- Research article
- Open Access
Association between serum 25-hydroxyvitamin D levels and carotid atherosclerosis in chronic kidney disease patients
BMC Nephrology volume 17, Article number: 151 (2016)
Epidemiological studies have shown an inverse relationship between vitamin D levels and cardiovascular diseases. However, this does not infer a causal relationship between the two. Chronic kidney disease (CKD) patients have a high prevalence of vitamin D deficiency and carotid atherosclerosis. Therefore, in this study we have aimed to determine the association between serum 25-hydroxyvitamin D levels and carotid atherosclerosis in the CKD population.
100 CKD stage 3–4 patients were included in the study. Direct chemiluminesent immunoassay was used to determine the level of serum 25-hydroxyvitamin D. All subjects underwent a carotid ultrasound to measure common carotid artery intima-media thickness (CCA-IMT) and to assess the presence of carotid plaques or significant stenosis (≥50 %). Vitamin D deficiency was defined as serum 25-hydroxyvitamin D < 25 nmol/L. Abnormal CCA-IMT was defined as CCA-IMT ≥ 0.8 mm. Plaque was defined as a focal structure that encroaches into the arterial lumen of ≥ 0.5 mm or 50 % of the surrounding IMT value. Significant stenosis was defined as peak-systolic velocities ≥ 125 cm/s and end-diastolic velocities ≥ 40 cm/s.
The vitamin D deficiency and non-deficiency groups did not differ significantly in terms of abnormal CCA-IMT (P = 0.443), carotid plaque (P = 0.349), and carotid stenosis (P = 0.554). No significant correlation between serum 25-hydroxyvitamin D levels and CCA-IMT (P = 0.693) was found. On a backward multiple linear regression model, serum 25-hydroxyvitamin D levels was not associated with CCA-IMT, abnormal CCA-IMT, or plaque presence.
No important association between serum 25-hydroxyvitamin levels and carotid atherosclerosis was found in CKD patients.
Atherosclerosis is characterized by the accumulation of lipids and fibrous cap in the arteries . It commonly affects coronary and carotid arteries. Carotid atherosclerosis includes a spectrum of intima-media thickening, plaque formation, stenosis, and eventually occlusion. Several stages of the atherogenic process have been described, starting from endothelial dysfunction, subendothelial accumulation of low-density lipoproteins (LDL), and chronic inflammation within the arterial wall leading to formation of plaque [2, 3].
Vitamin D is a group of fat soluble secosteroids which play an important role in musculoskeletal health by regulating calcium and phosphate metabolism . There are two major forms of vitamin D; ergocalciferol (D2) and cholecalciferol (D3). The former is found in plants while the latter is found in humans and is synthesized following irradiation by ultraviolet B . Both are converted to 25-hydroxyvitamin D (25(OH)D) by 25-hydroxylase (CYP2R1) in the liver and are activated by 1α-hydroxylase (CYP27B1) in the kidney to form 1,25-hydroxyvitamin D (1,25(OH2)D) . Serum 25(OH)D assay is used to measure vitamin D status due to its higher serum concentration and longer half-life. In addition, a developing vitamin D deficiency is compensated for by increased activation of 1α-hydroxylase which results from increased secretion of PTH, thus restoring 1,25(OH2)D levels and thereby masking vitamin D deficiency .
The chronic kidney disease (CKD) population has a high prevalence of carotid atherosclerosis [8, 9] and vitamin D deficiency [10, 11]. Numerous observational studies on the association between serum 25(OH)D and carotid atherosclerosis have showed inconsistent results . As for the CKD population, there have only been two studies; one demonstrated an inverse relationship  while the other showed mixed results . Thus, we have aimed to examine the relationship between serum 25(OH)D levels and carotid atherosclerosis in CKD patients as measured by CCA-IMT and the presence of carotid plaque or stenosis.
Study design and sampling method
This was a cross sectional study conducted between September 2015 and March 2016. It has adhered to the STROBE guidelines for observational studies. A consecutive sampling methodology was used for participant recruitment. The flow diagram is shown in Fig. 1.
A total of 100 pre-dialysis CKD stage 3–4 patients who attended nephrology, diabetic, and outpatient clinics at the University of Malaya Medical Centre (UMMC) were included. Patients who were 70 years old and above, had underlying coronary artery disease, heart failure, malignancy, active infection, or were on immunosuppressive drugs or vitamin D supplements were excluded.
Ethics approval and informed consent
Ethics approval (MECID 201412-878) was obtained from the UMMC Medical Ethics Committee which governs all research involving humans. Participants provided written informed consent prior to being enrolled in the study.
Data collection procedures
Socio-demographic data, medical history, alcohol and smoking history, and medication history were obtained from all subjects. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared (kg/m2). During the enrolment phase, previous biochemical tests were reviewed through the laboratory information system (TD-Web version 11.61B, Technidata SAS, France) and results within 2 weeks were exempted from repeat analysis. The biochemical analysis of blood samples was conducted in the same laboratory. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula was used to calculate the estimated glomerular filtration rate (eGFR). Participants were categorized into three CKD stages: stage 3A (45–59 mL/min per 1.73 m2), stage 3B (30–44 mL/min per 1.73 m2) and stage 4 (15–29 mL/min per 1.73 m2) according to Kidney Disease Outcome Quality Initiative (KDOQI) criteria.
Serum 25(OH)D and intact parathyroid hormone (PTH) levels were determined using direct chemiluminesent immunoassay (ADVIA Centaur XP; Siemens Healthcare Diagnostics, Tarrytown, New York, USA). The detection limit of the device was <10 nmol/L, with the intra- and inter-assay coefficient of variations of 4.2 and 11.9 % respectively. This assay demonstrated comparable performance with the reference standard, liquid chromatography tandem mass spectrometry (LC-MS/MS) [14–16]. A mean of 5 nmol/L was assumed for results reported as <10 nmol/L. Vitamin D status was defined as deficiency (< 25 nmol/L)  and non-deficiency (≥ 25 nmol/L). Serum calcium, inorganic phosphate, renal profiles and lipid profiles were measured using colorimetric methods (ADVIA 2400 Chemistry System; Siemens Healthcare Diagnostics, Tarrytown, New York, USA). Complete blood counts were analysed using fluorescent flow cytometry (XN-10; Sysmex, Kobe, Japan).
An ultrasound system equipped with high-resolution, linear-array transducers in the frequency of 4–9 MHz (Philips iU22; Philips, Seattle, Washington, USA) was used. Carotid arteries were imaged with L9-3 and L8-4 transducers. It was performed by a single certified sonographer and images were verified by an experienced stroke neurologist. All participants underwent a carotid ultrasound within 2 weeks from 25(OH)D assay to measure intima-media thickness (IMT) and to assess the presence of carotid plaque or stenosis at the common carotid arteries (CCA), internal carotid arteries (ICA), and external carotid arteries (ECA). Three IMT measurements were obtained at the far walls of the distal, 2 cm from the common carotid artery. The mean of these three measurements was recorded as the IMT for that side (left and right). CCA-IMT was defined as the average of left and right IMT. The images were obtained at a 30° angle and the length of the segments measured was 1 cm. The image analysis was done using QLAB Vascular Ultrasound Quantification software, version 7.1. The analysis was done offline. The presence of carotid plaque or significant stenosis (≥ 50 %) in the CCA, bifurcation, and ICA bilaterally were documented. Abnormal CCA-IMT was defined as CCA-IMT ≥ 0.8 mm which is beyond the 75th percentile as per the American Society of Echography Task Force recommendations [18, 19]. Plaque was defined as a focal structure that encroaches into the arterial lumen of ≥ 0.5 mm or 50 % of the surrounding IMT value . Significant stenosis was defined as peak-systolic velocities ≥ 125 cm/s and end-diastolic velocities ≥ 40 cm/s as recommended by the Society of Radiologists in Ultrasound .
A statistical analysis was performed using the Statistical Package for Social Sciences for Windows, version 23.0 (IBM Corp., Armonk, New York, USA). Clinical characteristics data was expressed as means ± standard deviation (SD). Differences between groups were analysed using independent t-test and one-way analysis of variance (ANOVA) when the dependent variable was normally distributed, otherwise by Mann-Whitney U and Kruskal-Wallis H tests. Appropriate transformations were made when necessary to ensure normality or linearity assumptions were met. The correlation between serum 25(OH)D levels and CCA-IMT was determined using Pearson’s product-moment correlation coefficients. Linear regression analysis was performed to determine the predictors of serum 25(OH)D levels. Multiple linear regression models were used to identify the predictors of CCA-IMT, abnormal CCA-IMT, and plaque presence. Age, gender, race, BMI, smoking habits, diabetes status, hypertension status, eGFR, serum triglyceride, LDL cholesterol, HDL cholesterol, calcium, phosphate, PTH, and 25(OH)D levels were taken as independent variables for modelling. Backward elimination was applied to remove insignificant variables. All P-values were calculated two-sided and a value of < 0.05 was considered as significant.
Demographic and clinical characteristics
A total of 100 CKD stage 3–4 patients were evaluated. The proportion of CKD patients at stage 3A was 29 %, stage 3B was 40 %, and stage 4 was 31 %. The mean age of the study population was 59 years. Fifty-seven percent of them were female. Ethnicity was comprised of 50 % Malay, 30 % Chinese, and 20 % Indian. The mean BMI was 28.16 kg/m2. The majority of the patients had hypertension (93 %), diabetes mellitus (76 %), and dyslipidaemia (79 %). The mean value of serum 25(OH)D levels was 39.83 ± 22.43 nmol/L. The participant’s characteristics were summarized in Table 1.
A one-way ANOVA was conducted to determine the difference in mean serum 25(OH)D levels between various CKD stages. The mean levels for stage 3A, stage 3B, and stage 4 were 42.69 ± 20.68 nmol/L, 40.35 ± 24.42 nmol/L and 36.48 ± 21.60 nmol/L respectively. A Tukey post hoc analysis revealed that the differences between the groups were not significant (P = 0.558), as shown in Table 2.
Demographic and clinical characteristics according to vitamin D status
Table 3 displays the detailed characteristics of participants according to their vitamin D status. Twenty-nine percent of the patients had vitamin D deficiency. Gender (P < 0.001), race (P = 0.002), smoking habits (P = 0.019), haemoglobin (P = 0.014), serum phosphate (P = 0.038), and serum PTH (P = 0.014) levels differed significantly by vitamin D status. The mean serum 25(OH)D levels for the vitamin D deficiency group was 13.76 ± 6.31 nmol/L while the non-deficiency groups was 50.48 ± 17.30 nmol/L.
Predictors of Serum 25(OH)D Levels
Univariate linear regression analysis showed that age (P = 0.023), male gender (P < 0.001), Chinese ethnicity (P < 0.001), smoking habits (P = 0.001), diabetes mellitus (P = 0.004), haemoglobin (P < 0.001), serum triglyceride (P = 0.041), serum LDL Cholesterol (P = 0.018), and serum PTH (P = 0.045) levels were predictors of serum 25(OH)D levels. Chinese ethnicity was the strongest predictor among all, as shown in Table 4.
Carotid outcomes of participants
Among the participants, 23 % had abnormal CCA-IMT and 67 % had carotid plaque. Carotid stenosis was only found in three subjects within the entire cohort, as shown in Table 5. Carotid outcomes were not significantly different among CKD stages.
Carotid outcomes of participants according to vitamin D status
The vitamin D deficiency and non-deficiency groups did not differ significantly in terms of abnormal CCA-IMT (P = 0.443), carotid plaque (P = 0.349), and carotid stenosis (P = 0.554), as shown in Table 6.
Association between Serum 25(OH)D Levels and Carotid Atherosclerosis
Correlation between Serum 25(OH)D Levels and CCA-IMT
Pearson’s product-moment correlation was used to examine the relationship between serum 25(OH)D levels and CCA-IMT. Figure 2 shows that no significant correlation (P = 0.693) was found.
Predictors of CCA-IMT, abnormal CCA-IMT, and plaque presence
Multiple linear regression analyses were performed to assess the association between serum 25(OH)D levels and CCA‐IMT, abnormal CCA‐IMT, and plaque presence. A backward elimination method adjusting for potential confounders namely age, gender, race, BMI, smoking habits, diabetes status, hypertension status, eGFR, serum triglyceride, LDL cholesterol, HDL cholesterol, calcium, phosphate, and PTH levels was applied. No significant association between serum 25(OH)D levels and CCA-IMT, abnormal CCA-IMT, and plaque presence was found. Notably, smoking habits was significantly associated with CCA-IMT (P = 0.003) and it predicted abnormal CCA-IMT (P = 0.003). Chinese ethnicity predicted abnormal CCA-IMT (P = 0.012) and plaque presence (P = 0.020) whilst serum PTH levels predicted plaque presence only. Table 7 displays the final step of each regression model.
The inverse relationship between serum 25(OH)D levels and cardiovascular diseases has been observed in epidemiological studies. However, no conclusions can be draw on the causality of this relationship. In fact, interventional studies have failed to show that vitamin D-raising interventions decreased cardiovascular events [22, 23]. The main findings of our study are: (1) no difference in CCA-IMT between vitamin D deficient and non-deficient patients; (2) no correlation between serum 25(OH)D levels and CCA-IMT; and (3) no relationship between serum 25(OH)D levels and CCA-IMT, abnormal CCA-IMT, and plaque presence in multivariate analysis which corroborates the findings from interventional studies.
Contrary to our findings, Yadav et al. reported that serum 25(OH)D levels were inversely associated with CCA-IMT in CKD patients . Notably, their study participants had more severe (stage 4 and 5) CKD stages. Our study has similar percentage of carotid plaque with a study by Gracia et al. . Again, no association between serum 25(OH)D levels and carotid plaque were observed. Instead, serum PTH levels predicted carotid plaque presence. To the best of our knowledge, PTH has only been reported to be associated with vascular calcification in animal model  and arterial stiffness in both diabetic patients  and postmenopausal women .
The link between vitamin D concentrations and carotid atherosclerosis was not clear, even in non-CKD population. Blondon et al. (n = 3251) reported that both vitamin D and PTH had no significant impact on carotid IMT and plaque in a multi-ethnic cohort with high cardiovascular risk . Similarly, Deleskog et al. (n = 3430) found no consistent association between serum 25(OH)D and carotid IMT in a high risk European population .
There are several explanations for the disparate results observed. Firstly, a longitudinal study has showed that CKD progression was independently associated with atheromatosis progression . Serum 25(OH)D levels also fall with eGFR decline and may therefore result in false association with atherosclerosis. Secondly, the demographic profiles of enrolled subjects were different. Different latitudes receive different amounts of sunlight, resulting in a different range of baseline serum 25(OH)D levels and carotid IMT. Countries that are far from the equator might have a seasonal variation of serum 25(OH)D concentrations and the impact of nadir serum 25(OH)D on carotid IMT might remain despite recovery of serum 25(OH)D levels. Thirdly, the relationship between vitamin D and carotid IMT was perhaps U-shaped, rather than linear [29, 30]. Recently, Van Dijk et al. suggested that the dip of a U-shaped relationship is at serum 25(OH)D levels of 50 nmol/L . This might support the findings of Melamed et al. who proposed a similar U-shaped relationship between serum 25(OH)D and all-cause mortality in participants of the Third National Health and Examination Survey (NHANES III) . In Blondon’s study , two thirds of the participants had baseline serum 25(OH)D ≥ 50 nmol/L, while most participants in Deleskog’s study  had serum 25(OH)D between 25 and 75 nmol/L. Analysis of these populations as a whole might attenuate the relationship between serum 25(OH)D and carotid atherosclerosis.
The observed non-linear relationship can be explained by the dualistic roles of vitamin D. It has both protective and harmful effects on vascular health. The anti-inflammatory and immune-modulatory properties are protective against atherosclerosis. It decreases endothelial oxidative stress, improves vascular muscle tone, inhibits formation of foam cells, regulates proliferation and migration of vascular smooth muscle cells (VSMC), inhibits release of pro-inflammatory cytokines, and suppresses pro-atherogenic T lymphocytes [3, 5, 32]. On the other hand, it may up-regulate vitamin D receptor (VDR) expression inducing osteogenic differentiation and mineralization of VSMC, promote production of matrix metalloproteinases leading to vascular remodelling, down-regulate calcification inhibitor fetuin-A expression, and increase calcium-phosphate product [33–36].
The renal expression of 1α-hydroxylase is regulated by serum calcium, phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23) levels. FGF23 is a hormone secreted from osteocytes in coordination with α-Klotho to promote renal phosphate excretion . FGF23 levels increase at early CKD stages which results in a decrease of serum α-Klotho and 1,25(OH2)D levels . Low levels of circulating 1,25(OH2)D via a negative feedback mechanism causes a rise of PTH concentrations to stimulate reabsorption of calcium, bone resorption and 1,25(OH2)D production. PTH also increases total collagen synthesis and reorganizes collagen in VSMC leading to vascular stiffness [39, 40]. In addition to secondary hyperparathyroidism, FGF23 excess and Klotho deficiency have been recognized as novel factors contributing to vascular calcification [41–43] which might in part explain the link between CKD progression and atherosclerosis. In a recent breakthrough, Chang et al. demonstrated the ability of intermedin1-53 to increase α-Klotho levels which can suppress vascular calcification and delay the progression of CKD . Both vascular calcification and elastin fibres degeneration cause arterial stiffening  which may increase risk of vessel wall damage and result in atherosclerosis . Hence, α-Klotho deficiency plays a pivotal role in accelerated atherosclerosis.
The strength of our study was the inclusion of a more comprehensive carotid plaque assessment rather than solely relying on a carotid IMT measurement. Our study had several limitations: (1) it included a relatively small number of patients thus may have a lack of statistical power; (2) it was a single-centre study so the results cannot be generalised; and (3) other confounding factors, such as α-Klotho and FGF23 were not taken into account.
Our study showed that there was no important association between serum 25(OH)D and CCA-IMT.
Body mass index
Common carotid artery
Common carotid artery intima-media thickness
Chronic kidney disease
External carotid artery
Estimated glomerular filtration rate
Fibroblast growth factor 23
High density lipoprotein
Internal carotid artery
Low density lipoprotein
University of Malaya Medical Centre
Vitamin D receptor
Vascular smooth muscle cells
Lusis AJ. Atherosclerosis. Nature. 2000;407(6801):233–41.
Carbone F, Montecucco F. The role of the intraplaque vitamin d system in atherogenesis. Scientifica. 2013;2013:620504.
Kassi E, Adamopoulos C, Basdra EK, Papavassiliou AG. Role of vitamin D in atherosclerosis. Circulation. 2013;128(23):2517–31.
Perez-Lopez FR. Vitamin D: the secosteroid hormone and human reproduction. Gynecol Endocrinol. 2007;23(1):13–24.
Menezes AR, Lamb MC, Lavie CJ, DiNicolantonio JJ. Vitamin D and atherosclerosis. Curr Opin Cardiol. 2014;29(6):571–7.
Holick MF. Vitamin D, deficiency. N Engl J Med. 2007;357:266–81.
Holick MF. Vitamin D, status: measurement, interpretation, and clinical application. Ann Epidemiol. 2009;19(2):73–8.
Kokubo Y. Carotid atherosclerosis in kidney disease. Contrib Nephrol. 2013;179:35–41.
Coll B, Betriu A, Martinez-Alonso M, Borras M, Craver L, Amoedo ML, et al. Cardiovascular risk factors underestimate atherosclerotic burden in chronic kidney disease: usefulness of non-invasive tests in cardiovascular assessment. Nephrol Dial Transplant. 2010;25(9):3017–25.
Nigwekar SU, Tamez H, Thadhani RI. Vitamin D and chronic kidney disease–mineral bone disease (CKD–MBD). BoneKEy Reports. 2014;3.
Williams S, Malatesta K, Norris K. Vitamin D and Chronic Kidney Disease. Ethn Dis. 2009;19(4 Suppl 5):S5-8-11.
Yadav AK, Banerjee D, Lal A, Jha V. Vitamin D deficiency, CD4 + CD28null cells and accelerated atherosclerosis in chronic kidney disease. Nephrol (Carlton, Vic). 2012;17(6):575–81.
Gracia M, Betriu A, Martinez-Alonso M, Arroyo D, Abajo M, Fernandez E, et al. Predictors of Subclinical Atheromatosis Progression over 2 Years in Patients with Different Stages of CKD. Clin J Am Soc Nephrol. 2016;11(2):287–96.
Carter GD. 25-Hydroxyvitamin D assays: the quest for accuracy. Clin Chem. 2009;55(7):1300–2.
Freeman J, Wilson K, Spears R, Shalhoub V, Sibley P. Influence of Vitamin D Binding Protein on Accuracy of 25-Hydroxyvitamin D Measurement Using the ADVIA Centaur Vitamin D Total Assay. Int J Endocrinol. 2014;2014:12.
Freeman J, Wilson K, Spears R, Shalhoub V, Sibley P. Performance evaluation of four 25-hydroxyvitamin D assays to measure 25-hydroxyvitamin D2. Clin Biochem. 2015;48(16–17):1097–104.
Lee JH, O’Keefe JH, Bell D, Hensrud DD, Holick MF. Vitamin D deficiency an important, common, and easily treatable cardiovascular risk factor? J Am Coll Cardiol. 2008;52(24):1949–56.
Onut R, Balanescu APS, Constantinescu D, Calmac L, Marinescu M, Dorobantu PM. Imaging Atherosclerosis by Carotid Intima-media Thickness in vivo: How to, Where and in Whom? Maedica (Buchar). 2012;7(2):153–62.
Howard G, Sharrett AR, Heiss G, Evans GW, Chambless LE, Riley WA, et al. Carotid artery intimal-medial thickness distribution in general populations as evaluated by B-mode ultrasound. ARIC Investigators. Stroke. 1993;24(9):1297–304.
Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Bornstein N, et al. Mannheim carotid intima-media thickness consensus (2004–2006). An update on behalf of the Advisory Board of the 3rd and 4th Watching the Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004, and Brussels, Belgium, 2006. Cerebrovasc Dis (Basel, Switzerland). 2007;23(1):75–80.
Grant EG, Benson CB, Moneta GL, Alexandrov AV, Baker JD, Bluth EI, et al. Carotid artery stenosis: gray-scale and Doppler US diagnosis--Society of Radiologists in Ultrasound Consensus Conference. Radiology. 2003;229(2):340–6.
Ford JA, MacLennan GS, Avenell A, Bolland M, Grey A, Witham M. Cardiovascular disease and vitamin D supplementation: trial analysis, systematic review, and meta-analysis. Am J Clin Nutr. 2014;100(3):746–55.
Elamin MB, Abu Elnour NO, Elamin KB, Fatourechi MM, Alkatib AA, Almandoz JP, et al. Vitamin D and cardiovascular outcomes: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2011;96(7):1931–42.
Neves KR, Graciolli FG, dos Reis LM, Graciolli RG, Neves CL, Magalhaes AO, et al. Vascular calcification: contribution of parathyroid hormone in renal failure. Kidney Int. 2007;71(12):1262–70.
Kun MX, Zhen LZ, Jun QG, Miao LH, Fei RG. Association between serum 25-hydroxyvitamin D3 concentration, parathyroid hormone, and arterial stiffness in patients with type 2 diabetes. Chin J Endocrinol Metab. 2013;29:836–9.
Pirro M, Manfredelli MR, Helou RS, Scarponi AM, Schillaci G, Bagaglia F, et al. Association of parathyroid hormone and 25-OH-vitamin D levels with arterial stiffness in postmenopausal women with vitamin D insufficiency. J Atheroscler Thromb. 2012;19(10):924–31.
Blondon M, Sachs M, Hoofnagle AN, Ix JH, Michos ED, Korcarz C, et al. 25-hydroxyvitamin D and parathyroid hormone are not associated with carotid intima-media thickness or plaque in the Multi-Ethnic Study of Atherosclerosis. Arterioscler Thromb Vasc Biol. 2013;33(11):2639–45.
Deleskog A, Piksasova O, Silveira A, Gertow K, Baldassarre D, Veglia F, et al. Serum 25-hydroxyvitamin D concentration in subclinical carotid atherosclerosis. Arterioscler Thromb Vasc Biol. 2013;33(11):2633–8.
van Dijk SC, Sohl E, Oudshoorn C, Enneman AW, Ham AC, Swart KM, et al. Non-linear associations between serum 25-OH vitamin D and indices of arterial stiffness and arteriosclerosis in an older population. Age Ageing. 2015;44(1):136–42.
Shroff R, Egerton M, Bridel M, Shah V, Donald AE, Cole TJ, et al. A Bimodal Association of Vitamin D Levels and Vascular Disease in Children on Dialysis. Clin J Am Soc Nephrol. 2008;19(6):1239–46.
Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med. 2008;168(15):1629–37.
Querfeld U. Vitamin D, and inflammation. Pediatr Nephrol. 2013;28(4):605–10.
Mizobuchi M, Ogata H, Koiwa F, Kinugasa E, Akizawa T. Vitamin D and vascular calcification in chronic kidney disease. Bone. 2009;45 Suppl 1:S26–9.
Hsu JJ, Tintut Y, Demer LL. Vitamin D and osteogenic differentiation in the artery wall. Clin J Am Soc Nephrol. 2008;3(5):1542–7.
Zittermann A, Koerfer R. Protective and toxic effects of vitamin D on vascular calcification: Clinical implications. Mol Asp Med. 2008;29(6):423–32.
Zittermann A, Schleithoff SS, Koerfer R. Vitamin D and vascular calcification. Curr Opin Lipidol. 2007;18(1):41–6.
Kuro-o M. Overview of the FGF23-Klotho axis. Pediatr Nephrol. 2010;25(4):583–90.
Pavik I, Jaeger P, Ebner L, Wagner CA, Petzold K, Spichtig D, et al. Secreted Klotho and FGF23 in chronic kidney disease Stage 1 to 5: a sequence suggested from a cross-sectional study. Nephrol Dial Transplant. 2013;28(2):352–9.
Carbone F, Mach F, Vuilleumier N, Montecucco F. Potential pathophysiological role for the vitamin D deficiency in essential hypertension. World J Cardiol. 2014;6(5):260–76.
Perkovic V, Hewitson TD, Kelynack KJ, Martic M, Tait MG, Becker GJ. Parathyroid hormone has a prosclerotic effect on vascular smooth muscle cells. Kidney Blood Pressure Res. 2003;26(1):27–33.
Olauson H, Vervloet MG, Cozzolino M, Massy ZA, Urena Torres P, Larsson TE. New insights into the FGF23-Klotho axis. Semin Nephrol. 2014;34(6):586–97.
Jimbo R, Kawakami-Mori F, Mu S, Hirohama D, Majtan B, Shimizu Y, et al. Fibroblast growth factor 23 accelerates phosphate-induced vascular calcification in the absence of Klotho deficiency. Kidney Int. 2014;85(5):1103–11.
Martín-Núñez E, Donate-Correa J, Muros-de-Fuentes M, Mora-Fernández C, Navarro-González JF. Implications of Klotho in vascular health and disease. World J Cardiol. 2014;6(12):1262–9.
Chang JR, Guo J, Wang Y, Hou YL, Lu WW, Zhang JS, et al. Intermedin1-53 attenuates vascular calcification in rats with chronic kidney disease by upregulation of alpha-Klotho. Kidney Int. 2016;89(3):586–600.
Covic A, Kanbay M, Voroneanu L, Turgut F, Serban DN, Serban IL, et al. Vascular calcification in chronic kidney disease. Clin Sci (London, England: 1979). 2010;119(3):111–21.
We thank Madam Nurul Ain binti Ambiak, Madam Nevehtha A/P Kunaratanam, all our nephrology colleagues and also the participants for their valuable contributions.
This work was supported by the Malaysian Society of Nephrology research grant (RG-1/2016) and the University of Malaya postgraduate research grant (PO010-2014B).
Availability of data and materials
Consent for publication of raw data was not obtained ad hoc and not possible to obtain post hoc as a number of study participants are not contactable. The dataset contains at least 3 patient identifiers and publication of data may constitute a risk of breach of confidentiality.
YMN conducted the study, collected the data, performed the statistical analysis, reviewed the literature and drafted the manuscript. SKL provided valuable and critical inputs in study design, statistical analysis, statistical interpretation and revision of the manuscript. PSK contributed to data collection and manuscript writing. MLST conceived and designed the study, provided inputs in statistical interpretation, verified the ultrasound carotid images and revised the manuscript. KAAK facilitated the ultrasound carotid imaging and assisted to study design. All authors read and approved the final manuscript and met the criteria for authorship.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
Ethics approval (MECID 201412-878) was obtained from the UMMC Medical Ethics Committee and written informed consent was obtained from all participants prior to study enrolment.
About this article
Cite this article
Ng, Y., Lim, S., Kang, P. et al. Association between serum 25-hydroxyvitamin D levels and carotid atherosclerosis in chronic kidney disease patients. BMC Nephrol 17, 151 (2016). https://doi.org/10.1186/s12882-016-0367-7
- Vitamin D
- Parathyroid hormone
- Carotid atherosclerosis
- Carotid intima-media thickness
- Carotid plaque
- Chronic kidney disease