|Year : 2019 | Volume
| Issue : 3 | Page : 571-580
|Vascular calcification in patients with chronic kidney disease on dialysis in the Kingdom of Saudi Arabia: A cross-sectional study
Mohammed Abdulrahman AlGhonaim1, Adel A Fathalla2
1 Department of Medicine, College of Medicine, King Saud University, King Khalid University Hospital, Riyadh, Saudi Arabia
2 Medical Manager of Oncology/Hematology Franchise, Thrombosis, Cardiovascular, Anti-Psychotics, Anti-Infectives, Nephrology and Bio-Surgery, Sanofi, Riyadh, Saudi Arabia
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|Date of Submission||13-Feb-2018|
|Date of Acceptance||25-Feb-2018|
|Date of Web Publication||26-Jun-2019|
| Abstract|| |
The study aimed to provide a unique nationwide data and a valuable update on the current situation of vascular calcification (VC) among chronic kidney disease (CKD) patients in the Kingdom of Saudi Arabia. The study included all patients diagnosed with CKD over a period of one year and six months from September 2015 to February 2017 and underwent dialysis. All analyses were done using IBM-SPSS. Of the 842 enrolled patients, 836 (99.3%) constituted the descriptive population. The mean age of patients was 51.8 ± 15.4 years. A total of 759 (90.8%) patients had cardiovascular risk factors. The prevalence of VC in patients with CKD is 40.8%. In the multivariate analysis, prognostic factors for VC were physical inactivity with odd ratio 2.87 [95% confidence interval (CI): (1.89–4.63), P < 0.01], history of ischemic heart disease 2.34 [95% CI: (1.30–4.22), P < 0.01], dyslipidemia 1.56 [95% CI: (1.01–2.40), P = 0.04], and older age 1.06 [95% CI: (1.05–1.07), P <0.01]. At inclusion, the mean ± standard deviation for high-density lipoprotein cholesterol, low cholesterol, total cholesterol, and triglycerides was 41 ± 30, 79.7 ± 29.9, 144.2 ± 38.5, and 143.4 ± 95.3 mg/dL, respectively. This study reports useful information about the prevalence of VCs in CKD stage 5D in a Middle Eastern country as the Kingdom of Saudi Arabia. Furthermore, it offers information on the predictors or associated factors of a VC in CKD patients.
|How to cite this article:|
AlGhonaim MA, Fathalla AA. Vascular calcification in patients with chronic kidney disease on dialysis in the Kingdom of Saudi Arabia: A cross-sectional study. Saudi J Kidney Dis Transpl 2019;30:571-80
|How to cite this URL:|
AlGhonaim MA, Fathalla AA. Vascular calcification in patients with chronic kidney disease on dialysis in the Kingdom of Saudi Arabia: A cross-sectional study. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Oct 17];30:571-80. Available from: http://www.sjkdt.org/text.asp?2019/30/3/571/261329
| Introduction|| |
Chronic kidney disease (CKD) is one of the serious diseases that spread widely. It is characterized by the gradual reduction of renal functions. This may lead to high risk of cardiovascular diseases and the end stage of renal disease (ESRD). More than 14% of the general population was affected by CKD. The main two causes of CKD are elevated blood pressure and diabetes mellitus (DM)., According to National Institute of Diabetes and Digestive and Kidney Diseases, CKD consists of five stages: Stage I: kidney damage with normal renal function, Stage II: kidney damage with mild loss of renal function, Stage III: mild to severe loss of renal function, Stage IV: severe loss of renal function, and Stage V: kidney disease that require treatment or transplant which known as ESRD. The most important cause of mortality among the patients with CKD is cardiovascular-related complications.
Vascular calcification (VC) is a serious condition, characterized by reducing the elasticity of the vessels. VC is associated with increased mortality in patients with CKD. VC may cause congestive heart failure, hypertension, myocardial infarction, and aortic stenosis.,, Many studies approved the correlation and causation between CKD and VC. According to the site of calcification, there are two major types: atherosclerosis calcification which presents in the intimal layer and Monckeberg sclerosis that presents in elastic lamellae of the middle layer. The last type is the most common type in patients with CKD. Hypophosphatemia and hyper-kalemia are associated with VC in patients with dialysis., The elevation of calcium and phosphate is not the only cause of VC but also the apoptosis of vascular smooth muscle cells and the transformation of it into osteoblast-like cells. Many investigators reported that the risk of VC is increased in patients undergoing renal dialysis., The objective of this study was to evaluate the prevalence and characteristics of VC in CKD dialysis from Kingdom of Saudi Arabia and to determine possible associated factors. This study will provide a unique nationwide data and a valuable update on the current situation of VC among CKD patients in the Kingdom of Saudi Arabia, allowing investigation of patient and treatment characteristics.
| Patients and Methods|| |
Study design and participants
This was a multicentral, cross-sectional, noninterventional study that was carried in Kingdom of Saudi Arabia over a period of one year and six months from September 2015 to February 2017. The study aimed to enroll 1000 Saudi CKD patients on dialysis from twelve to fourteen centers all over the country.
Selection of centers decided based on selection criteria and in the agreement between the sponsor and principal investigator aiming to have representative samples from all over the kingdom.
The patients included in this study were adult Saudi CKD patients on dialysis. Evaluations are determined by the treating physician in accordance with the standard of care and individual clinical practice. To limit biases of subject selection, all consecutive and eligible CKD patients on dialysis visiting the study center were included.
Inclusion criteria were patients with signed informed consent; male and female patients aged 18 years and above; patients diagnosed with CKD/ESRD and on dialysis; patients for whom the treating physicians have decided to perform arterial calcification measurements routinely; and patients who were not participating in any other clinical trial.
Patients with acute kidney injury, active inflammatory diseases, parathyroidectomy or evident malignancies, patients with conditions making arterial calcification detection technically impossible or unreliable, such as cardiac arrhythmias, amputations, or severe peripheral vascular lesions, and pregnant or breastfeeding females were excluded.
Sampling and data management
The sample size was calculated using the following equation:
Where “n” is the required sample size, “Z’ is a constant equal 1.96, and “p” is the expected rate of VC. Among CKD patients on dialysis, “d” is the desired absolute precision (5%) and “DEFF” is the estimated design effect. The primary objective of this study was to assess the prevalence of VC among CKD patients on dialysis. As prevalence for VC among CKD is unknown in the Saudi population and the Arab population in general, the value of 50% was retained because it produces the largest sample size.
The required sample size of the study was calculated using single population proportion formula by considering the following assumption: a 95% confidence level, 5% marginal error, 50% expected proportion of VC among CKD patients on dialysis, nonresponse rate of 10%, and 2 estimated design effect. Calculated sample size was 845 CKD patients. Thus, the smallest sample size required to this cross-sectional study is estimated to be around 845. This rounded up to 1000 patients.
Data were collected using a paper-based Case Report Form (CRF). Monitoring team checked CRFs against the source documents. The automated handling of data by RAY Contract Research Organization (CRO) after receipt of the CRFs had generated additional requests (including queries about primary and secondary objectives) to which the investigator responded by confirming or modifying the data questioned. The requests with their responses were appended to the CRFs. The data release consent form included a statement that allowed the sponsor’s duly authorized personnel, the ethic committee (IRB/IEC), and the regulatory authorities to have direct access to original medical records which support the data on the CRFs.
Primary outcome: To assess the rate of VC in CKD patients on dialysis.
Secondary outcomes: To identify the predictor or associated factors of VC in CKD patients; compare the extent of VC between type 2 diabetic CKD patients and nondiabetic CKD patients; and determine the percentage of patients achieving serum phosphorus, calcium, and intact parathyroid hormone (iPTH) according to Kidney Disease Outcomes Quality Initiative (KDOQI) and Kidney Disease Improving Global Outcomes (KDIGO) guidelines, respectively.
| Statistical Analysis|| |
The most statistical analysis was descriptive; reporting patient counts, means, standard deviations (SDs), medians, minima, and maxima for continuous variables (e.g., age) as well as frequencies and percentages for categorical variables. Data were presented as prevalence rate, and 95% confidence interval (CI) was calculated for the rates. The level of significance was set at 0.05. All analyses were done using Statistical Package for Social Sciences version 22.0 for Windows (IBM Corp., Armonk, NY, USA), and a two-tailed P < 0.05 was considered statistically significant or less. We conducted a multivariate analysis to investigate the impact of the risk factors (age, hypertension, DM, and physical activity) on the renal vascular. If the data were not following the normal distribution, nonpara-metric alternatives were used such as the Mann–Whitney and Fisher exact test.
| Results|| |
Our study included 842 patients from nine centers all over the country. Of the 842 enrolled patients, 836 (99.3%) constituted the descriptive population, which included all eligible patients who had signed the data release consent form and fulfilled the eligibility criteria. Six patients (0.7%) were ineligible as they were under the age of 18 years at the baseline visit. The mean age of patients was 51.8 ± 15.4 years. More than 63% of our included participants were male. Furthermore, about 61% were Caucasian and 36% were Asian. The mean systolic blood pressure was 141 ± 21.6 mm Hg, and the mean diastolic blood pressure was 77 ± 12.3 mm Hg. The mean heart rate was 80.3 ±11 beat/min, and the average body temperature was 36.6 ± 0.4°C [Table 1].
The mean duration since the first diagnosis of CKD was 8.1 ± 6.3 years. The most common causes for CKD were diabetic nephropathy 254 (30.4%) and hypertensive nephropathy 214 (25.6%) while 225 (26.9%) of patients had an unknown cause for CKD [Table 1].
All patients enrolled in the study were undergoing dialysis as per the inclusion criteria. Duration since the start of dialysis (dialysis vintage) ranged from 0.1 to 29 years with an average of 5 ± 4.6 years. Most patients, i.e., 802 (95.9%) had three times per week dialysis frequency. Dialysis session duration ranged from 120 to 270 min with an average 220 ± 24.2 min. Of all participants, 516 (61.7%) of patients were hemodialyzed using high-flux dialysis membrane type, 133 (15.9%) poly-sulfone, 131 (15.7%) low-flux, and 56 (6.7%) helixone [Table 2]. Hemodialysis (HD) treatment adequacy was assessed using Kt/V dimensionless ratio and dialysate calcium concentration. Kt/V ratio ranged from 0.47 to 3.63 with an average 1.35 ± 0.33 and dialysate calcium concentration ranged from 1.05 to 2.06 with an average 1.51 ± 0.16 (mmol/L).
Cardiovascular risk factors
A total of 759 (90.8%) patients had cardiovascular risk factors. The most commonly reported were hypertension 719 (86%), Type 2 DM 284 (34%), dyslipidemia 194 (23.2%), obesity 107 (12.8%), ischemic heart disease (IHD) 81 (9.7%), and smoking 52 (6.2%). Furthermore, we found that more than 30% of participants had no physical activity. The patients with a family history of heart disease were 61 (7.3%), and 147 (17.6%) reported an unhealthy diet [Table 3].
Pharmacologic treatment of CKD
Regarding the treatment, 453 (54.2%) of patients were using phosphate binder (Ca++ free nonabsorbable polymer phosphate binder), 390 (46.7%) CaCO3 (calcium-based phosphate binders), 327 (39.1%) Vitamin D analog, 245 (29.3%) erythropoietic agents, 124 (14.8%) iron supplement, 119 (14.2%) antihyperpara-thyroidism, and 66 (7.9%) combined calcium and Vitamin D supplement. However, every individual may have more than one pharma-cologic treatment of CKD and hyperphos-phatemia.
The most commonly reported concomitant medications were Ca channel blockers – 416 (49.8%), statins – 216 (25.8%), beta-blockers – 199 (23.8%), nonsteroidal antiinflammatory drugs – 174 (20.8%), and insulin – 141 (16.9%).
Vascular calcification and tisk factors
Our results show that less than half of participants – 341 (40.8%) [95%CI; (I37.5%: 44.1%)] are suffering from cardiovascular calcification. The univariate model demonstrates a significant association between all of the following variables and VC: dyslipidemia, obesity, history of IHD, physical inactivity, and unhealthy diet (P <0.01). Moreover, there is an association between VC and hypertension (P = 0.03), longer duration since first diagnosis of CKD, longer dialysis vintage, and lower dialysate calcium concentration (P < 0.01) [Table 4].
|Table 4: Results of univariate analysis of the relationship between the vascular calcification and risk factors.|
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In the multivariate analysis for VC, the significant variables were physical inactivity with odd ratio (OR) 2.87 [95% CI: (1.894.63), P < 0.01], history of IHD – 2.34 [95% CI: (1.30–4.22), P < 0.01], dyslipidemia – 1.56 [95% CI: (1.01–2.40), P = 0.04], older age – 1.06 [95% CI: (1.05–1.07), P < 0.01], longer dialysis vintage – 1.10 [95% CI: (1.05–1.15), P < 0.01], and lower levels of dialysate calcium concentration – 1.03 [95% CI: (1.01–1.10), P < 0.01] [Table 5].
The mean hemoglobin level was 10.8 ±1.6 g/dL, and the mean hematocrit value was 33.6 ± 5.1%. The mean ± SD for HDL-cholesterol, LDL-cholesterol, total cholesterol (TC), and triglycerides was 41 ± 30, 79.7 ± 29.9, 144.2 ± 38.5, and 143.4 ± 95.3 mg/dL, respectively. The mean ± SD for glucose, urea, uric acid, and creatinine was 130 ± 73.8, 88.8 ± 49.7, 6.3 ± 1.5, and 9.7 ± 3.1 mg/dL, respectively. The mean ± SD for serum albumin was 3.6 ± 0.5 g/dL, serum ferritin was 481.8 ± 451.6 ng/mL, and alkaline phosphatase was 166.3 ± 168.3 U/L.
Calcium and phosphorus according KDIGO/ KDOQI guidelines
Mean serum total calcium 8.5 ± 1.0 mg/dL and phosphate 5.0 ± 1.6 mg/dL were within (KDOQI) dialysis target ranges. Patients had secondary hyperparathyroidism (mean iPTH, 607.8 ± 630.7 pg/mL). KDOQI guidelines were met by 17.5% [95% CI; (15%: 20.2%)] of patients for iPTH (150–300 pg/mL), 48.9% [95% CI; (45.5%: 52.3%)] for calcium (8.4–9.5 mg/dL), and 47.1% [95% CI; (4.8%: 50.5%)] for phosphorus (3.5–5.5 mg/dL). While KDIGO guidelines were met by 30.5% [95% CI; (27.5%: 33.7%)] for calcium (8.9–10.1 mg/dL) and 35.8% [95% CI; (32.6%: 39.1%)] for phosphorus (2.5–4.5 mg/dL).
| Discussion|| |
In this cross-sectional, multicenter, disease registry study, we enrolled 836 CKD centers across Kingdom of Saudi Arabia to determine the proportion of patients with VC in CKD patients on dialysis. The mean age of patients was 51.8 ± 15.4 years. The total numbers of patients who showed VC through examination by plain X-ray chest and abdomen, echocardiography, or multislice computed tomography were 341 (40.8%). A cross-sectional study conducted by Elsamman et al reported that the prevalence of VC in patients with HD was 50%. García-Canton et al demonstrated a high prevalence of VC (77.6%) in nondialysis CKD patients Stage IV and V. The prevalence of VC among predialysis CKD patients was 79% and approached 100% in patients starting dialysis., These findings show that the prevalence of VC in patients with nondialysis or predialysis is superior to dialysis patients.
Our study demonstrated significant association in univariate analysis between the cardiovascular events, especially hypertension and VC. Another study shows a high prevalence of VC in patients with CKD associated with hypertension. The association between hypertension and VC is insignificant in multivariate analysis, but it is still respectable as a serious risk factor. The same study reported that there is a significant association between DM and VC in the patient with CKD with high OR 14.23 [95% CI; (5.50–36.82), P < 0.001]. However, our multivariate analysis shows an insignificant association between the two variables with OR 1.07 [95%CI; (0.73–1.57), P = 0.74]. The multivariate analysis of IHD history shows a significant correlation with VC2.34 [95% CI: (1.30–4.22), P < 0.01].
Regarding physical activity, there was a significant association in univariate/multi-variate analysis between physical inactivity and VC in patients with CKD. The optimal level of physical activity to prevent calcification of vessels is still a matter of debate.
A large cohort study which enrolled 8565 middle-aged men reported a significant increase in coronary artery calcium (CAC) among the people who exercised more than three times per week. Some others explain this finding in a marathon runner with high CAC by the promotion of oxidative stress by this arduous aerobic activity. On another hand, many studies failed to detect any significant association between physical activity and VC., Moreover, a recent randomized clinical trial demonstrated that aerobic exercise for 15 min after 2 h of dialysis for two months would help in increasing dialysis efficacy and protect against VC deposition., Another study suggests that intervention of 40 min exercise training during each HD session for three months is effective in arterial stiffness and blood pressure control., This difference occurs due to the population, age, or gender heterogeneity. Furthermore, the difference in study samples and designs may cause this debate.
Concerning dyslipidemia, multivariate analysis shows significant suffering from VC state of dyslipidemia 1.56 [95% CI: (1.01–2.40), P = 0.04]. Familial hypercholesterolemia (FH) develops premature aortic calcification that may lead to the development of porcelain ascending aorta. Many studies reported a strong correlation between calcification score and age not with TC., Al Kindi et al scanned 16 patients’ heterozygous FH who show a significant increase in aortic calcification from 9801 ± 10,728 to 17,202 ± 17,374 Agatston U over an 8.2 ± 08 years. It is remarkable that lipid-lowering therapy has a role in reducing VC and coronary artery disease in patients with FH., In a recent animal study applied on mice with FH, they found that interleukin 1β has a significant role in reducing the risk of aortic calcifications.
Time on dialysis was another factor related to the presence of calcifications. In this study, longer dialysis vintage – 1.10 [95% CI: (1.05–1.15), P < 0.01] increased the risk of VCs. Furthermore, a prospective study of CKD patients undergoing HD supported our finding and reported a highly significant correlation between dialysis vintage and VC in univariate/ multivariate analysis 1.17 [95% CI: (1.05–1.31), P = 0.005] and 1.16 [95% CI: (1.05–1.27), P = 0.002], respectively.
This study had some limitations as its cross-sectional design lacking biomarkers involved in the physiopathology of vascular calcifications such as FGF23 and Fetuin-A. However, the present study is the first one focused on the prevalence of VC in patients on dialysis in Kingdom of Saudi Arabia and had a multi-centric design coupled with a good representative smaple from theall the regions of the country. Additionally the strengths include the number of patients included and use of readily available nonexpensive diagnostic method as the plain X-ray. Since it is a cross-sectional disease registry, there were no reported adverse drug reactions during the study period.
| Conclusions|| |
VC is a serious complication of CKD. In Saudi dialysis patients, the prevalence was high. Some factors such as physical inactivity, history of IHD, dyslipidemia, older age, longer dialysis vintage, and lower levels of dialysate calcium concentration may contribute to VC in dialysis population.
| Acknowledgment|| |
Authors would like to thank all clinical investigators (Dr. Saad Alshohaib, Dr. Ayman Jazairi, Dr. Sheikh Rizwan, Dr. Mohammed Al-Omi, Dr. Fathy El-Basuony, Dr. Ibrahim Jubran, Dr. Ali Hakami, and Dr. Ghassan Salah) at the participating centers and health facility staff, and Ray CRO for statistical analysis and Sanofi Medical team in Kingdom of Saudi Arabia for medical writing support, collating comments from all authors and editing the final manuscript.
Conflict of interest Sanofi KSA has funded and provided oversight on the conduct of the study, including design, collection and compilation of data.
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Mohammed Abdulrahman AlGhonaim
College of Medicine, King Saud University, King Khalid University Hospital, P. O. Box 7805, Riyadh 11472
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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