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8 Therapeutic Implications: Selective Vitamin D Receptor Activators in CKD
J. Bover et al.
[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 .
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
. 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 . 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 .
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 , the benefit seemed to be more pronounced in the low-dose
range and among patients who received selective VDR activators . 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 , 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
Vitamin D Receptor and Interaction with DNA
vitamin D definitely reduce mortality in patients with CKD, but the opposite cannot
be said yet beyond all reasonable doubt . In fact, given the paucity of good
quality data, the reliability of the pooled results is still uncertain , 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 , 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 . 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 . 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) . 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 . On the other hand, although
there are no data on this action in humans, Malluche et al.  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
J. Bover et al.
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 . 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 .
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 . In patients with stage 3–4 CKD, paricalcitol has
been shown to improve endothelium-dependent vasodilation , although these
results have not been confirmed in patients with type II diabetes and CKD . 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 . 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 .
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 . 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 . 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,
Vitamin D Receptor and Interaction with DNA
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 . 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 .
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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