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8 Therapeutic Implications: Selective Vitamin D Receptor Activators in CKD

8 Therapeutic Implications: Selective Vitamin D Receptor Activators in CKD

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[194, 195], – raising the possibility that their actions could be VDR independent -,

it has also been recently shown in a novel organ culture model that direct suppression of PTH gene expression by doxercalciferol (a selective VDR activator) and

25(OH)D requires the VDR [196].

Since an excessive Ca and P loading is the most undesirable untoward effect of

1,25(OH)2D3, especially in patients with CKD, VDR activators have been developed to reduce the capacity to induce in-vivo hypercalcemia, hyperphosphatemia

and hypercalciuria, and thus the concept of selective VDR activators has evolved

[197]. For instance, paricalcitol and maxacalcitol are considered selective VDR

activators because they seem to preferentially effect parathyroid glands by retaining

the action on PTH suppression while having less effect on Ca and P intestinal

absorption or bone resorption [34, 198–200]. Consequently, these selective VDR

activators could possibly avoid deleterious effects derived from serum high levels of

Ca and P, including possible passive extraskeletal calcification in vessels or heart

valves. Potentially, these differential effects could also have an impact on survival.

Experimental studies have shown distinct actions of calcitriol or other VDR activators on extraosseous calcification, the former being a classic dose-dependent inductor of experimental vascular calcification especially in the presence of a high P

exposure, or as a result of vitamin-D-induced systemic accumulation of Ca and P

rather than a local effect on the arterial wall [162, 201–203]. On the other hand,

lower doses of both calcitriol and paricalcitol seemed to be protective probably

through restoration of klotho and osteopontin expression [19, 136, 204]. Thus, a

bimodal effect of VDR activators has been described with regard to regulation of

vascular calcification. This issue is further complicated by the differential expression and regulation of klotho in experimental uremia, and the tissue-dependent

effect of a VDR activator such as paricalcitol, recently described [205]. In this study,

paricalcitol prevented the decrease of klotho in the kidney, increased expression in

the parathyroid, had no effect in the aortic media, but blunted the increase of klotho

in the aortic adventitia –probably expressed by fibroblasts [205].

In general, the experimental data supporting less toxicity of some VDR activators compared with calcitriol are not consistent across studies, but they seem to

support the claim that there is reduced induction of vascular calcification with different VDR activators, favoring paricalcitol [162, 199, 201, 206, 207]. However,

there are no prospective randomized clinical trials that have evaluated the impact of

native vitamin D or VDR activators on human vascular calcification. Finally, a

robust and consistent survival benefit of VDR activators in hemodialysis patients

has been described in several retrospective studies [208, 209], and although it has

been questioned [210], the benefit seemed to be more pronounced in the low-dose

range and among patients who received selective VDR activators [208]. Finally, a

recent meta-analysis including 14 observational studies (194,932 patients) has

shown that therapies with VDR activators are associated with reduced mortality in

CKD patients [211], although another recent meta-analysis and a smaller study in

peritoneal dialysis patients do not confirm these previous results [212, 213]. Again,

no randomized clinical trial has been performed to prove or rule out this survival

hypothesis. Consequently, it is not the time to say that interventions based on



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vitamin D definitely reduce mortality in patients with CKD, but the opposite cannot

be said yet beyond all reasonable doubt [214]. In fact, given the paucity of good

quality data, the reliability of the pooled results is still uncertain [214], warranting

the need of larger trials on clinically significant hard-outcomes.

The alleged difference among analogs and their effects on different target organs

may be related, among other factors, to different pharmacokinetic/pharmacodynamic properties by distinctly interacting with serum-binding proteins (e.g. affinity

to circulating DBP) or differential metabolism in a tissue-selective manner. For

instance, it has been shown that maxacalcitol has about 400–500 times less binding

affinity to DBP than 1,25(OH)2D3 [215], and thus has a shorter half-life and is

cleared more rapidly from the circulation. It has also been shown that VDR analogs

have a lower affinity for VDR than 1,25(OH)2D3 [216, 217] and differential regulation of 24-hydroxylase in target tissues may also determine the half-life of

1,25(OH)2D3 and analogs [217]. Interestingly, selective VDR activators seem to

interact differentially with VDR coregulators and, based on conformational differences induced by these molecules, gene expression may be modified when the VDR/

RXR complex binds to the VDRE, causing selectively distinct effects on DNA transcription in different cells and tissues [101, 218, 219]. Thus, the diversity of coregulators and multiple multicomponent complexes help explain receptor, target gene

and cell-selective responses to different ligands at the same VDR [73]. As an example, calcitriol has ten times more affinity for binding to the VDR than the selective

VDR activator paricalcitol [199, 216]; nevertheless, this difference in binding affinity is not the same for all body tissues, as the affinity of paricalcitol for the VDR in

the parathyroid glands is three to four times lower than that of 1,25(OH)2D3.

Paricalcitol is less active than 1,25(OH)2D3 in inducing homodimerization (VDR:VD)

and heterodimerization of VDR: receptor-associated coactivator 3 (RAC3), and

more active than calcitriol in inducing heterodimerization of VDR/RXR and VDRglucocorticoid receptor interacting protein 1 (DRIP1) [120]. Clinically, it has been

shown that selective VDR activators allow synthesis and secretion of PTH to be

inhibited more efficiently and with a lower impact on intestinal absorption of Ca and

P [199, 220]. Therefore, they are attributed a lower risk of hypercalcemia, hyperphosphatemia, and elevated Ca x P levels. In a five sixths nephrectomized rat model,

when paricalcitol is compared with calcitriol, its impact at the same doses is three to

four times less than calcitriol on PTH levels and ten times less on Ca and P levels

meaning that paricalcitol can act with a larger therapeutic margin for the prevention

and treatment of secondary hyperparathyroidism in early stages of CKD, as well as

in patients on hemodialysis, and with a lower potential impact on vascular calcification [221, 222]. It has been also shown that switching 1,25(OH)2D3 to selective vitamin D receptor activators such as paricalcitol can help controlling previously

uncontrolled secondary hyperparathyroidism [223]. On the other hand, although

there are no data on this action in humans, Malluche et al. [200] state, based on

experimental data, that the vitamin D analogs paricalcitol and maxacalcitol could

control PTH levels with a lower suppression of bone remodeling.

The differential effects of selective VDR activators have also been seen on gene

expression in various types of cells and tissues, including the expression of



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molecules involved in the process of vascular calcification. Using DNA microarray

technology to evaluate gene expression profiles in VSMC incubated with

1,25(OH)2D3 or paricalcitol, it was shown that, though most of the expression profile was similar, paricalcitol activates and deactivates different genes than

1,25(OH)2D3. These differences are not explained by dissimilar doses; thus, in an

experimental model of active vascular calcification induced by uremia and high

dietary P, it was shown that comparable doses of 1,25(OH)2D3, paricalcitol and doxercalciferol have significant differences in mRNA expression of Cbfα1 (Runx2) and

osteocalcin in aortic tissues, favoring paricalcitol [201, 206]. Paricalcitol, unlike

1,25(OH)2D3, did not increase the expression of transcription factor Cbfα1, which

activates one of the signaling pathways for transformation of VSMC into osteoblast-like cells [201, 206, 207]. It has also been shown that paricalcitol prevents the

activation of the P-induced Wnt/β-catenin pathway, and also reduces calcification

by downregulating the expression of BMP-2 [221, 224]. It is noteworthy that the

risk of calciphylaxis was recently reported to be increased in patients treated with

calcitriol but not in patients treated with selective vitamin D analogues such as paricalcitol or doxercalciferol [225]. Finally, the combination of nutritional vitamin D

supplementation and paricalcitol, at doses ineffective to suppress PTH when given

alone, prevented the increases in parathyroid, renal and/or macrophage TACE

expression induced by five sixths nephrectomy, thereby markedly reducing parathyroid gland enlargement, proteinuria and aortic calcification [25].

Different VDR agonists also exhibit differential effects on endothelial function

and aortic gene expression in five sixths nephrectomized rats, with alfacalcidol

exhibiting less of an effect [226]. In patients with stage 3–4 CKD, paricalcitol has

been shown to improve endothelium-dependent vasodilation [227], although these

results have not been confirmed in patients with type II diabetes and CKD [228]. On

the other hand, despite vitamin D deficiency seems to be a risk factor for arterial

hypertension, vitamin D supplementation in hypertensive patients with low circulating 25(OH)D levels had no significant effect on blood pressure and several CV risk

factors, but it was associated with a significant increase in triglycerides in a recent

randomized clinical trial [229]. In contrast to the widely described inverse association between circulating 25(OH)D levels and hypertension risk, calcitriol levels

have been recently associated positively with a higher risk of hypertension [230].

Reduction in myocardial VDR expression in rats with renal failure has also been

related to myocardial remodeling and an increase in arrhythmogenesis, being

reverted by paricalcitol by restoring myocardial VDR levels and prolonging action

potentials [231]. VDR activation by different VDR analogs has also been shown to

distinctly affect left ventricular hypertrophy, and paricalcitol was the only VDR activator which showed a relevant beneficial effect in the reduction of myocardial fibrosis, a key factor in the myocardial dysfunction in CKD patients [232]. Nevertheless,

these apparently positive results are not uniform in all studies [233–235], despite it

is now known that VDR may be a negative regulator of the TGF-β/Smad signaling,

influences the regulation of T cells and inflammatory cytokines and may ameliorate

epithelial-to-mesenchymal transition in different models [236, 237]. Many other

studies have also shown positive effects of VDR activation on myocardial structure,



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left ventricular function or cardiovascular events, including dialysis and pre-dialysis

patients [44, 235, 238–241]. However, two prospective RCT’s in CKD patients

using paricalcitol did not show a significant benefit in their predefined outcomes of

left ventricular structure measured by cardiac magnetic resonance and LV function

[242, 243], although some positive results (decrease in cardiovascular-related hospitalizations, left atrial volume index, attenuation of BNP rise) were described in secondary or post-hoc analysis [242, 244].

Finally, VS-105, a novel VDR activator, has been recently shown to improve

cardiac function in five sixths nephrectomized rats [245]. A thorough review of the

different VDR activators that are being developed in different areas, including CKD,

heart disease or oncology, is completely beyond the scope of this chapter [73].

However, the current available information underlines the increasing importance of

the vitamin D/VDR pleiotropic multifunctional axis, both in health and disease.

Nevertheless, it is important to recognize that RCTs are required to confirm all the

cardiovascular or survival alleged benefits of the old and these new compounds [34,

44, 219, 220].



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