Vitamin D and vascular calcification in chronic kidney disease
Introduction
Vascular calcification is categorized into two types: atherosclerotic intimal layer calcification and medial layer calcification. Medial layer calcification (Monckeberg's calcification) is common in patients with chronic kidney disease (CKD) [1], [2]. Vascular smooth muscle cells (VSMCs) have been shown to possess 25-hydroxyvitamin D3-1α hydroxylase [3] and the vitamin D receptor (VDR) [4], [5], [6], [7] indicating that the vitamin D-VDR axis has an important role in VSMC function locally. Besides mineral metabolism, vitamin D possesses several properties also in physiological response including anti-inflammatory actions [8], [9]. In clinical settings, vitamin D excess and deficiency are associated with not only vascular calcification, but also cardiovascular disease, the most common cause of mortality in patients with CKD [10], [11], [12], [13], [14]. Recently, both low and high vitamin D levels have been shown to be associated with vascular calcification (a U-curve relationship) [14]. Several recent observational cohort studies have shown an association of treatment with calcitriol or its analogs and improved survival of patients with CKD [15], [16], [17], [18], [19], [20], [21]. Taking these factors into consideration, the appropriate VDR activation, especially in organs that relate to cardiovascular disease, would be essential in avoiding the increase in mortality of patients with CKD. In this manuscript, we focus on the relationship between vitamin D and vascular calcification especially in uremic milieu.
Section snippets
Mechanisms of vascular calcification: an active osteogenic process
The detailed mechanisms of vascular calcification in uremic milieu have not been completely understood. For many years vascular calcification has been considered a passive, unregulated process due to elevated serum calcium (Ca) and phosphate (P) levels, and high calcium-phosphate (Ca x P) product resulting in supersaturated plasma. However, recent observations have revealed that vascular calcification is not simply a passive process, but also an active process that is applicable to the
Experimental observations
Because the VDR is found in VSMCs, it is reasonable to assume that calcitriol, the main ligand for the VDR has an effect on VSMCs. Calcitriol at concentrations as low as 0.1 nM has been shown to decrease VSMC proliferation by inhibiting the activation of epidermal growth factor [33]. In addition, exposing cultures of rat [34] or rabbit [5] VSMCs to calcitriol produces an up-regulation of the VDR expression. Thus, calcitriol has a number of effects on VSMCs mediating the VDR. Calcitriol has been
Clinical observations
Vitamin D is widely used to control secondary hyperparathyroidism. In the general population, a decrease in serum calcitriol levels is associated with an increased risk of vascular calcification [49], [50]. Naturally enough, calcitriol could induce vascular calcification by indirect effects on bone metabolism as well as on serum Ca and P levels. In patients undergoing dialysis, low-turnover bone disease with which serum PTH levels are low is associated with vascular calcification [51], [52].
Conclusions
Research efforts have provided us the multiple factors and mechanisms implicated in the progression of vascular calcification in patients with CKD. Many questions remain to be resolved. To obtain greatly improved knowledge about vascular calcification, an interdisciplinary research group in mineral metabolism and cardiovascular disease may be needed. Experimental data shows that only supraphysiologic concentrations of calcitriol induce vascular calcification via the elevation of extracellular
Conflict of interest
None.
Acknowledgment
We thank Miss Larenda Mielke for helpful suggestions.
References (61)
- et al.
Vascular calcification in chronic kidney disease
Am. J. Kidney Dis.
(2004) - et al.
1,25-Dihydroxyvitamin D3 stimulates 45Ca2+-uptake by cultured vascular smooth muscle cells derived from rat aorta
Biochem. Biophys. Res. Commun.
(1988) - et al.
1,25-dihydroxyvitamin D3 receptor is upregulated in aortic smooth muscle cells during hypervitaminosis D
Life Sci.
(2002) - et al.
Effects of Vitamin D analogs on gene expression profiling in human coronary artery smooth muscle cells
Atherosclerosis
(2006) - et al.
Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients
Kidney Int.
(2006) - et al.
Mortality risk among hemodialysis patients receiving different vitamin D analogs
Kidney Int.
(2006) - et al.
Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD)
Kidney Int.
(2005) - et al.
Uremia induces the osteoblast differentiation factor Cbfa1 in human blood vessels
Kidney Int.
(2003) - et al.
1,25-Dihydroxyvitamin D3 stimulates vascular smooth muscle cell proliferation through a VEGF-mediated pathway
Kidney Int.
(2006) - et al.
Effect of etidronate on aortic calcification and bone metabolism in calcitriol-treated rats with subtotal nephrectomy
J. Pharmacol. Sci.
(2005)
Prevention of aortic calcification by etidronate in the renal failure rat model
Eur. J. Pharmacol.
Uremia-related vascular calcification: more than apatite deposition
Kidney Int.
Differential effects of vitamin D receptor activators on vascular calcification in uremic rats
Kidney Int.
Development of adynamic bone in patients with secondary hyperparathyroidism after intermittent calcitriol therapy
Kidney Int.
Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease?
J. Am. Coll. Cardiol.
Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease
Kidney Int.
1,25(OH)2-vitamin D3 actions on cell proliferation, size, gene expression, and receptor localization, in the HL-1 cardiac myocyte
J. Steroid Biochem. Mol. Biol.
Intravenous calcitriol regresses myocardial hypertrophy in hemodialysis patients with secondary hyperparathyroidism
Am. J. Kidney Dis.
The vascular biology of calcification
Semin. Dial
25-hydroxyvitamin D3–1alpha-hydroxylase is expressed in human vascular smooth muscle cells and is upregulated by parathyroid hormone and estrogenic compounds
Circulation
VDR-mediated gene expression patterns in resting human coronary artery smooth muscle cells
J. Cell Biochem.
Vitamin D
Am. J. Physiol. Renal. Physiol.
Vitamin D analogs: Therapeutic applications and mechanisms for selectivity
Mol. Aspects Med.
K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease
Am. J. Kidney Dis.
25-Hydroxyvitamin D3, arterial calcifications and cardiovascular risk markers in haemodialysis patients
Nephrol. Dial Transplant
Vascular calcifications in uremia: old concepts and new insights
Semin. Dial
Vascular calcification: pathobiological mechanisms and clinical implications
Circ. Res.
A bimodal association of vitamin D levels and vascular disease in children on dialysis
J. Am. Soc. Nephrol.
Lower risk for cardiovascular mortality in oral 1alpha-hydroxy vitamin D3 users in a haemodialysis population
Nephrol. Dial Transplant
Activated injectable vitamin D and hemodialysis survival: a historical cohort study
J. Am. Soc. Nephrol.
Cited by (39)
Types and pathology of vascular calcification
2019, Coronary Calcium: A Comprehensive Understanding of Its Biology, Use in Screening, and Interventional ManagementVascular calcification in chronic kidney disease: different bricks in the wall?
2017, Kidney InternationalCitation Excerpt :Next, vitamin D (mainly active forms of vitamin D) has been a focus of interest in that it may modulate vascular calcification. In animal models and clinical studies it has been shown to induce VC, probably only at high doses,83 while at more physiological doses vitamin D could even be protective as shown in CKD models.84 Of note, vitamin D deficiency has also been linked to VC, arterial stiffness, and CV mortality in CKD.85
Native vitamin D in dialysis patients
2015, Nephrologie et TherapeutiqueAssociation between Serum 25-Hydroxyvitamin D and Abdominal Aortic Calcification: A Large Cross-Sectional Study
2023, International Journal of Clinical Practice