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5 Vitamin D and CKD-Associated Conditions That Predispose to Endothelial Dysfunction

5 Vitamin D and CKD-Associated Conditions That Predispose to Endothelial Dysfunction

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M. Apetrii and A. Covic


In type 2 diabetes, low circulating vitamin D levels favor poor glycemic control, and

the reduction of immature endothelial progenitor cells that are involved in endothelial repair and angiogenesis, thus promoting endothelial function impairment [37].

Vitamin D protects against the negative effects of AGE on eNOS activity [38] and

also has antiatherogenic effects by inhibiting foam cell formation [39]. Despite this,

randomized controlled trials (RCT) of diabetic patients with suboptimal serum vitamin D levels (<30 ng/ml) did not show any significant changes induced by vitamin

D repletion regarding circulating endothelial progenitor cells, FMD or blood pressure. However, FMD was significantly ameliorated by vitamin D repletion in a posthoc analysis of diabetic patients that specifically had baseline endothelial dysfunction

[40]. Clinical studies assessed only the circulating 25(OH)D form, while the active

intracellular form is represented by 1,25(OH)2D3. Therefore, vitamin D activation

by 1α-hydroxylase may alter the relationship between 25(OH)D and markers of

arterial function [41]. As mentioned before, it is also possible that in diabetic

patients that are on vasoactive medication, vitamin D supplementation may not further induce any significant change.



One of the main mechanisms that is excessively activated in both hypertension and

CKD having deleterious effects on vasculature is the RAAS [42]. Vitamin D regulates vascular tone through both genomic and non-genomic mechanisms [42, 43].

Through genomic mechanisms, calcitriol negatively regulates renin gene transcription: VDR-bound calcitriol inhibits the interaction between cyclic adenosine monophosphate (cAMP) response element binding and cAMP response element in the

renin gene promoter, thus inhibiting the transcription of renin gene [44]. Further on,

calcitriol down-regulates angiotensin II receptor 1 (AT1R) expression in renal arteries, thus blunting the deleterious effects induced by angiotensin II binding to its

receptor: in both renal and systemic arteries, vitamin D is responsible for a reduction in angiotensin II-induced ROS excessive generation [43]. ROS promote endothelium dysfunction and finally hypertension: [1] ROS alter eNOS activity, being

responsible for eNOS uncoupling and thus for impaired NO-dependent endothelial

function, ROS promote the expression of cyclooxygenases-derived contracting factors in the endothelium [3, 45, 46]. Also by genomic regulation, calcitriol downregulates the expression of oxidative-stress associated enzyme, NADPH oxidase in

renal arteries. The vascular anti-oxidative action of calcitriol also comprises upregulation of SOD-1 and SOD-2 enzymes in renal arteries. The effects of calcitriol

on NADPH oxidase and SOD expression may partially be mediated by the downregulation of AT1R, as AT1R activation is responsible for ROS production. Thus, by

regulating RAAS and ROS production, vitamin D protects both kidney and systemic vessels from ED in hypertension [43].

20 Vitamin D and Endothelial Function in Chronic Kidney Disease


Through non-genomic mechanisms, calcitriol regulates calcium influx in endothelial cells. The increased production of endothelium-derived contracting factors

(EDCF) depends on a high concentration of free intracellular calcium. In endothelial cells, calcitriol prevents the high calcium influx that is needed for the production

of EDCF and therefore attenuates endothelium-dependent contractions [47].

Studies on animal models showed that vitamin D supplementation may improve

blood pressure values, but most interventional trials failed to confirm these results

in humans. Despite this, there is still convincing evidence from animal studies and

in vitro studies that vitamin D contributes to endothelial function regulation in

hypertension and CKD by diminishing the deleterious impact of RAAS activation

and not only [42, 43].



CKD is associated with major alterations of lipid metabolism resulting in dyslipidemia. Firstly, CKD patients have hypertriglyceridemia and also a high concentration of serum triglyceride-transporting lipoproteins, such as very-low-density

lipoproteins (VLDLs). This is due to decreased activity of lipoprotein lipase and to

CKD-associated insulin resistance which enhances VLDL production. Secondly, in

CKD there is an increase in the concentration of highly atherogenic small dense

low-density lipoproteins (LDL). Thirdly, CKD is associated with low levels of circulating high-density lipoprotein (HDL) particles, which also have their anti-oxidant

and anti-inflammatory actions impaired [48].

Dyslipidemia in CKD promotes ED, increases CV risk and also promotes CKD

progression [48, 49]. It has been suggested that vitamin D regulates endothelial

function also by interfering with lipid metabolism. Vitamin D levels positively associate with HDL-cholesterol and negatively associate with triglycerides in observational studies. Unexpectedly, in some studies, vitamin D levels positively correlate

with LDL-cholesterol also. Despite this, vitamin D remains negatively associated

with LDL-cholesterol/HDL-cholesterol ratio, suggesting that the most significant

effect of vitamin D does not regard cholesterol fractions taken individually, but

implies the favorable modulation of lipid balance. However, results from interventional studies that evaluated the effects of vitamin D supplementation on lipid profile are conflicting: some did not reveal any influence; other reported significantly

increased levels of LDL-cholesterol or of both LDL-cholesterol and triglycerides

[50]. In a meta-analysis performed by Wang et al. [51] that included RCTs, contrary

to expectations, vitamin D supplementation was shown only to increase LDLcholesterol, without any significant effect on the other lipid fractions.

Statin therapy moderately improves vitamin D status by significantly increasing

25(OH)D levels in vitamin D-deficient, hyperlipidemic patients. Furthermore, they

improves renal endothelial function by increasing basal NO activity in the renal endothelium also. The mechanisms by which statins interfere with vitamin D levels are not

known. It has been speculated that the inhibition of hydroxyl-methyl-glutaryl-CoA


M. Apetrii and A. Covic

reductase (HMG-CoA reductase) by statins favors high levels of vitamin D precursor

in the skin [31]. However, contradictory results been reported by other groups; thus,

patients treated by statins exhibit lower 25(OH)D3 values have by an unclear mechanism [52]. It is also known that statins have pleiotropic effects. Besides having antiinflammatory and direct anti-atherogenic effects, statins also protect the endothelium:

statins blunt eNOS down-regulation induced by oxidized LDL and increase eNOS

expression at the post-translational level [53]. Statins also increase the number of

circulating endothelial progenitor cells, which are known to promote endothelial

repair and thus conserve endothelial function [10, 53].

In CKD, the triangle vitamin D-lipids-endothelial function seems to be affected

at all levels. Vitamin D deficiency and dyslipidemia may have additive negative

effects on endothelial function, although evidence suggests that vitamin D deficiency and lipid abnormalities may actually potentiate one another.



The pleiotropic effects of vitamin D also include immunomodulatory properties:

vitamin D deficiency contributes to CKD-associated inflammatory state and also

promotes cardiovascular inflammation and by this, ED [54]. Vitamin D deficiency

is associated with increased expression of proinflammatory NF-kB and IL-6 in

endothelial cells [55] and with high circulating levels of CRP and IL-6 [56].

Paricalcitol administration in CKD down-regulates circulating high-sensitivity

CRP and both serum and mononuclear cells expression of TNF-α and IL-6 [57].

High levels of CRP activate the endothelium by promoting increased expression

of adhesion molecules and lead to ED by triggering endothelin-1 release and

down-regulating eNOS [49]. IL-6 triggers oxidative stress generation via up-regulation of AT1R and RAAS activation in the vessels, leading to impaired

endothelium-dependent vasodilation and, finally, atherosclerosis [58]. At the

same time, inflammatory markers are predictors of CVD and mortality in the

CKD population: CRP predicts CVD in CKD non-dialysis patients, CRP and IL-6

are predictors of CV and all-cause mortality in ESRD, TNF-α predicts all-cause

mortality in ESRD [59].

The mechanisms through which vitamin D regulates proinflammatory cytokines

expression are various. Firstly, vitamin D inhibits the activation of TNF-α converting enzyme (TACE), which causes renal and systemic inflammation by releasing

TNF-α and soluble adhesion molecules. Also vitamin D suppresses RAAS activation, also a trigger of TACE activation. Secondly, vitamin D is negatively correlated

with albuminuria which is per se a proinflammatory condition in CKD, where it is

associated with high IL-6 concentration. Thirdly, vitamin D down-regulates NF-kB

activation and subsequently the overexpression of regulated on activation, normal T

cell expressed and secreted RANTES (regulated on activation, normal T cell

expressed and secreted chemokine) protein, a chemokine responsible with leukocyte recruitment and promotion of chronic inflammation [54, 60].

20 Vitamin D and Endothelial Function in Chronic Kidney Disease


Therefore, vitamin D deficiency triggers and maintains the low-grade inflammation

in CKD, in addition to other factors (e.g. uremia, AGEs, oxidative stress, atherosclerosis, obesity, etc.). This leads to endothelial dysfunction and CV injury, thus partially explaining why CVD is the main cause of death in ESRD patients [54, 59].


Secondary Hyperparathyroidism

Secondary hyperparathyroidism (SHPT) due to vitamin D deficiency in CKD may

also have deleterious effects on the vasculature. Increased PTH has been linked to a

higher mortality and to a significant decrease in median life expectancy in elderly

subjects [61]. Serum PTH levels above 250 pg/ml significantly increases the risk for

coronary artery disease in chronic hemodialysis patients with SHPT [62]. In patients

with primary hyperparathyroidism, high PTH independently predicts a lower FMD

[63]. Even in mild primary hyperparathyroidism, parathyroidectomy improves

endothelial function (FMD) in patients having endothelial dysfunction prior to the

intervention [64].

In animal models of CKD, parathyroidectomy increases eNOS expression and

activity, which are down-regulated in chronic renal failure rats without parathyroidectomy. Similar effects are obtained by administrating calcium channel blockers

instead of performing parathyroidectomy, suggesting that NOS impairment in CKD

is due to CKD-associated calcium disequilibrium [65]. However, there are studies

that showed a direct effect exerted by PTH on endothelial cells. Thus, Chen at al.

demonstrated that serum from SHPT patients inhibited human endothelial cell proliferation in vitro [66]. Also, PTH increases the gene and protein expression of AGE

receptors, and also of IL-6 gene expression, in endothelial cells. Hence, PTH can

trigger endothelium cells activation which is the first step towards the installment of

ED [10, 67].

Therefore, vitamin D deficiency alters endothelial function in CKD also by triggering SHPT and subsequent calcium disturbances. SHPT promotes ED directly,

and also by SHPT-induced hypercalcemia.


Klotho-Fibroblast Growth Factor-23 (FGF-23) Axis

FGF23 has emerged as a new biomarker for CKD progression and also for CV and

bone metabolism complications associated to CKD. This is due to the fact that

FGF23 rises early in CKD to enhance renal phosphate excretion and thus to maintain phosphorus homeostasis. Despite being the main phosphaturic hormone,

FGF23 in high concentrations also has numerous off-target effects, especially on the

cardiovascular system. This explains why FGF23 in ESRD patients is associated

with vascular calcifications, left ventricular calcifications and increased mortality

risk [68].


M. Apetrii and A. Covic

Phosphorus is the main stimulus for FGF23 production and release from the

bone. High serum levels of FGF23 contribute to vitamin D deficiency in CKD by

inhibiting the activity of renal 1α-hydroxylase. Experimental studies showed that

calcitriol is also a potent inducer of circulating FGF23, independently of phosphate

and PTH [69]. This raises the question whether calcitriol administration in CKD

increases serum FGF23 levels and thus indirectly has deleterious CV effects.

However, the increased serum FGF23 levels depends on vitamin D cumulative dose

and may be prevented by associating cinacalcet to low-dose therapy with calcitriol

or vitamin D analogs in ESRD that actually results in serum FGF23 decrease [70,

71]. The reported vitamin D effects on circulating FGF23 are inconsistent: cholecalciferol treatment did not modify serum FGF23 levels in CKD stage 3–4 patients in

the study performed by Chitalia et al. [33]. In addition, escalating doses of calcitriol

analogs failed to significantly increase FGF23 in ESRD patients from the ACHIEVE

trial [71].

Although the effect of vitamin D supplementation on serum FGF23 levels in

CKD is not yet clarified, high serum FGF23 concentration encountered in CKD

triggers vitamin D deficiency and SHPT, two conditions associated with ED

[72, 73]. FGF23 is associated with impaired endothelial vasodilator response to

acetylcholine in elderly subjects with normal kidney function and with arterial

stiffness in elderly subjects with impaired renal function [74]. It seems that high

serum FGF23 levels predict not only ED, but also its progression to arterial

stiffness as kidney function declines. In this direction, FGF23 is an independent

positive predictor of carotid IMT, a marker of subclinical atherosclerosis, in

ESRD patients [75, 76].

FGF23 signaling pathway activation requires klotho, a transmembrane protein

that functions as a critical co-factor by increasing the affinity of FGF receptors for

FGF23 in the kidney [77]. Klotho has pleiotropic effects: the extracellular domain

is secreted into the circulation and partly mediates klotho anti-aging actions. In this

regard, klotho also protects endothelial cells against senescence and apoptosis, two

processes that are known to promote ED and atherosclerosis [78]. Klotho is downregulated in CKD by increased RAAS activity [79]. This contributes to ED, as

klotho deficit is associated with low NO and impaired endothelium-dependent vasodilator response to acetylcholine in mice. The mechanism by which klotho regulates

NO still needs clarifying [80].

Nevertheless, CKD is associated with important imbalances of the vitamin

D-FGF23-klotho axis, with all elements disturbed and contributing to ED. Vitamin

D deficiency is acquired in CKD due to limited availability of 1α-hydroxylase and

decreased activity but also due to increased serum FGF23 levels [72, 79]. Further

on, vitamin D deficit allows renin gene to be up-regulated (see above) [44].

Activation of RAAS and overexpression of angiotensin II down-regulates klotho

renal expression and thus impairs FGF23 signaling and leads to FGF23 resistance.

Subsequently, hyperphosphatemia aggravates and this stimulates even a greater

release of FGF23, which closes the loop by further inhibiting 1α-hydroxylase activity. Low serum vitamin D levels, high circulating FGF23 and low klotho levels and

RAAS overactivation all lead to ED [79].

20 Vitamin D and Endothelial Function in Chronic Kidney Disease




Endothelial dysfunction is the major common pathway through which CV risk factors lead to CVD in CKD. In fact, it represents the initial arterial lesion that eventually leads to atherosclerosis and arteriosclerosis. Abnormal vitamin D metabolism

is a sine qua non condition of CKD that has also been related to ED. Vitamin D

deficiency promotes ED in even in the early stages of CKD through both direct and

indirect mechanisms. Locally activated 1,25(OH)2D3 is an important regulator of

endothelial functions: it promotes NO synthesis and thus endothelium-dependent

vasodilation and also endothelial cell proliferation and survival. 1,25(OH)2D3 also

has anti-inflammatory and anti-oxidative effects in the endothelium. Moreover, in

diabetic patients with CKD, vitamin D deficit favors poor glycemic control and

atherogenesis. In addition, vitamin D deficit triggers overactivation of RAAS,

increased generation of oxidative stress, abnormal lipid metabolism, increased systemic and renal inflammation and SHPT, all with deleterious effects on the endothelium. Further on, SHPT leads to increased FGF23 synthesis and release while

RAAS downregulates klotho, two actions which bring additional injury to the vessels. Therefore, vitamin D deficiency activates a wide cascade of events that potentiate one another, finally leading to a closed loop where each element is responsible

for the altering of endothelium function in CKD. Although interventional studies

have proven the benefits of administering both vitamin D and vitamin D analogues

in rickets/osteomalacia and osteoporotic fractures treatment, they are however limited for the improvement of endothelial function in CKD. There is much less evidence for beneficial effects on inflammation, autoimmune or cardiovascular

diseases, although this could be due to the existence of different therapeutic target

levels for each disease. Therefore, vitamin D supplementation for targeting ED in

CKD remains an open chapter, where much remains to be written.


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Chapter 21

Vitamin D and Cardiovascular Calcification

in Chronic Kidney Disease

Lucie Hénaut, Aurélien Mary, Said Kamel, and Ziad A. Massy

Abstract Cardiovascular calcification is a common problem among chronic kidney disease (CKD) patients. Altered vitamin D status (another key feature of CKD)

has a major impact on mineral and bone disorders, including cardiovascular calcification. Preclinical and clinical studies have shown that both abnormally low and

abnormally high vitamin D levels have local and systemic effects on cardiovascular

calcification in CKD patients. This complex situation has major repercussions on

the choice and monitoring of the dose of vitamin D prescribed to prevent and/or

treat cardiovascular calcification in CKD.

Keywords Chronic kidney disease • Dialysis • Cardiovascular calcification •

Vitamin D



Chronic kidney disease (CKD) is characterized by the appearance of proteinuria

and/or a progressive reduction in the glomerular filtration rate. Subsequently, blood

levels of organic waste compounds called uraemic toxins rise progressively. Over

the last few decades, the harmful effects of a large number of uraemic toxins on

L. Hénaut, PhD

INSERM Unit 1088 and Department of Biochemistry, University Hospital,

University of Picardie Jules Vernes and CHU d’amiens, Picardie, France

A. Mary, PharmD, PhD

INSERM Unit 1088, University of Picardie Jules Vernes, Amiens, France

S. Kamel, PharmD, PhD

INSERM Unit 1088 and Department of Biochemistry, University Hospital,

University of Picardie Jules Vernes and CHU d’amiens,

Centre Universitaire de Recherche en Santé (CURS),

Chemin du Thil, Amiens, Picardie, France

Z.A. Massy, MD, PhD, FERA (*)

Division of Nephrology, Ambroise Paré University Hospital, Boulogne, France

e-mail: ziad.massy@aphp.fr

© Springer International Publishing Switzerland 2016

P.A. Ureña Torres et al. (eds.), Vitamin D in Chronic Kidney Disease,

DOI 10.1007/978-3-319-32507-1_21


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