Vitamin D and vascular calcification

Armin Zittermann, Stefanie S. Schleithoff and Reiner Koerfer

Purpose of review
Vascular calcification is frequently found in patients with
osteoporosis, atherosclerosis and chronic kidney disease,
leading to high morbidity and mortality rates. The effects of
vitamin D excess and deficiency on vascular calcification
are reviewed in this article.
Recent findings
There is evidence from experimental studies that
mediacalcinosis induced by vitamin D excess is an active
and reversible process. Vitamin D excess, however, is rarely
seen in the general human population. Experimental data
also demonstrate that physiologic vitamin D actions include
the inhibition of processes that are important for intimal and
medial artery calcification such as pro-inflammatory
cytokine release, adhesion molecule release, and
proliferation and migration of vascular smooth muscle cells.
In uremic rats, low levels of the vitamin D hormone calcitriol
are associated with massive vascular and soft tissue
calcifications. Whereas retrospective studies already
indicate a beneficial effect of active vitamin D on mortality
rates in chronic kidney disease, little is yet known about the
effect of vitamin D deficiency on cardiovascular morbidity
and mortality in the general population.
Summary
Available data indicate that vitamin D exerts a biphasic
dose response curve on vascular calcification with
deleterious consequences not only of vitamin D excess but
also of vitamin D deficiency.
Keywords
calcification, calcitriol, calcium, renal insufficiency,
vitamin D
Curr Opin Lipidol 18:4146. 2007 Lippincott Williams & Wilkins.

Introduction
The essential role of vitamin D and calcium in the
maintenance of skeletal health has long been recognized.
There is now increasing evidence that vitamin D exerts
important physiological actions not only in bone but
also in the vasculature and that vitamin D deficiency
might be involved in the process of vascular calcification
(see below). Animal and human studies with supraphysiological amounts of vitamin D have also emphasized the role of excessive vitamin D in vascular toxicity
indicating a biphasic cardiovascular dose response curve
with deleterious consequences of vitamin D deficiency or
excess.
The aim of this review is to summarize the present
knowledge concerning the role of vitamin D in vascular
calcification.

Vitamin D physiology
Vitamin D physiology includes skin synthesis by the
ultraviolet B spectrum of the sunlight or dietary intake,
a hepatic hydroxylation into calcidiol (25-hydroxyvitamin
D), and a renal hydroxylation into the vitamin D hormone
calcitriol (1,25 dihydroxyvitamin D) (Fig. 1) [1]. Renal
calcitriol synthesis is under control of parathyroid hormone (PTH). In the circulation, both calcidiol and calcitriol are bound to vitamin D binding protein (DBP). This
plasma protein is not only a major carrier of vitamin D
metabolites but also has several functional properties [2]
and seems to be involved in the process of vascular
calcification [3]. Vitamin D receptors (VDRs) have been
identified in almost all tissues, among them vascular
smooth muscle cells (VSMCs), cardiomyocytes and endothelial cells [4].

Department of Cardiothoracic Surgery, Northrhine Westfalia Heart Center, Ruhr

University Bochum, Bad Oeynhausen, Germany
Correspondence to Armin Zittermann, PhD, Associate Professor, Department of
Cardio-Thoracic Surgery, Heart Center Northrhine-Westfalia, Ruhr University of
Bochum, Georgstrae 11, 32545 Bad Oeynhausen, Germany
Tel: +49 5731 97 1912; fax: +49 5731 97 2020;
e-mail: azittermann@hdz-nrw.de
Current Opinion in Lipidology 2007, 18:4146
Abbreviations
DBP
ESRD
MMP
PTH
VDR
VSMC

vitamin D binding protein

end-stage renal disease
matrix metalloproteinase
parathyroid hormone
vitamin D receptors
vascular smooth muscle cell

2007 Lippincott Williams & Wilkins

0957-9672

Clinical importance of vascular calcification

Vascular calcium accumulates when there is a net calcium
efflux from bone [5,6]. The inverse relationship between
the amount of vascular and skeletal calcium can explain
why vascular calcification is often associated with osteoporosis [7,8]. Vascular calcification has been defined as a
risk factor for cardiovascular mortality. Almost all angiographically atherosclerotic lesions are calcified [9]. In the
general population, the presence of vascular calcification
is a predictor of poorer 5-year survival [10]. In patients
with severe vascular calcification, such as end-stage renal
disease (ESRD) patients undergoing hemodialysis or
peritoneal dialysis, adjusted cardiovascular mortality is
1020 times higher than in the general population [11].
41

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42 Nutrition and metabolism

Figure 1 Vitamin D physiology
PTH, parathyroid hormone. Adapted
with permission [1].

Mechanisms of vascular calcification

Vascular calcification is a complex process that is dependent not only on the physicochemical effects of calcium
and phosphate, and pH, but also on smooth muscle
factors that may be regulated by these ions as well as
by PTH and calcitriol.
Vascular calcification can roughly be catagorized into
atherosclerotic intimal calcification, valvular calcification,
and medial artery calcification. Intimal artery calcification
is associated with atherosclerosis, T-helper cell type I
infiltration into the subendothelial space in response
to oxidized low-density lipoprotein, accumulation of
VSMCs at sites of vascular injury, and macrophage activation. Activated macrophages secrete pro-inflammatory
cytokines such as IL-1b, IL-6 and TNF-a [12,13]. These
alterations also promote the production of matrix metalloproteinases (MMPs), connective tissue enzymes involved in remodeling of the vascular wall and myocardium.
They function to destabilize the plaque to cause rupture
andthrombosis within the lumen. Mice deficientin MMP-2
and MMP-9 did not develop vascular calcification [14].
Moreover, inhibition of MMP activity can reduce calcium
accumulation in the arterial wall of rodents [15].
Medial artery calcification is characterized by a concentric
calcium deposition in the arterial VSMC layer. The

principal biologic effect of VSMCs is the production

of inhibitors of calcification. Humans lacking an enzyme
that produces extracellular pyrophosphate, a known
inhibitor of hydroxyapatite formation, develop severe
medial calcification, indicating that calcification can occur
at normal calcium and phosphate levels in the absence
of inhibition. Medial calcification results in arterial stiffening, which has adverse hemodynamic consequences
and is closely linked with left ventricular hypertrophy
[12]. The risks for the development of medial calcinosis
include renal failure and diabetes [16,17]. In ESRD
patients, vascular calcification is extremely common.
An elevated calcium  phosphate product (>72) and high
serum phosphorus concentrations (>6.5 mg/dl) are associated with cardiovascular complications and an increased
mortality [18].
Although calcification has been studied in VSMCs in
culture, these cells undergo phenotypic changes into
osteoblast-like cells and lack a normal extracellular
matrix including elastin, the principle site of medial
calcification in vivo. Recently performed studies in
VSMCs [19] indicate that the complex regulation of
vascular calcification in vivo cannot be easily replicated in
ex-vivo or in-vitro models. Therefore, an in-vitro model
of vascular calcification in rat aortas has been developed
under conditions that maintain viability and normal

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Vitamin D and vascular calcification Zittermann et al. 43

histology during long-term culture. This experimental

model demonstrates that calcification is enhanced by
alkalemia in the range observed after hemodialysis,
whereas PTH and calcitriol do not affect calcification
directly [20].

Experimental data on vascular toxicity of

vitamin D
The changes in arterial histology of experimental animals
with hypervitaminosis D have been well characterized.
Sublethal vitamin D doses (7.5 mg/kg) plus nicotine can
rapidly produce calcium overload in the young rat. Such
treatment produces a lasting 10 to 40-fold increase in the
aortic calcium content, the major site of calcium deposition being on the medial elastic fibres near the lumen.
Treatment results in calcification of medial elastic fibres
leading to destruction of elastic fibres and arterial stiffness [21]. Moreover, left ventricular hypertrophy occurs
in this model of calcium overload. An elevation in MMP9 levels in the aortic wall may be one factor explaining
vascular calcification after administration of sublethal
vitamin D3 doses (7.5 mg/kg) [15]. Similar to administration of the parent vitamin D, calcitriol treatment
(1 mg/kg) induces time-dependent vascular calcifications
in the media of the aorta in rats with intact renal function
[22]. In addition, widespread soft tissue calcification is
also detected after calcitriol treatment. It is noteworthy,
however, that the dosage of calcitriol used in the mentioned study to produce vascular calcification was much
higher than what would be administered for therapeutic
purposes. After calcitriol withdrawal, vascular calcifications regressed rapidly, with aortic calcium and phosphorus decreasing by 75% within 9 weeks. Results
indicate that regression of vascular calcification seems
to be an active cellular process. Obviously, cells from the
monocyticmacrophage lineage are involved in this process. The reversibility of extraskeletal calcifications is an
important and yet unsolved issue.
The consequences of toxic vitamin D exposure on vascular calcification in healthy rats cannot simply be
extrapolated to the human situation. We recently provided evidence that in the general population the risk for
vitamin D intoxication and thus for vitamin D-induced
vascular calcification is extremely rare [23]. Reasons for
the low risk are the homeostatic regulation of vitamin D
synthesis in the skin and the very low vitamin D intake by
foods and food supplements.
In uremic rats oral calcitriol treatment at nonhypercalcemic dosage (0.25 mg/kg/day) results in diffuse aortic
calcification involving the intima and media layer [24].
Moreover, animals show left ventricular hypertrophy.
Data indicate a permissive effect of uremia for cardiovascular damage induced by nonhypercalcemic doses of
calcitriol. Similar results were obtained by Henley et al.

[25] in a rat model of secondary hyperparathyroidism

after calcitriol treatment (0.250.28 mg/kg) on aortic
calcification, whereas no significant calcification was
observed in vehicle-treated animals groups. Calcitriol
reduced serum PTH, but also resulted in elevated serum
calcium, serum phosphorus and the calcium  phosphate
product above pretreatment levels, or those seen with
vehicle. Data are in line with the fact that common
therapeutic interventions with calcium and calcitriol in
ESRD patients with secondary hyperparathyroidism
have come under scrutiny for associations with the development of vascular calcification. Nevertheless, it should
be mentioned that the adenine-induced rat model of
uremia, which results in extremely high PTH levels
and progressive increase in inorganic phosphate, also
shows medial calcification in the aorta and metastatic
calcification in soft tissue despite decreased levels of
serum calcium and calcitriol [26]. Data provide important evidence that medial calcification does occur when
serum calcitriol levels are still low. Thus, vascular calcification is not initiated by vitamin D.

Protective actions of vitamin D on vascular

calcification
DNA microarray technology has demonstrated that calcitriol and the vitamin D analogue paricalcitol result in an
upregulation of more than 100 genes and a downregulation of more than 50 genes [27]. These genes are
involved in the cell cycle and lead to inhibition of
proliferation and induction of differentiation. Their
activation and deactivation, respectively, can reduce
thrombogenicity, and can increase fibrinolysis, vessel
relaxation, and endothelial regeneration. Earlier studies
in VDR knockout mice have already demonstrated that
the absence of vitamin D action leads to enhanced
thrombogenicity [28].
Out of the various vitamin D actions, one physiologic
vitamin D effect seems to be the suppression of inflammatory processes [1]. Evidence has emerged that endothelial cells may express a 1-a hydroxylase activity that
produces calcitriol as paracrine/intracrine regulator of
endothelial cell activation to inflammation [29]. In
endothelial cells calcitriol inhibits antigen-induced, cytokine-mediated endothelial cell activation in general
and TNF-a-induced adhesion molecule expression in
particular [30,31]. These effects may be of physiologic
importance, since there is considerable evidence for the
involvement of adhesion molecules at an early stage of
atherosclerosis. Cells found in human atherosclerotic
lesions such as endothelial cells, carry vascular cell
adhesion molecule-1 on their surface [30]. Recently
performed studies also demonstrate that DBP is released
at sites of endothelial injury and can induce proliferation
and migration of VSMCs and thus represents a novel
pathway favouring accumulating of VSMCs at sites of

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44 Nutrition and metabolism

Figure 2 A biphasic doseresponse curve for vitamin D in vascular calcification

Risk of
deficiency
or excess

100%

50%

Pro-inflammatory

Hypercalcemia

cytokines

Metalloproteinases

Metalloproteinases

Medial calcification

Protective factors of

Arterial stiffness

endothelial cells

Left ventricular hypertrophy

0%
Vitamin D dosage

vascular injury [3]. In the mentioned study, calcidiol and

calcitriol could inhibit the activity of DBP on VSMCs,
assuming that an adequate vitamin D status may contribute to the protection of vascular disease. Calcitriol and
the vitamin D analogue 22-oxa-1,25-dihydroxyvitamin
D3 can also reduce the expression of MMP-2, MMP-9,
and vascular endothelial growth factor [32]. Besides its
suppression of MMP-9 activity, calcitriol can increase
activity of tissue inhibitors of MMP-1. The effect on
MMP-9 is due to reduced mRNA stability [33]. Remarkably, MMP-9 levels were inversely related to serum
calcidiol levels among an apparently healthy population
of South Asians in Great Britain. The MMP-9 levels
increased progressively when serum calcidiol level were
below 100 nmol/l [34]. Keeping in mind that vitamin D
excess also leads to elevated MMP-9 levels (see above),
data support the assumption of a biphasic cardiovascular
doseresponse curve with deleterious consequences of
vitamin D deficiency or excess (Fig. 2).

Clinical studies
Most currently available clinical studies have focused
on vascular calcification in chronic kidney disease. Data
indicate that even young adults who have suffered from
ESRD since childhood have systemic cardiovascular disease characterized by a decrease in arterial elasticity, the
occurrence of coronary artery calcification and changes in
left ventricular morphology [35]. These alterations may
be due at least in part to a disturbed vitamin D metabolism. When renal function impairs, the serum concentrations of calcitriol are reduced [36]. Activity of the renal
1a-hydroxylase is attenuated in chronic renal failure due
to phosphate load as well as to the decreased number of
viable nephrons [37]. ESRD patients suffer from hyperparathyroidism, which is caused by several factors, prim-

arily hypocalcemia and reduced production of calcitriol.

Moreover, resistance to physiological concentrations of
calcitriol may develop during the early phase of chronic
renal failure [37]. Results of Qunibi et al. [38] indicate
that coronary arterial calcification and peripheral arterial
calcification are already common and severe in diabetic
patients with chronic kidney disease prior to treatment
with dialysis, calcium-containing phosphate binders, calcitriol, or vitamin D analogues. Data support experimental results and suggest especially that a lower level of
renal function is associated with increased burden of
vascular calcification in predialysis patients with chronic
kidney disease. In line with these findings the doses of
calcium salts and of 1-a vitamin D3 were not significantly
associated with vascular calcifications in patients with a
medium length of dialysis [39]. There is also some
evidence that low calcidiol availability can contribute
to the low calcitriol levels in renal failure [40]. In a
recently performed study [41], only 29 and 17% of
subjects with moderate and severe chronic kidney
disease, respectively, had sufficient calcidiol levels
(>75 nmol/l). Therefore, calcidiol repletion (>75 nmol/l)
has been recommended in uremic patients [42].
Two very large retrospective studies in Japanese and US
ESRD patients have shown that VDR activators (calcitriol and paricalcitol) provide a 20 and 24% survival
advantage, respectively, over no VDR activator therapy
[43,44]. In particular, cardiovascular mortality was significantly lower in the vitamin D group compared to the
nonvitamin D group [44]. In a small cohort of Japanese
ERSD patients, the use of 1a-hydroxyvitamin D3 was
associated with a 70% lower risk of death from cardiovascular disease when compared with a group of 1ahydroxyvitamin D3 nonusers. The median intake of

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Vitamin D and vascular calcification Zittermann et al. 45

1a-vitamin D was 0.5 mg/day for a median follow-up of

61 months [45]. In another large retrospective study the
mortality rate was 16% lower among those patients administered the vitamin D analogue paricalcitol than among
those administered calcitriol over a 3-year period [46]. It
has been suggested that the beneficial effect of the
vitamin D analogue seems to be at least in part due to
the less calcemic effect of paricalcitol compared with
calcitriol. In line with this assumption and with the
possible toxic effects of relatively low calcitriol doses
in uremic rats (see before), treatment of secondary hyperparathyroidism with calcitriol and calcium is often complicated in ERSD patients by hypercalcemia and hyperphosphatemia. Since therapy with calcium-containing
phosphate binders and active vitamin D preparations
has been independently associated in a dose-dependent
manner with surrogate markers for cardiovascular disease
[35], the therapeutic window for calcitriol seems to be
narrow in ESRD patients.
Relatively few data concerning vascular calcification and
vitamin D deficiency/insufficiency are currently available
in nonchronic kidney disease patients. Although mild
renal impairment, insufficient calcidiol levels, and secondary hyperparathyroidism are common in elderly residents of aged care facilities [47], their impact on vascular
calcification has not been studied in this population group
yet. There is, however, already evidence from two human
populations at high and moderate risk for ischemic heart
disease for an inverse association of serum calcitriol levels
with vascular calcification [48]. There is also some evidence that vitamin D surrogates are inversely associated
with cardiovascular disease mortality in the general population [23]. Interestingly, supplementation with vitamin
D can suppress serum TNF-a levels and can increase
IL-10 levels [49]. While TNF-a plays an important role
in intimal atherosclerosis and calcification, IL-10 has
antiatherogenic properties [50].

in the general population need to be studied in more

detail.

References and recommended reading

Papers of particular interest, published within the annual period of review, have
been highlighted as:

of special interest
 of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 9497).
1

Zittermann A. Vitamin D in preventive medicine: are we ignoring the evidence?

Br J Nutr 2003; 89:552572.

Speeckaert M, Huang G, Delanghe JR, et al. Biological and clinical aspects of

the vitamin D binding protein (Gc-globulin) and its polymorphism. Clin Chim
Acta 2006; 372:3342.
This comprehensive review demonstrates that vitamin D binding protein has
important functional properties beside its carrier function for vitamin D metabolites.

2


Raymond MA, Desormeaux A, Labelle A, et al. Endothelial stress induces the

release of vitamin D-binding protein, a novel growth factor. Biochem Biophys
Res Commun 2005; 338:13741382.
This interesting experimental study that gave new insight in possible mechanisms
of vascular injury.

3


Towler DA, Clemens TL. Vitamin D and cardiovascular medicine. In: Feldman
D, Pike JW, Glorieux FH, editors. Vitamin D, 2nd edition. Amsterdam: Elsevier
Academic Press; 2005. pp. 899910.

Moon J, Bandy B, Davison AJ. Hypotheis: are imbalances in the calciferol

endocrine system implicated? J Amer Coll Nutr 1992; 11:567583.

Price PA, Faus SA, Williamson MK. Bisphosphonates alendronate and

ibandronate inhibit artery calcification at doses comparable to those that
inhibit bone resorption. Arterioscler Thromb Vasc Biol 2001; 21:817824.

Banks LM, Lees B, MacSweeney JE, et al. Effect of degenerative spinal and
aortic calcification on bone density measurements in postmenopausal
women: links between osteoporosis and cardiovascular disease? Eur J
Clin Invest 1994; 24:813817.

Barengolts EI, Berman M, Kukreja SC, et al. Osteoporosis and coronary

atherosclerosis in asymptomatic postmenopausal women. Calcif Tissue Int
1998; 62:209213.

Honye J, Mahon DJ, Jain A, et al. Morphological effects of coronary balloon

angioplasty in vivo assessed by intravascular ultrasound imaging. Circulation
1992; 85:10121025.

10 Margolis JR, Chen JT, Kong Y, et al. The diagnostic and prognostic significance of coronary artery calcification. A report of 800 cases. Radiology
1980; 137:609616.
11 Foley RN, Parfrey PS, Sarnaak MJ. Clinical epidemiology of cardiovascular
disease in chronic renal disease. Am J Kidney Dis 1998; 32 (5 Suppl
3):S112S119.
12 Doherty TM, Fitzpatric LA, Inoue D, et al. Molecular, endocrine, and genetic
mechanisms of arterial calcification. Endocr Rev 2004; 25:629672.
13 Tomasek JJ, Gabbiani G, Hinz B, et al. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 2002; 3:349
363.

Conclusion
Current knowledge concerning the effect of vitamin D on
vascular calcification primarily rely on experimental
studies and clinical studies with calcitriol or vitamin D
analogues in patients with renal insufficiency. Experimental data indicate that not only the process of vascular
calcification but also the inhibition of vascular calcification is actively mediated by various vitamin D-mediated
local factors. Renal impairment in association with low
calcitriol levels is a risk factor for vascular calcification and
for high mortality rates. The window for calcitriol therapy
in patients with chronic kidney disease, however, is
obviously narrow.
In future, the effects of low serum levels of vitamin D
metabolites on vascular calcification and mortality rates

14 Basalyga DM, Simionescu DT, Xiong W, et al. Elastin degradation and

calcification in an abdominal aorta injury model: role of matrix metalloproteinases. Circulation 2004; 110:34803487.
15 Qin X, Corriere MA, Matrisian LM, et al. Matrix metalloproteinase inhibition

attenuates aortic calcification. Arterioscler Thromb Vasc Biol 2006;
26:15101516.
This was another interesting experimental study providing evidence that vascular
calcification and also its inhibition is an actively regulated process.
16 London GM, Marty C, Marchais SJ, et al. Arterial calcifications and bone
histomorphometry in end-stage renal disease. J Am Soc Nephrol 2004;
15:19431951.
17 Schinke T, Karsenty G. Vascular calcification: a passive process in need of
inhibitors. Nephrol Dial Transplant 2000; 15:12721274.
18 Block GA, Hulbert-Shearon TE, Levin NW, et al. Association of serum
phosphorus and calcium x phosphate product with mortality risk in chronic
hemodialysis patients: a national study. Am J Kidney Dis 1998; 31:607617.
19 Wu-Wong JR, Noonan W, Ma J, et al. Role of phosphorus and vitamin D
 analogs in the pathogenesis of vascular calcification. J Pharmacol Exp Ther
2006; 318:9098.
Extensively performed in-vivo and ex-vivo studies provided evidence that vascular
calcification in vivo cannot be easily replicated in ex-vivo or in-vitro models.

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

46 Nutrition and metabolism

20 Lomashvili K, Garg P, ONeill WC. Chemical and hormonal determinants of

vascular calcification in vitro. Kidney Int 2006; 69:14641470.
Authors used a new model of vascular calcification in chronic renal failure to study
the effects of possible risk factors.
21 Niederhoffer N, Lartaud-Idjouadiene I, Giummelly P, et al. Calcification of
medial elastic fibers and aortic elasticity. Hypertension 1997; 29:9991006.
22 Bas A, Lopez I, Perez J, et al. Reversibility of calcitriol-induced medial artery
 calcification in rats with intact renal function. J Bone Miner Res 2006;
21:484490.
This study in experimental animals is of clinical importance because it demonstrated the reversibility of vascular calcification.
23 Zittermann A, Schleithoff SS, Koerfer R. Putting cardiovascular disease and

vitamin D insufficiency into perspective. Br J Nutr 2005; 94:483492.
This comprehensive review provides several lines of evidence for an association of
vitamin D insufficiency with cardiovascular disease.
24 Haffner D, Hocher B, Mu ller D, et al. Systemic cardiovascular disease in
uremic rats induced by 1,25(OH)2D3. J Hypertens 2005; 23:10671075.
25 Henley C, Colloton M, Cattley RC, et al. 1,25-Dihydroxyvitamin D3 but not
cinacalcet HCl (Sensipar/Mimpara) treatment mediates aortic calcification in
a rat model of secondary hyperparathyroidism. Nephrol Dial Transplant 2005;
20:13701377.
26 Tamagaki K, Yuan Q, Ohkawa H, et al. Severe hyperparathyroidism with bone
 abnormalities and metastatic calcification in rats with adenine-induced uraemia. Nephrol Dial Transplant 2006; 21:651659.
Another important investigation in experimental animals supported the hypothesis
that calitriol deficiency is involved in vascular calcification.
27 Wu-Wong JR, Nakane M, Ma J, et al. Effects of vitamin D analogs on gene
 expression profiling in human coronary artery smooth muscle cells. Atherosclerosis 2006; 186:2028.
An important investigation demonstrated that gene activation and deactivation by
vitamin D plays a central role in the metabolism of arterial smooth muscle cells.
28 Aihara K, Azuma H, Akaike M, et al. Disruption of nuclear vitamin D receptor
gene causes enhanced thrombogenicity in mice. J Biol Chem 2004;
279:3579835802.
29 Zehnder D, Bland R, Chana RS, et al. Synthesis of 1,25-dihydroxyvitamin D(3)
by human endothelial cells is regulated by inflammatory cytokines: a novel
autocrine determinant of vascular cell adhesion. J Am Soc Nephrol 2002;
13:621629.
30 Equils O, Naiki Y, Shapiro AM, et al. 1,25-Dihydroxyvitamin D inhibits lipo
polysaccharide-induced immune activation in human endothelial cells. Clin
Exp Immunol 2005; 45:5864.
The authors describe several well performed ex-vivo experiments that provide
evidence for protective effects of calcitriol on endothelial cells.
31 Martinesi M, Bruni S, Stio M, et al. 1,25-Dihydroxyvitamin D3 inhibits tumor

necrosis factor-alpha-induced adhesion molecule expression in endothelial
cells. Cell Biol Int 2006; 30:365375.
Well performed experimental studies gave new insights in the beneficial effects of
vitamin D on endothelial cells.
32 Nakagawa K, Sasaki Y, Kato S, et al. 22-Oxa-1alpha,25-dihydroxyvitamin D3
inhibits metastasis and angiogenesis in lung cancer. Carcinogenesis 2005;
26:10441054.
33 Bao BY, Yeh SD, Lee YF. 1a,25-dihydroxyvitamin D3 inhibits prostate cancer

cell invasion via modulation of selective proteases. Carcinogenesis 2006;
27:3242.
Although from studies performed in prostate cancer cells, these experimental data
support the central role of vitamin D in the regulation of cellular processes.
34 Timms PM, Mannan N, Hitman GA, et al. Circulating MMP9, vitamin D and
variation in the TIMP-1 response with VDR genotype: mechanisms for
inflammatory damage in chronic disorders? QJM 2002; 95:787796.

35 Briese S, Wiesner S, Will JC, et al. Arterial and cardiac disease in young adults

with childhood-onset end-stage renal disease-impact of calcium and vitamin D
therapy. Nephrol Dial Transplant 2006; 21:19061914.
This casecontrol study indicated that active vitamin D preparations are independently associated in a dose-dependent manner with cardiovascular disease.
Data support the assumption that the therapeutic window for active vitamin D may
be narrow in patients with chronic kidney disease.
36 Juttmann JR, Buurman CJ, DeKam E, et al. Serum concentrations of metabolites of vitamin D in patients with chronic renal failure. Clin Endocrinol 1981;
14:225236.
37 Fukagawa M, Kurokawa K. Renal failure and secondary hyperparathyroidism. In: Feldman D, Pike JW, Glorieux FH, editors. Vitamin D, 2nd
edition. Amsterdam: Elsevier, Academic Press, Amsterdam; 2005. pp. 1820
11832.
38 Qunibi WJ, Abouzahr F, Mizani MR, et al. Cardiovascular calcification in
Hispanic Americans (HA) with chronic kidney disease (CKD) due to type 2
diabetes. Kidney Int 2005; 68:271277.
39 Al Humoud H, Al-Hilali N, Ahmad AAMH, et al. Vascular calcification in dialysis

patients. Transplant Proc 2005; 37:41834186.
This epidemiological investigation compared several possible risk factors for
vascular calcification in two groups of dialysis patients.
40 Halloran BP, Schaefer P, Lifschitz M, et al. Plasma vitamin D metabolite
concentrations in chronic renal failure: effect of oral administration of
25-hydroxyvitamin D3. J Clin Endocrinol Metab 1984; 59:1063
1069.
41 LaClair RE, Heilman RN, Karp SL, et al. Prevalence of calcidiol deficiency in
CKD: a cross-sectional study across latitudes in the United States. Am J
Kidney Dis 2005; 45:10261033.
42 Monge M, Shahapuni I, Harbouche L, et al. Cinacalcet and vascular calcifica
tions induced by calcitriol. Nephrol Dial Transplant 2006; 21:551.
This is a letter to the editor that provides arguments for calcidiol repletion in uremic
patients.
43 Nakai S, Shinzato T, Nagura Y, et al. An overview of regular dialysis treatment
in Japan (as of 31 December 2001). Ther Apher Dial 2004; 8:332.
44 Teng M, Wolf M, Ofsthun MN, et al. Activated injectable vitamin D and
hemodialysis survival: a historical cohort study. J Am Soc Nephrol 2005;
16:11151125.
45 Shoji T, Shinohara K, Kimoto E, et al. Lower risk for cardiovascular mortality in
oral 1alpha-hydroxy vitamin D3 users in a haemodialysis population. Nephrol
Dial Transplant 2004; 19:179184.
46 Teng M, Wolf M, Lowrie E, et al. Survival of patients undergoing hemodialysis
with paricalcitol or calcitriol therapy. N Engl J Med 2003; 349:446456.
47 Zochling J, Chen JS, Seibel M, et al. Calcium metabolism in the frail elderly.

Clin Rheumatol 2005; 24:576582.
This epidemiological study demonstrated the high prevalence of mild renal
impairment and vitamin D insufficiency in frail elderly subjects.
48 Watson KE, Abrolat ML, Malone LL, et al. Active serum vitamin D levels are
inversely correlated with coronary calcification. Circulation 1997; 96:1755
1760.
49 Schleithoff SS, Zittermann A, Tenderich G, et al. Vitamin D supplementation
 improves cytokine profile in patients with congestive heart failure: a doubleblind, randomized, placebo-controlled trial. Am J Clin Nutr 2006; 83:754
759.
This important prospective study demonstrated that oral vitamin D intake is able
to suppress pro-inflammatory cytokines and to enhance anti-inflammatory cytokines.
50 Mallat Z, Besnard S, Duriez M, et al. Protective role of interleukin-10 in
atherosclerosis. Circ Res 1999; 85:e17e24.

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