marrow-derived stromal cells. OPG has a pivotal role in the regulation of the bone turnover inhibiting osteoclast differentiation and acts like a decoy receptor for the receptor activator of nuclear factor-kB ligand (RANKL system). OPG-deficient mice have been shown to develop both severe aortic calcifications and osteoporosis .
On the one hand, OPG is considered to prevent vascular calcification as it blocks the bone remodeling process in the vascular tissue following the interaction between RANK (expressed by osteoclast-like cells) and RANKL (expressed by osteoblast-like cells). It is also a neutralizer of the proapoptotic actions of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), which strongly activates vascular cell apoptosis .
On the basis of these experimental considerations, OPG deficiency should be associated with an increased risk of extraosseous calcification; however, things appear to be quite different in humans, especially during the uremic condition .
Patients on dialysis have increased OPG levels when compared with the normal population. Moreover, elevated OPG levels have been found to be independently associated with aortic calcification .
A similar observation was already made in the nondialysis population in which higher OPG levels pointed to an increased cardiovascular risk – this phenomenon was termed a 'seeming paradox' . It currently remains an unanswered question whether OPG upregulation is predominantly a marker of cardiovascular disease , an important but incomplete self-defense mechanism trying to counteract excessive atherosclerosis and calcification, or possesses potentially damaging properties in humans that have not yet been identified .
The multidetector computed tomography scan system enables noninvasive detection of coronary artery disease, with an early detection of rupture-prone soft plaques . Since 2001, multislice computed tomography (MSCT) has been able to display a promising capability in detecting not only coronary calcium but also the noncalcified component of plaques .
Thus, these advantages make MSCT a powerful tool that could be used in the early detection of vascular and valvular calcifications in patients on dialysis and even in patients with end-stage renal disease (ESRD).
Therefore, the aim of this study was to investigate the role of the serum inhibitors of calcifications – fetuin-A and OPG with MSCT – in early detection of CACs in patients with ESRD and in patients on dialysis [hemodialysis (HD) and peritoneal dialysis (PD)] with comparing the risk of CAC between the two modalities of dialysis.
| Patients and Methods|| |
We studied 60 patients with kidney disease; 20 of them with ESRD were on maintenance PD for more than 6 months, with a mean age of 28.95 ± 7.94 years (group I). Group IIa comprised 10 patients with ESRD on maintenance HD for 1–5 years by bicarbonate HD (4 h per se ssion, three times weekly) using polysulfone dialyzer with a surface area of 1.3 m 2, with a mean age of 25.50 ± 6.62 years; group IIb comprised 10 patients with ESRD on maintenance HD for 5–10 years, with a mean age of 28.80 ± 5.87 years; and group IIc comprised 10 patients on maintenance HD for more than 10 years, with a mean age of 27.50 ± 6.31years. Ten patients with ESRD, with creatinine clearance of average 20 ml/min, and a mean age of 26.10 ± 5.22 years, were included in group III. Exclusion criteria for the present study included diabetes mellitus, chronic inflammatory diseases, active infections, smoking, hyperlipidemia, and coronary heart diseases.
As the control group we selected 10 healthy volunteer subjects accurately age and sex matched to patients with ESRD and those on dialysis, with a mean age of 25.10 ± 4.36 years. To be selected, healthy subjects had to have no alteration at an extensive clinical and biochemical work-up, and had to have normal urine analysis and estimated glomerular filtration rate equal or greater than 90 ml/min/1.73 m 2, which is recommended threshold for the diagnosis of CKD.
The study was conducted in accordance with the ethical guidelines of the 1975 Declaration of Helsinki. An informed consent was obtained from all participants in the study.
All patients and controls were subjected to thorough history-taking, which included the history of phosphate binders with or without calcium content. In addition, full clinical examination was carried out with special observation for signs of calcemic uremic arteriolopathy (calciphylaxis).
Laboratory investigations included complete blood count , renal function tests (blood urea, serum creatinine, and creatinine clearance) , serum ionized calcium, phosphorus with calculation of calcium-phosphorus product, alkaline phosphatase, and serum intact parathyroid hormone level . Lipid profile , erythrocyte sedimentation rate, high-sensitive C-reactive protein (hs-CRP) , and plasma fibrinogen were also estimated .
Estimation of dialysis adequacy by measuring total weekly Kt/V for both HD and peritoneal patients was carried out ,. Furthermore, patients on PD were subjected to total weekly test of peritoneal permeability by using the peritoneal equilibration test .
Serum fetuin-A measurement 
Serum fetuin-A and OPG levels were measured using the quantitative sandwich enzyme-linked immunosorbent assay technique. Quantizing kit, as described by Axelsson, was used for the study.
The Quantikine Human Fetuin-A Immunoassay contains NS0-expressed recombinant human fetuin-A and was performed according to the manufacturers' protocol provided by R&D Systems Inc. (Minneapolis, Minnesota, USA).
Serum osteoprotegerin measurement 
Detection of the serum level of OPG was carried out using the sandwich enzyme-linked immunosorbent assay kit using streptavidin-HRP, as described by Morena and colleagues. OPG was provided by DRG International Inc. (USA).
CACs were assessed by using MSCT with 128-detector scanner for quantification of CAC (calcium scoring) by using the Agatston method .
Quantification of calcifications is based on a score published in a study by Agatston et al. . The 'calcium score' was determined by multiplying the area of calcification by a weighted density score: 1 = 130–199 HU, 2 = 200–299 HU, 3 = 300–399 HU, and 4>400 HU. Individual scores were calculated for the left main coronary artery, the descending branch of the left coronary artery, the circumflex branch of the left coronary artery, and the right coronary artery. The total coronary score is the sum of these individual scores .
Statistical analysis of the data 
All calculations were carried out on a personal computer with IBM SPSS software package (version 20.0) for Windows .
Qualitative data were presented as numbers (n) and percentages (%). Quantitative data were presented as mean and SD. Comparison between the means of quantitative variables was performed using the one-way analysis of variance (F-test). The correlations between different variables were evaluated by using Pearson's or Spearman's correlation coefficients according to the distribution of variables (continuous or discontinuous quantitative variables, respectively). P value less than or equal to 0.05 was accepted as statistically significant.
| Results|| |
Clinical and biochemical characteristics of the study participants are presented in [Table 1].
Blood urea, serum albumin, serum ionized calcium, serum phosphorus, calcium×phosphorous product, serum alkaline phosphatase, serum intact parathormone level, serum fibrinogen, hs-CRP had a significant difference all through the three groups (P < 0.001); their levels were significantly higher in patients on HD for more than 10 years than in patients on PD and controls. There was no significant difference between the groups as regards other clinical parameters such as age.
Circulating serum fetuin-A levels were significantly higher in patients on PD and controls than in all patients on HD (1.26 ± 0.28 and 1.49 ± 0.23 g/l, respectively, vs. 0.56 ± 0.32/0.42 ± 0.14/0.30 ± 0.07 g/l in group IIa, IIb, and IIc, respectively). Furthermore, it was significantly higher in patients on PD than in patients with ESRD in group III (1.26 ± 0.28 vs. 0.69 ± 0.70 g/l).
Serum OPG levels were significantly higher in patients on HD, especially group IIc (more than 10 years on HD), than in patients on PD and controls (10.65 ± 3.05 vs. 3.25 ± 0.98 ng/ml in PD and 2.84 ± 0.89 ng/ml in controls).
The mean value of CAC scoring using MSCT in patients on HD, especially in patients for more than 10 years on HD, was significantly higher than in patients on PD (321.6 ± 166.2 vs. 89.6 ± 52.3). In addition, using MSCT we found that 30% of the patients on HD for more than 10 years had increased calcifications (101–400 vs. only 10% of the patients on PD); meanwhile extensive calcifications (>400) were observed in 30% of the patients on HD compared with 0% in patients on PD.
Correlations between CAC scoring and different parameters in the different groups are shown in [Table 2] and [Figure 1].
|Table 2: Correlation between coronary artery calcification, fetuin-A, and osteoprotegerin with different parameters in each group and total sample|
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|Figure 1: Correlation between coronary artery calcium score with osteoprotegerin (OPG) and fetuin-A in each group and total sample.|
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CAC scoring was correlated positively and significantly with the serum level of ionized calcium, phosphorus, calcium×phosphorus product, alkaline phosphatase, intact parathyroid hormone, hs-CRP, and fibrinogen.
CAC scoring was correlated positively and significantly with the serum level of OPG in the total samples (r = 0.345* and P = 0.0270).
CAC scoring was correlated negatively and significantly with the serum level of fetuin-A in the total samples (r = −0.411* and P = 0.002).
| Discussion|| |
In the present study, serum OPG (P = 0.015) was significantly higher in patients on HD for more than 10 years (group IIc) than in all other participants; meanwhile its level was significantly lower in patients on PD (group I) and controls. In this study, there was a positive correlation between increased OPG serum level and elevated calcium scoring (P = 0.027, r = 0.345*).
In agreement with our study, Lee et al.  showed in their study that increasing serum levels of OPG in patients on HD was independent of age, HD duration, systolic blood pressure, pulse wave velocity, cholesterol, and triglycerides. In addition, the new cardiovascular events were higher among those with higher serum levels of OPG. A study by Pateinakis et al.  found out that OPG was the only variable that was independently associated with carotid intimal medial thickness and that the OPG level had a positive correlation with vascular calcifications.
Furthermore, the study conducted by Ozkok et al.  showed that both baseline and first-year serum OPG levels were significantly higher in the group of patients with progressive coronary calcification (OPG: 0.26 pmol/l, CACs: 495) compared with the nonprogressive group (OPG: 0.18 pmol/l, CACs: 2.15).
In the current study, the serum levels of fetuin-A in patients on HD for more than 10 years (group IIc) were significantly lower than that of participants in all other groups. Meanwhile, patients on PD, as well as the controls, showed significantly higher serum levels of fetuin-A than did patients on HD and those with ESRD. There was a negative correlation between the serum level of fetuin-A and CAC score (r = −0.411* and P = 0.002).
In agreement with the current work, Turkmen et al.  conducted a study on 78 patients on HD, all patients on dialysis for more than 6 months. CAC scores were determined. Serum C-reactive protein, interleukin-1b (IL-1b), IL-6, tumor necrosis factor-a, and serum fetuin-A levels were measured. They found out that there was a negative relationship between fetuin-A levels and total CAC scores.
In another study conducted by Stenvinkel et al.  on 258 patients with ESRD starting renal replacement therapy, hs-CRP, fetuin-A, S-albumin, and IL-6 were measured. Their study showed that a low fetuin-A level was associated with malnutrition, inflammation, and increased cardiovascular and all-cause mortality.
In their cross-sectional study on 81 stable chronic HD patients, Pateinakis et al.  measured carotid-to-femoral pulse wave velocity reflecting arterial stiffness, and common carotid intima–media thickness, a surrogate of early atherosclerosis, as well as the serum levels of fetuin-A and OPG. They concluded that common carotid intima–media thickness was negatively associated with fetuin-A and positively with OPG; they also found that both fetuin-A and OPG were independently associated with carotid-to-femoral pulse wave velocity.
In contrast to the findings of our study, a study by Hermans et al.  found no association between circulating fetuin-A and pulse wave velocity and cardiovascular mortality.
Another study, conducted by Reslerova et al. , showed that the serum levels of fetuin-A were negatively correlated with the CAC score, although the fetuin-A levels in subjects with no calcification did not differ from those with mild calcification (score 1–200) or with severe calcification (score>200), although a trend was present.
In the current study, CAC was assessed using the calcium score calculated by using MSCT; it was found that coronary calcification in patients on HD patients, specially patients on HD for more than 10 years, was significantly higher and more extensive than in patients on PD.
In agreement with the current work, Rubin  and Bazeeda et al.  in their respective studies assessed the role of computed tomography in diagnosing CAC in patients with ESRD patients and those on HD; they demonstrated that CAC progressively increased with the decline in the estimated glomerular filtration rate, and that measurement using noncontrast computed tomography has greater reliability and substantially with lower radiation exposure as it provides risk stratification of asymptomatic individuals with the intent of targeting therapy to prevent coronary heart disease and acts as a gatekeeper to cardiac catheterization to minimize unnecessary invasive diagnostic coronary procedures.
Studies conducted by Hernandes et al.  and Barreto et al.  reported results comparable to those of the present work. The first study, conducted on 23 adult patients on dialysis, demonstrated no CAC in 30% of the patients, moderate calcification in 12%, and severe calcification in 36% of the patients; and the second study, conducted on 101 patients on HD, demonstrated that the range of the calcium score was 0.5547; a total of 52 patients showed moderate and severe CAC, and 20% of them had calcium scores greater than 1000.
| Conclusion|| |
Serum levels of OPG were significantly lower in patients on PD than in patients on HD and there was significant positive correlation between the serum level of OPG and CAC assessed by using the calcium scoring calculated using MSCT. Serum levels of fetuin-A were significantly higher in patients on PD than in patients on HD, with significant negative correlation with CACs. Thus, serum OPG and fetuin-A can be regulatory markers for CAC, conjunction with CAC scoring using MSCT contribute noninvasive assessment of CACs in ESRD patients as well a dialysis patients. In addition, we conclude that the low incidence and level of calcification in patients on PD make it an important modality of treatment of patients with ESRD.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]