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Abstract

New data on vitamin D has emerged in the last fifteen years and continues to expand practically every day. It's almost impossible to describe its full actions in a short article. In this review only a few aspects of this family of compounds are described, namely its endocrine pathway, and a few of its pleiotropic effects. Some of the known consequences of vitamin D deficiency are listed and special attention is given to its metabolism and the best way to supplement it, according to the author
145
Vitamin D – new insights into an old molecule
Cristina Jorge
Nephrology Department, Hospital de Santa Cruz – Centro Hospitalar de Lisboa Ocidental, Lisbon,Portugal
REVIEW ARTICLE
Port J Nephrol Hypert • Advance Access publication 23 September 2019
THE DISCOVERY OF VITAMIN D
McCollum et al inferred the existence of vitamin D in 1922, when
they discovered that animals fed a low calcium diet grew appropriately
if cod liver oil was added to their food. They assumed that a substance
present in fat liver oil had anti-rachitic properties1. Steenbock et al
found in 1924-1925 that the irradiation of ultraviolet (UV) light on
animals as well as their foods could result in the activation of a lipid
that had anti-rachitic properties1. In spite of this, the structure of
vitamin D was only discovered later, in 1932, by Askew and colleagues,
who isolated vitamin D2 after the UV light irradiation of ergosterol2.
Vitamin D3 was identified in 1936 by Windaus and Bock3. In 1977
Holick et al identified the process of synthesis of previtamin D3 from
7-dehydrocholesterol by the action of UV light on the skin4. In 1978,
Esvelt and co-workers isolated and identified vitamin D3 by mass
spectrometry5.
VITAMIN D METABOLISM
Vitamin D is either synthesized in the skin or absorbed in the diet.
Skin synthesis is obtained by the action of UVB light (290-315 nm),
which transforms 7-dehydrocholesterol into previtamin D3. This is
turned into vitamin D3 or cholecalciferol by heat, entering the circula-
tion. Skin irradiation never leads to toxic levels of vitamin D, since
continuing sunlight by itself destroys excess vitamin D6. The cutaneous
synthesis of the vitamin is influenced by age, skin pigmentation, sun-
screen use, time of the day, weather, season, latitude, altitude and
air pollution7,8. As we get older, the amount of 7-dehydrocholesterol
in the skin, and consequently our ability to produce vitamin D, dimin-
ishes6. In response to UV light, white humans produce more vitamin
D than melanodermic humans, since melanin absorbs UV light and
constitutes a natural filter to it. Proper use of sunscreen of factor (SPF)
8 reduces vitamin D synthesis by 92.5% and SPF 15 by 99%6.
Vitamin D2 (ergocalciferol) comes from various plant species, such
as mushrooms, after irradiation of UVB light. Vitamin D3, synthesized
in the skin, is also present in several fatty fish, including salmon, mack-
erel and sardines. The amount of vitamin D in food is usually not enough
for humans, and the main source of vitamin D comes from the skin,
after sun irradiation6.Vitamin D2 or D3 absorbed by the diet is incor-
porated in chylomicrons and transported into the circulation.
Once in the circulation, vitamin D (either D2 or D3), which is trans-
ported by the vitamin D binding protein (VDBP), can be stored in fat
tissue (and later released from it), or can pass through the liver, where
it suffers hydroxylation by the action of 25 hydroxylase (the main
enzyme being CYP2R1) and turns into 25 hydroxyvitamin D (25(OH)
vitamin D), also known as calcidiol6. In fact, there seem to be other
25 hydroxylases apart from CYP2R1. However, this one in particular
has remained stable through several vertebrate species and appears
to be responsible for most of the 25 vitamin D hydroxylation9. Calcidiol
also binds itself to VDBP and returns to the circulation afterwards.
This first hydroxylation of vitamin D is an unregulated process10.
When passing through the kidney, the complex 25(OH)vitamin D/
VDBP attaches itself to the megalin receptor of proximal tubule cells,
is internalized and transformed into either 1,25 (OH)2 vitamin D (cal-
citriol) by the action of 1 alpha hydroxylase (now known as CYP27B1)
or into 24,25 (OH)2 vitamin D (an inactive metabolite) by the action
of CYP24A1 (24 hydroxylase). Calcidiol is the main form of circulating
vitamin D in our organism and, due to its longer half-life (approximately
2-3 weeks) its blood level is thought to be indicative of the vitamin D
status of an individual6,11. The half-life of vitamin D is indeed about
24 hours, and that of 1,25(OH)2 vitamin D is only a few hours11,12.
The molecular structure of vitamin D3, vitamin D2, 25(OH) vitamin
D3 and 1,25 (OH)2 vitamin D3 is depicted in Fig. 1. These molecules
are considered secosteroid hormones (steroids with a broken ring).
THE ENDOCRINE ROLE OF VITAMIN D
Calcitriol is the active form of vitamin D. It has the important task
of controlling calcium and phosphorous levels and calcifying bone.
ABSTRACT
New data on vitamin D has emerged in the last fifteen years and continues to expand practically every day. It’s almost impossible to describe
its full actions in a short article. In this review only a few aspects of this family of compounds are described, namely its endocrine pathway,
and a few of its pleiotropic effects. Some of the known consequences of vitamin D deficiency are listed and special attention is given to its
metabolism and the best way to supplement it, according to the author.
Vitamin D, Bone, PTH, Immune system, Human disease

146 Port J Nephrol Hypert 2019; 33(3): 145-152
Cristina Jorge
This is evidenced by rickets, which develop in children without ade-
quate production of calcitriol (or with flaws in its metabolic machinery),
and in adults by osteomalacia, a condition which causes a lack of
mineralization of the osteoid matrix resulting in the accumulation of
unmineralized osteoid tissue in the trabecular and cortical bone13.
Under normal conditions only the calcitriol that is produced in the
kidney gets into circulation14. The classical mode of action of active
vitamin D is depicted in Fig. 2.
The renal synthesis of 1,25 (OH)2 vitamin D is tightly regulated and
controlled by calcium (inhibition), the parathyroid hormone (PTH)
(stimulus) and fibroblast growth factor-23 (FGF23) (inhibition). When
serum calcium is low, PTH is released, which stimulates 1 alpha hydroxy-
lase (CYP27B1) and consequently increases calcitriol synthesis. Calcitriol
induces calcium absorption from the intestine (mainly through the
transcellular pathway, but also through the paracellular pathway) and
reabsorption of calcium (in conjunction with the PTH) from the distal
tubule in the kidney and the mobilization of calcium from bone15,16.
PTH inhibits 24 hydroxylase (CYP24A1), which catabolises calcitriol to
its inactive metabolites, and so limits the degradation of calcitriol.
Calcitriol, in turn, suppresses the production of PTH directly (at the
transcription level) and indirectly (after increasing calcium levels and
upregulating and increasing the calcium sensing receptor at the para-
thyroid gland). Also, calcitriol limits its own production by inhibiting
CYP27B1 and promotes its own degradation by stimulating CYP24A116.
FGF23, which is produced by osteocytes, is a phosphaturic factor
that acts by precluding phosphate absorption in the proximal tubule
of the kidney. It is released in response to high phosphate levels and
1,25 (OH)2 vitamin D. FGF23 needs a cofactor (αKlotho), in order to
interact with its receptor (FGFR) in the kidney. Klotho is a transmem-
brane protein that is highly abundant in the proximal and distal
tubule17. The complex FGF23-Klotho suppresses 1 alpha hydroxylase
(CYP27B1) and stimulates CYP24A1. As such, it acts in two ways: inhib-
iting the production of calcitriol and promoting its degradation16.
THE EFFECTS OF VITAMIN D ON BONE
Apart from influencing calcium levels, a more complex view of the
actions of vitamin D in bone, was recently defended. Effectively, it
appears that the action of vitamin D in bone depends on its target
cell, as well as the extracellular calcium13,18. In order to understand
it, it is convenient to remember that the receptor activator of NF-κB
Figure 1
Molecular structure of vitamin D
Vitamin D3 – colecalciferol Vitamin D2 – ergocalciferol
 
Port J Nephrol Hypert 2019; 33(3): 145-152 147
ligand (RANKL), which is produced by several cell types including
osteocytes and osteoblasts, is a membrane protein that acts as an
osteoclast differentiation and activation factor, after connecting to
RANK in the osteoclast or its precursors19,20. Osteoprotegerin (OPG),
a soluble glycoprotein that is highly expressed in osteoblastic lineage
cells, (among others), binds to RANKL and therefore avoids its con-
nection to its receptor RANK in the osteoclasts, inhibiting bone resorp-
tion20. As such, the ratio RANKL/OPG in bone is a marker of bone
resorption20. It is now known that bone formation is linked to the
wingless (Wnt) signalling, which stimulates the osteoblastic lineage
cells. One of its co-receptors is the lipoprotein receptor-related protein
(LRP)-5. Returning to vitamin D, Goltzman describes in detail what is
known in terms of the action of vitamin D in bone. So, in the presence
of hypocalcemia, the consequent increase of 1,25(OH)2 vitamin D,
acting through the VDR in immature osteoblasts, increases osteoclas-
togenesis by increasing the ratio RANKL/OPG, and therefore stimulat-
ing osteoclastic bone resorption, and reducing trabecular bone. On
the other hand, in the presence of normal levels of 1,25 (OH)2 vitamin
D (and in the absence of hypocalcemia), calcitriol, acting in mature
osteoblasts or osteocytes, through their VDR, may mediate an increase
in bone formation and a decrease in bone resorption simultaneously.
In fact, this last action is mediated by the decrease in the ratio RANKL/
OPG in those cells. Furthermore, the bone formation seems to be
mediated through the increased expression of (LRP)-5 of the Wnt
pathway. Due to this, it is now believed that vitamin D may have either
a catabolic or an anabolic effect on bone.
NON-CLASSICAL ACTIONS OF VITAMIN D
It is now widely accepted that the machinery for the metabolism
of vitamin D is present in numerous cell types and tissues. This implies
that vitamin D or 25(OH) vitamin D can get inside the cell and be
hydroxylated to either 25(OH) vitamin D or 1,25(OH)2 vitamin D, and
then destroyed to inactive metabolites inside the same cell. This intra-
cellular active vitamin D (1,25(OH)2 vitamin D) acts locally, indepen-
dently of the endocrine system. Until recently it was thought to exert
its actions exclusively in the cell nucleus, activating or inactivating
numerous genes. Nowadays, it is known to act also in the cytoplasm
and to exert non-genomic actions, as we will see below.
When it comes to the availability of vitamin D, it is important to
mention the work made with rats null for VDBP21. In these models,
the only way vitamin D can get into the cell is by diffusion. And
Vitamin D – new insights into an old molecule
Figure 2
Metabolism and action of vitamin D
148 Port J Nephrol Hypert 2019; 33(3): 145-152
Cristina Jorge
effectively, they show a normal growing if fed daily with vitamin D21.
As stressed by Hollis and Wagner, the main determinant of how long
a vitamin D metabolite will stay in the circulation is its affinity for
VDBP11. This affinity is higher for 25(OH) vitamin D, followed by vitamin
D and smallest for 1,25 (OH)2 vitamin D, matching their half-lives. This
affinity (or constant dissociation) also dictates the free circulating
compound that is available to diffuse freely across cellular membranes.
In fact, it is highest for 1,25 (OH)2 vitamin, intermediate for vitamin
D and smallest for 25(OH)vitamin D11. So, vitamin D (cholecalciferol)
is more easily diffused through the cellular membrane than 25(OH)
vitamin D. It is important to remember that, in the kidney, the megalin-
cubilin endocytic system is responsible for the internalization of the
complex 25 (OH) vitamin D/VDBP11. In the parathyroid gland, where
megalin is also present, a similar process is likely in place. The same
endocytic system also operates in the placenta11. In tissues where
this system is not operative, the diffusion of these steroids becomes
essential to their entry into the cell.
LESSONS FROM MATERNITY AND NEW DATA
Some information has become available from human observations
concerning pregnancy and breast-feeding. In pregnant women the
levels of 1,25(OH)2 vitamin D are much higher than in normal, non-
pregnant adults. In spite of this, there is no hypercalcemia during
pregnancy. Therefore, the levels of 1,25(OH)2 vitamin D during preg-
nancy are uncoupled to the calcium homeostasis and are largely
dependent on the availability of the substrate, 25(OH) vitamin D22. It
is believed that the role of 1,25(OH)2 vitamin D during pregnancy is
mainly related to immune modulation and maternal tolerance towards
the fetus22. An association between preeclampsia and low levels of
1,25 (OH) vitamin D is known to exist in the mother23. Recently, 2
small randomized controlled studies found a beneficial effect of vitamin
D supplementation in the incidence of this entity24,25. However, a
mendelian study with thousands of pregnant women did not find a
clear causal effect between preeclampsia or hypertension during
pregnancy with vitamin D deficiency26. This condition, preeclampsia,
which is defined as the existence of de novo hypertension accompanied
by proteinuria after 20 weeks’ gestation, is associated with vasculitis
and inflammation27. It is viewed as an endothelial dysfunction28.
Recently, as elegantly shown by Gibson et al on human microvascular
endothelial cells, vitamin D was found to exert an important role in
the stabilization of intercellular connections on the endothelium.
Moreover, this action was accomplished either by vitamin D, 25(OH)
vitamin D or 1,25(OH)2 vitamin D, but the most potent molecule to
perform this task was proved to be the first one29. This was a new
finding: until then, it was believed that vitamin D per se had no impor-
tant role to play in the human body. As also shown by the authors,
this action of vitamin D happened within minutes, and they concluded
that it was non-genomic, seemingly independent from the VDR. This
action of vitamin D could explain the association of vitamin D deficiency
with numerous human pathologies like hypertension, cardiovascular
disease and overall mortality29. In terms of importance of the sterol
vitamin D, Hollis and Wagner have defended its crucial role for some
time, coming to that conclusion after conducting various experiments
with lactating women. First, Greer et al published in 1984 an article
analysing the vitamin D content of human milk and found that when
mothers were irradiated with UVB light, their serum content of both
vitamin D and 25(OH) vitamin D increased, as expected. In spite of
this, only the vitamin D in the milk rose after UVB exposure, without
change in the amount of 25(OH) vitamin D30. So, the transfer of vitamin
D from serum to human milk is much more efficient than the transfer
of 25 (OH) vitamin D. Hollis and Wagner, who have been working in
this area for decades, debated the topic in depth in a 2013 article
where they analysed the importance of vitamin D itself11. They believe
that, rather than the bonding of vitamin D to VDBP, it is the higher
free serum concentration of vitamin D that permits the easier free
diffusion of vitamin D across the mammary gland to the milk, rather
25(OH) vitamin D. So, in terms of breast-feeding, and in order to sup-
ply the baby with enough vitamin D, the mother should be replenished
with vitamin D. If sun exposure is not adequate or possible, then a
daily supplement of at least 6000 UI of vitamin D should be adminis-
tered to the mother, according to the same authors. It is noteworthy
to remember that, during pregnancy, the passage of vitamin D to the
fetus is carried out mainly by calcidiol. It is thought that this happens
because 25(OH) vitamin D has high affinity for VDBP and, in the pla-
centa, the megalin-cubilin endocytic system is operative11.
As discussed above, it has become evident that some of the
observed effects of vitamin D were too fast to be considered at the
gene level. Previously it was thought that all the vitamin D actions
resulted from the coupling of calcitriol to VDR, which belongs to a
sub-family of nuclear receptors. By forming a heterodimer with retinoic
X receptor (RXR), and VDR, 1,25(OH)2 vitamin D induces activation of
VDR, which connects to a vitamin D response element (VDRE) and
initiates transcription of a variety of genes. These depend on the cell
type, maturation status of the cell, among other factors31. It is esti-
mated that vitamin D may interact with or influence up to 2000 genes7.
EFFECTS OF VITAMIN D ON THE IMMUNE SYSTEM
Vitamin D has an important role in both innate and adaptive immu-
nity. Immune system cells, such as monocytes and dendritic cells,
express the VDR and possess the machinery necessary to convert 25
(OH) vitamin D to 1,25 (OH)2 vitamin D and to metabolize it to inactive
vitamin D metabolites. As extensively reviewed by Hewison, vitamin
D induces bacterial killing of Mycobacterium tuberculosis by mono-
cytes, through a VDR synthesis of cathelicidin and beta-defensin 2.
These peptides have bactericidal properties. The intracellular synthesis
of 1,25(OH)2 vitamin D also induces autophagy, a cytoplasmic process
that enhances bacterial killing32. T and B Lymphocytes, although with
a very low expression in resting state, show increased levels of VDR
upon cellular activation. As such, in sites of inflammation it is possible
to convert 25 (OH) vitamin D to its active form at a cellular level33.
Peelen et al in 2011, published an article on the effects of vitamin D
in each cell of the immune system, where the reader can find an in
depth and detailed description of this subject33. In general, the effects
of vitamin D on the immune system appear to go into an immunomodu-
latory and tolerogenic action. Specifically, vitamin D induces a shift in
the balance T helper 1 / T helper 2 cells towards a predominant T
helper 2 cells and decrease of T helper 17 cells response33. Recently
various studies performed with human cells and even humans, have
confirmed those assumptions. Drozdenko et al supplemented 25 peo-
ple with different doses of cholecalciferol (between 2000 until 8000
UI per day) for 12 weeks in order to attain blood levels of 25 (OH)
Port J Nephrol Hypert 2019; 33(3): 145-152 149
vitamin D of at least 44 ng/mL (or 110 nmol/L). Those individuals were
compared to a control group of 18 people, which did not receive
vitamin D34. They found that supplemented people showed an
increased frequency of CD38 in peripheral B Lymphocytes and that
this happened after 25(OH) vitamin D blood concentrations of approxi-
mately 28 ng/mL (69 nmol/L). They also noticed a decrease in IFN
gamma and IL-17 secreting T cells after vitamin D supplementation
and concluded that this happened for 25(OH) vitamin D concentrations
of at least 28 ng/mL (70 nmol/L). They found no differences in immu-
noglobulin concentration or in IL-10 producing T cells. Prietl et al
showed in 2010, in an uncontrolled pilot study performed on 46 appar-
ently healthy adults, an increase in circulating regulatory T cells
(CD4+CD25++FOXP3+ cells with low or absent expression of CD127)
at 4 and 8 weeks after intramuscular supplementation with 140 000
UI cholecalciferol at baseline and four weeks later. They also observed
growing of the mean serum levels of 25 (OH) vitamin D at 4 and 8
weeks (the duration of the study), from insufficiency (23.9 ± 12.9 ng/
mL) to 58.0 ± 15.1 ng/mL at 8 weeks35. More recently, it was recorded
in a community study involving 77 infants and children up to 12 years
old, with community acquired pneumonia, that the patients with
vitamin D deficiency had lower peripheral lymphocytes, less CD19
Lymphocytes and higher neutrophil counts than patients with vitamin
D sufficiency36. The immunomodulatory effects of vitamin D have
been argued to explain the action of vitamin D in several diseases like
autoimmune disorders, response to infections or cancer7.
VITAMIN D AND HUMAN DISEASE
Apart from rickets, a disease that has been known for decades
(causally associated with vitamin D deficiency), numerous pathologies
have been linked to vitamin D in the recent years.
There are several epidemiologic studies relating vitamin D defi-
ciency with the cardiovascular disease, cancer, immune mediated
diseases, neuroendocrine diseases and infectious conditions, among
others7.
Studies with animals confirmed that vitamin D influences the car-
diovascular system. Indeed VDR or CYP27B1 null mice have increased
renin and angiotensin II, are hypertensive and have left ventricular
hypertrophy (LVH)37,38. Low serum levels of vitamin D are associated
with increased PTH levels39. BrouliK et al showed, back in 1986, that
PTH infusion in humans was found to cause increased renin activity
as well40. In spite of this, in a group of 17 humans (6 to 36 year-old)
with Hereditary Vitamin D–Resistance Rickets (HVDRR), the human
disease to which the VDR null mice corresponds to, no increased
renin activity, nor hypertension or LVH was found, at least until the
age of 36. Although these patients had both high 1,25 (OH)2 vitamin
D and PTH serum levels41. Despite this, a prospective human study
that involved 3296 patients submitted to coronary angiography, an
inverse association between 25 (OH) vitamin D and 1,25(OH)2 vitamin
D with plasma renin and angiotensin 2 concentrations was found42.
So, even in human studies into vitamin D, the results are not consist-
ent. Another way vitamin D seems to influence the cardiovascular
system is through its action in the endothelium. Lower 25 (OH) vitamin
D levels have been correlated with increased arterial stiffness and
endothelial dysfunction in a population of 554 apparently healthy
volunteers aged 20 to 79 years, in a cross sectional and observational
study performed by Al Mheid et al43. One possible mechanism for
this vitamin D mediated action might be through interference with
nitric oxide levels44,45, by modulating inflammation45 or even by direct
actions of vitamin D in the endothelial cells29,45. Further, vitamin D
has been implicated in the process of vascular calcification. Either
deficient or excess vitamin D levels have been associated with the
active process of vascular calcification. Although the exact mecha-
nisms to explain these outcomes are yet to be fully understood, a
recent theory considers that there may be a biphasic response to
vitamin D in the vasculature, and it may be related not only to serum
levels but also to local regulators and intracellular metabolic pathways
of vitamin D46.
Also, vitamin D deficiency has been associated to mortality. Obser-
vational studies and meta-analysis of observational studies have
persistently shown low serum levels of 25(OH) vitamin D and
increased overall mortality risk, sometimes with cardiovascular death
or cancer related death47-52. In 2017, Martin Gaksch et al, published
a meta-analysis of individual participant data, comprising a total of
26916 people that were followed for a median period of 10.5 years.
The 25 (OH) vitamin D measurements were performed according to
the certified liquid chromatography–tandem mass spectrometry
method. They found an increasing mortality risk for 25 (OH) vitamin
D levels less than 20 ng/mL52. One of the most recent population-
based studies was conducted in Olmsted County, Minnesota (USA)
and included 11022 individuals, of whom 723 died after a median
follow-up of 4.8 years. This population had a 25(OH) vitamin D mean
(±SD) level of 30 ± 12.9 ng/mL. White people with 25 (OH) vitamin
D less than 20 ng/mL had greater all-cause mortality than those
with higher 25 (OH) vitamin D levels. In patients of other races/
ethnicities this association between low levels of 25 (OH) vitamin D
and mortality was not found53. In spite of an inverse association
between vitamin D and mortality being consensual, the causality
cannot be defined with these studies. Naturally, sicker individuals
may have lower vitamin D levels as a consequence of their disease.
Mendelian randomization studies try to find a genetically defined
characteristic with a specific outcome, and therefore can be useful
in the search for causality. Afzal et al reported in 2014 a mendelian
randomization study on alleles of genes implicated on the synthesis
of 25 (OH) vitamin D (in the skin, from 7 dehydrocolesterol-DHCR7
and in the first hydroxylation in the liver-CYP2R1) in 95766 people
of Denmark54. They concluded that genetically determined low levels
of vitamin D were associated with increased overall and cancer mor-
tality. They did not find a causal relationship with cardiovascular
mortality and hypothesized that this association in previous studies
could be due to confounding. Recently a second mendelian rand-
omization study analysed single nucleotide polymorphisms on the
pathway of vitamin D synthesis and mortality in 10501 individuals
from Iceland, Germany and Norway55. The 25 (OH) vitamin D evalu-
ation was performed under the Vitamin D Standardization Program,
to ensure all samples were analysed according with the certified
liquid chromatography–tandem mass spectrometry method. The
authors of this study concluded that there was an increase in mortal-
ity for 25(OH) vitamin D levels less than 16 ng/mL. Lastly, a meta-
analysis recently published, which analysed 84 articles (from 2006
until 2018), and included 57 studies comprising mainly elderly people
and with a follow-up that varied from 1.7 to 37 years, concluded
Vitamin D – new insights into an old molecule
150 Port J Nephrol Hypert 2019; 33(3): 145-152
Cristina Jorge
that the majority of the studies found an inverse relationship
between vitamin D levels and mortality56. In fact, there was a pro-
gressively lower mortality with higher levels of vitamin D up to a
certain threshold beyond which there was no survival benefit. They
considered that this relationship was mainly with mortality due to
cancer and respiratory diseases and was much weaker with cardio-
vascular disease. In these last reports, a J or U-shaped curve between
vitamin D and mortality was not noticed. Previous studies that found
such a U-shape relationship47,57,58 were probably tainted with con-
founding or included people that were supplemented with vitamin
D too late in the course of the disease59,60.
Despite all this knowledge, there is not, until now, a supplementa-
tion study with vitamin D that proved its ability to decrease mortality
or cure diseases. The defenders of vitamin D argue that this is because
of the varying doses and mode of administration of vitamin D, the
short duration of the studies, the lack of quality of most studies (not
randomized controlled studies), and so on. Surely, one should not expect
that a study that lasts weeks or even months should show significant
results in such a short period. Apart from this, and since mortality
seems to be related with deficient 25(OH) vitamin D levels, it is reason-
able to argue that vitamin D supplementation studies should be directed
to people with low or very low levels of 25 (OH) vitamin D levels, in
order to show a clear benefit from supplementation. Given the fact
that most supplementation studies supplement everyone included,
independently from the basal vitamin D levels, the net results of these
studies may be diluted with people in whom supplementation does
not bring any additional benefit. In this regard, Robert Heaney wrote
guidelines to assist in the design, performance and interpretation of
studies concerning nutrients, in which vitamin D can be included61.
VITAMIN D IN CKD – RECOMMENDATIONS
Active vitamin D and its analogs have long been used in chronic
kidney disease (CKD) patients to control secondary hyperparathy-
roidism. The current guidelines concerning vitamin D supplementation
in CKD patients, issued by the KDIGO group, advise the use of native
vitamin D in these patients just as in the general population, in order
to correct vitamin D deficiency or insufficiency62. These guidelines
also recommend caution when using active vitamin D in patients not
on dialysis, due to the risk of hypercalcemia. Specifically, they recom-
mend the use of either active vitamin D or active vitamin D analogs
only in patients with CKD stages 4 to 5 with severe or progressive
secondary hyperparathyroidism. In fact, studies with vitamin D analogs
in CKD patients not on dialysis, such as the Primo study and the Opera
study, in which paricalcitol was compared to placebo, respectively for
48 and 52 weeks, including about 260 patients, most with secondary
hyperparathyroidism, and all with mild to moderate LVH, showed no
benefit in the use of paricalcitol to reduce LVH or modify diastolic
function63,64. Despite reducing PTH, more patients in the paricalcitol
groups showed hypercalcemia in respect to placebo (22.6 % versus
0.9 % and 43.3% versus 3.3%) in both studies. The same guidelines
refer to meta-analyses in which calcitriol and active vitamin D analogs
were used which also showed increased hypercalcemia65,66.
On the other hand, the use of native vitamin D (cholecalciferol
or ergocalciferol) in CKD patients has been found to be generally
safe, not causing hypercalcemia nor hyperphosphatemia. Moreover,
in CKD stages 3 through 4 it decreased (although modestly) PTH67.
In the 2017 paediatric guidelines for CKD, it is recommended to
supplement children with CKD stages 2 to 5D to maintain 25 (OH)
vitamin D levels over 30 ng/mL and to control secondary hyperpar-
athyroidism, with either cholecalciferol or ergocalciferol68. If needed,
the use of active vitamin D in order to control secondary hyperpar-
athyroidism should be the least amount possible in order to diminish
PTH and to maintain normocalcemia. According to the authors, there
is no advantage in using one type of active vitamin D analog over
the other69.
HOW AND HOW MUCH TO SUPPLEMENT
WITH NATIVE VITAMIN D
In 2011, the Endocrine Society (ES) issued guidelines on the evalu-
ation and treatment of vitamin D deficiency. The expert panel, after
reviewing available data, defined vitamin D deficiency as a 25(OH)
vitamin D level lower than 20 ng/mL, insufficiency a level between
21-29 ng/mL and sufficiency a level of at least 30 ng/mL and they
considered safe a level up to 100 ng/mL70. In fact, as it was shown in
a population of 1500 postmenopausal women in the United States,
regarding the relation between PTH and 25 (OH) vitamin D, the PTH
increases gradually with levels of 25(OH) vitamin D lower than 30 ng/
mL71. The previously mentioned definitions were also adopted by
other American and international associations72.
Since the prevalence of vitamin D deficiency is so frequent and
seems to cause damage, and also given that its supplementation has
shown to be safe, the question of why to supplement has a clear
answer: within the physiologic limits, it does not harm, and might do
some good…
However, a harder question to answer is how and how much…
First, supplementing with either ergocalciferol or cholecalciferol
seems to cause similar effects in the long term, due to the fact that
when chronically supplementing with each one, the levels of 25 (OH)
vitamin D rise in a similar way73,74. A study compared the amount of
1,25 (OH)2 vitamin D produced by the kidney after 11 weeks of sup-
plementation and found that in response to taking 1000 IU of ergoc-
alciferol per day, there was production of 1,25 (OH)2 vitamin D2 and
the amount of 1,25 (OH)2 vitamin D3 decreased accordingly, so that
the total 1,25 (OH)2 vitamin D was kept constant. In response to the
supplementation of 1000 IU of cholecalciferol per day, the kidney
produced 1,25 (OH)2 vitamin D3. As such, the amount of total 1,25
(OH)2 vitamin D was similar, and (unsurprisingly) did not change, since
the level of 1,25 (OH)2 vitamin D is tightly regulated by the endocrine
system. Noteworthy, the amount of 25 (OH) vitamin D2 or D3 rose
comparably with each type of vitamin D74.
The ES divides their amount recommendation into the daily allow-
ance, i.e. the minimum requirement per day, and the tolerable upper
limit (UL). Although to most people (from infants to adults) the mini-
mum recommended dose varies between 400 – 800 IU per day, in
order to attain the sufficient 25 (OH) vitamin D (over 30 ng/mL) blood
level, most people will need at least 1500-2000 IU per day70. The ES
Port J Nephrol Hypert 2019; 33(3): 145-152 151
does not specify the regularity of administration (daily, weekly, monthly
or even three times a year), necessary to obtain effective levels of
25(OH) vitamin D. From the previous discussion in this article we can
assume that, in terms of vitamin D levels, there is a difference between
receiving it daily or three times per week or monthly. So in my opinion,
if possible, and in order to maintain stable levels of not only 25 (OH)
vitamin D, but also vitamin D, administration should ideally be daily
(or maybe 3 times per week, as we have been doing in hemodialysis
patients)75. In our report we used a liquid formulation of vitamin D3
(vigantol®), which contains 667 IU of vitamin D3 per drop.
FINAL REMARKS
There is still a lot we don’t know about vitamin D. Its main role
seems to be within mineral and bone metabolism, as evidenced by
diseases like rickets in children and osteomalacia in adults. Nowadays,
it is known that vitamin D and/or its metabolites have numerous
pleiotropic effects. Epidemiologic studies have associated low vitamin
D levels with several diseases and mortality. In spite of that, to date,
no randomized controlled study has shown to reduce mortality or
improve significant outcomes in the general population, but we cannot
forget those studies have limitations, as explained before. Since it
seems to do no harm, supplementing deficient people with physiologi-
cal doses of nutritional vitamin D appears to be safe and may be
beneficial. This might be particularly important in specific populations
like children, pregnant and breastfeeding women, those in menopause,
the elderly and people with CKD.
Disclosure of potential conflicts of interest: none declared
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
Cristina Jorge, MD
Nephrology Department
Hospital de Santa Cruz – Centro Hospitalar de Lisboa Ocidental
Av. Prof. Dr. Reinaldo dos Santos, 2790-134 Carnaxide
E-mail: cristinamjorge@gmail.com
... Vitamin D deficiency is a very prevalent finding in CKD patients. Traditionally, it has been associated with hyperparathyroidism and mineral bone disease; however, studies have demonstrated its pleiotropic effects, which include modulation of the immune system, regulation of inflammatory responses and suppression of the renin-angiotensin system, among others 50,51 . In fact, vitamin D repletion was linked to a decreased Th1 mediated autoimmune diseases and an increased bactericidal activity 52 . ...
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