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Vitamin D and immune function in chronic kidney disease

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Clinica Chimica Acta 450 (2015) 135–144

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Clinica Chimica Acta

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Invited critical review

Vitamin D and immune function in chronic kidney disease

Wen-Chih Liu a,b, Cai-Mei Zheng a,c, Chien-Lin Lu a,d, Yuh-Feng Lin a,c, Jia-Fwu Shyu e,
Chia-Chao Wu f,⁎⁎,1, Kuo-Cheng Lu g,⁎,1
a
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, No.250, Wuxing Street, Taipei 110, Taiwan
b
Division of Nephrology, Department of Internal Medicine, Yonghe Cardinal Tien Hospital, No.80, Zhongxing St., Yonghe Dist., New Taipei City 234, Taiwan
c
Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, No.291, Zhongzheng Rd., Zhonghe Dist., New Taipei City 235, Taiwan
d
Division of Nephrology, Department of Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, No.95, Wen Chang Road, Shih Lin Dist., Taipei 111, Taiwan
e
Department of Biology and Anatomy, National Defense Medical Center, No.161, Sec. 6, Minquan E. Rd., Neihu Dist., Taipei 114, Taiwan
f
Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, No.325, Sec. 2, Cheng-Kung Rd., Neihu Dist., Taipei 114, Taiwan
g
Department of Medicine, Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, No.362, Chung-Cheng Rd, Hsin-Tien Dist., New Taipei City 231, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: The common causes of death in chronic kidney disease (CKD) patients are cardiovascular events and infectious
Received 30 June 2015 disease. These patients are also predisposed to the development of vitamin D deficiency, which leads to an
Received in revised form 13 August 2015 increased risk of immune dysfunction. Many extra-renal cells possess the capability to produce local active
Accepted 14 August 2015
1,25(OH)2D in an intracrine or paracrine fashion, even without kidney function. Vitamin D affects both the innate
Available online 17 August 2015
and adaptive immune systems. In innate immunity, vitamin D promotes production of cathelicidin and
Keywords:
β-defensin 2 and enhances the capacity for autophagy via toll-like receptor activation as well as affects
Chronic kidney disease complement concentrations. In adaptive immunity, vitamin D suppresses the maturation of dendritic cells and
Vitamin D weakens antigen presentation. Vitamin D also increases T helper (Th) 2 cytokine production and the efficiency
Innate immunity of Treg lymphocytes but suppresses the secretion of Th1 and Th17 cytokines. In addition, vitamin D can decrease
Adaptive immunity autoimmune disease activity. Vitamin D has been shown to play an important role in maintaining normal
immune function and crosstalk between the innate and adaptive immune systems. Vitamin D deficiency may
also contribute to deterioration of immune function and infectious disorders in CKD patients. However, it
needs more evidence to support the requirements for vitamin D supplementation.
© 2015 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
2. Vitamin D metabolism, function, and regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
2.1. Vitamin D metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
2.2. Vitamin D function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
2.3. Vitamin D regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
2.3.1. Vitamin D regulation in normal subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
2.3.2. Vitamin D regulation in CKD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
3. Vitamin D and immune regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
4. Innate immune responses and vitamin D metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
4.1. Vitamin D promotes innate immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
4.2. Vitamin D and antimicrobial peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
4.2.1. Cathelicidin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
4.2.2. Beta-defensins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
4.3. Vitamin D and autophagy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

⁎ Correspondence to: K-C. Lu, Division of Nephrology, Department of Medicine, Cardinal Tien Hospital, School of Medicine, Fu-Jen Catholic University, No.362, Chung-Cheng Rd, Hsin-
Tien Dist., New Taipei City 231, Taiwan.
⁎⁎ Corresponding author.
E-mail addresses: wucc@ndmctsgh.edu.tw (C.-C. Wu), kuochenglu@gmail.com (K.-C. Lu).
1
These authors have contributed equally to this work.

http://dx.doi.org/10.1016/j.cca.2015.08.011
0009-8981/© 2015 Elsevier B.V. All rights reserved.
 Author's personal copy

136 W.-C. Liu et al. / Clinica Chimica Acta 450 (2015) 135–144

5. Vitamin D and adaptive immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

5.1. Vitamin D and antigen presentation cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
5.2. Vitamin D and T cell proliferation and activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
5.3. Vitamin D and T regulatory cells (Treg cells) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
5.4. Vitamin D and B-cell function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
6. Immune dysfunction and role of vitamin D in CKD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
6.1. Immune dysfunction in CKD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
6.2. Role of vitamin D in immune dysfunction (crosstalk between innate and adaptive immunity) . . . . . . . . . . . . . . . . . . . . . . 141
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Conflict of interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

1. Introduction
Chronic kidney disease (CKD) patients have chronic inflammation,
which is the most important reason for the high morbidity and mortal-
ity associated with CKD [1]. Despite well-established treatments for
CKD, these patients still have a high incidence of cardiovascular and in-
fectious morbidities [1,2]. Mounting evidence indicates the relationship
between cardiovascular complications, infection, and abnormalities in
immunity [3–6]. Due to impaired renal function and 1α-hydroxylase
deficiency, advanced CKD and end-stage renal disease (ESRD) patients
generally lack both 25-hydroxyvitamin D [25(OH)D; calcidiol] and
1,25-dihydroxyvitamin D [1,25(OH)2D; calcitriol], which leads to an in-
creased risk of developing infectious complications and cardiovascular
disease. Many factors are involved in the deterioration of immunity in
CKD patients, including anemia, chronic kidney disease — mineral
bone disorder (CKD–MBD), poor nutrition, chronic inflammation, and
dialysis sequelae [1,7,8]. Both the innate and adaptive immune systems
are clearly impaired in CKD patients.
In innate immunity, when pathogen-associated molecular patterns
(PAMPs) stimulate toll-like receptors (TLRs), a kind of pattern recogni-
tion receptor (PRR), on monocytes/macrophages, vitamin D receptor
(VDR) and the expression of 1α-hydroxylase increases. Consequently,
this situation increases the conversion of 25(OH)D to 1,25(OH)2D
within monocytes/macrophages in an intracrine manner, producing
cathelicidin and β-defensin to enhance the disinfectant effects of mac-
rophages [9,10] and promote autophagy of intracellular microbes [11].
In contrast, adaptive immunity is set up by antigen presenting cells
(APCs), such as dendritic cells (DCs) and macrophages, which present an-
tigens to T and B lymphocytes. Vitamin D also has an inhibitory effect on
the adaptive immune system by regulating the function of APCs to induce
T lymphocyte activation, proliferation, and cytokine secretion [12–14].
However, a reciprocal relationship exists between innate immunity
and adaptive immunity. Interestingly, vitamin D plays a role in the
crosstalk between innate and adaptive immunity because it influences
DCs. This review focuses on the influence of vitamin D on innate/
adaptive immunity in CKD patients and discusses the use of vitamin D
to improve immunity in CKD patients.
2. Vitamin D metabolism, function, and regulation
2.1. Vitamin D metabolism
The sources of vitamin D are UVB-dependent endogenous production,
nutritional sources, and supplements. In the skin, 7-dehydrocholesterol
(7-DHC) changes into pre-vitamin D3 when exposed to enough ultravio-
let radiation B (UVB), and vitamin D3 (cholecalciferol) are easily synthe-
sized with heat [15]. Dietary vitamin D can be divided into plant vitamin
D2 (ergocalciferol) and animal vitamin D3 (cholecalciferol). Ergocalciferol
and cholecalciferol are metabolized in the liver by the enzyme vitamin
D-25-hydroxylase and converted to 25-hydroxyvitamin D [25(OH)D]
(calcidiol) as 25(OH)D2 and 25(OH)D3. Clinically, 25(OH)D is the main
circulating form and determines vitamin D status.
When 25(OH)D combines with vitamin D binding protein (DBP), the
resulting complex undergoes glomerular filtration in the kidney. Entry
of the filtered 25(OH)D-DBP compound into proximal renal tubular
cells is facilitated by megalin receptor-mediated endocytosis [16].
Megalin, which is expressed in the renal proximal tubule, is a
multiligand receptor that facilitates the uptake of extracellular ligands.
25(OH)D is delivered to enzyme 1α-hydroxylase by intracellular vita-
min D-binding protein 3 (IDBP3) and changes to active form. The mito-
chondrial 24-hydroxylase protein initiates the degradation of 25(OH)D
and 1,25(OH)2D by hydroxylation of the side chain to form the inactive
blood metabolite 24,25(OH)2D and calcitroic acid [17,18]. The half-life
of Vitamin D is different depending on its form; the half-life of nutrition-
al vitamin D is 60 days, 25(OH)D is 2–3 weeks, and 1,25(OH)2D is
8–12 h [19]. In the circulation, 1,25(OH)2D has 1000 times stronger
affinity for the specific vitamin D receptor than 25(OH)D in serum, it
delivers a higher biologic activity and a shorter half-life [20]. However,
the level of 25(OH)D is 1000 times greater than the level of
1,25(OH)2D [21].
Interestingly, vitamin D is also metabolized to active 1,25(OH)2D
without kidney function, as numerous extra-renal cells possess their
own 1α-hydroxylation capability [10,22–27]. Circulating 25(OH)D is
converted to 1,25(OH)2D in the extra-renal tissues and acts locally in
both an autocrine and paracrine manner. The percentage of extra-
renal 1α-hydroxylation may be higher in CKD [27,28]. Furthermore,
VDR is found not only in many traditional organs, such as bone and
the kidneys, but also in the immune system [29–31]. Rationally, the
extra-skeletal functions of vitamin D consist of protecting renal func-
tion, protecting the cardiovascular system, regulating the immune sys-
tem, and preventing cancer, among others.
2.2. Vitamin D function
The traditional effects of 1,25(OH)2D are related to bone metabolism
via the regulation of blood calcium, phosphate, and parathyroid hor-
mone concentrations [32]. In addition to the management of calcium
and phosphorus homeostasis, 1,25(OH)2D has many beneficial effects
due to non-calciotropic actions. Several studies have shown that
1,25(OH)2D induces anti-cell differentiation, inhibits cell proliferative
activity, and regulates adaptive immunity by decreasing the production
of inflammatory cytokines [12,22,33–35].
In addition, stimulation of TLRs on monocytes/macrophages by
pathogens, such as Mycobacterium tuberculosis and other bacteria,
leads to increased expression of VDR in macrophages/monocytes [36].
Therefore, 1,25(OH)2D enhances the production of cathelicidin to pro-
mote the disinfectant effects of macrophages and monocytes [9,10].
2.3. Vitamin D regulation
2.3.1. Vitamin D regulation in normal subjects
Vitamin D regulates organ functions by binding to its receptor on the
cell surface. In the kidneys, vitamin D protects the kidney function
by decreasing the progression of renal fibrosis, inflammation, and
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W.-C. Liu et al. / Clinica Chimica Acta 450 (2015) 135–144 137

proteinuria [37]. In bone mineralization, 1,25(OH)2D is recognized by its
receptor on osteoblasts to promote osteoblast maturation and increases
calcium and phosphate absorption in the small intestine by combining
with the vitamin D receptor–retinoic acid x-receptor complex (VDR–
RXR) to augment the expression of the epithelial calcium channel [36].
In addition, 1,25(OH)2D diminishes the synthesis and secretion of
parathyroid hormone (PTH) in the parathyroid gland.
2.3.2. Vitamin D regulation in CKD
Advanced CKD and ESRD patients are prone to deficiencies in both
25(OH)D and 1,25(OH)2D. When renal function worsens, serum
1,25(OH)2D levels decline, even before any changes in serum calcium
or phosphorus concentrations. The ideal levels of 25(OH)D in the
serum is unknown but may be slightly higher than 30 ng/ml in CKD
patients [30] for extra-renal production of 1,25(OH)2D and regulation
of PTH secretion. Vitamin D deficiency can occur in CKD patients for a
number of reasons.
2.3.2.1. Decreased 25(OH)D (calcidiol) in CKD. Because renal mass and
the glomerular filtration rate (GFR) are decreased in CKD patients, lim-
ited 25(OH)D enters the renal tubules and less 25(OH)D is taken up. In
addition, damaged kidneys have decreased megalin expression, which
impairs 25(OH)D reabsorption. Furthermore, albuminuria will occupy
the megalin route and fewer receptors will be available to reabsorb
25(OH)D-DBP. In addition, as a consequence of proteinuria, proximal
tubular cells are damaged and express less megalin [38] (Fig. 1).
Therefore, CKD reduces 25(OH)D resorption and results in the
formation of less 1,25(OH)2D in a substrate-dependent process [39].
2.3.2.2. Decreased 1α-hydroxylase activity and increased 24-hydroxylase
activity. Renal tubular cells contain two enzymes related to vitamin D
metabolism: 1α-hydroxylase and 24-hydroxylase. These enzymes can
hydroxylate 25(OH)D to either 1,25(OH)2D or 24,25(OH)2D, an inactive
metabolite. CKD, diabetic, increased FGF-23, and the use of active vita-
min D decrease the activity of 1α-hydroxylase and 25-hydroxylase

Fig. 1. Vitamin D metabolism and its regulations. Very few foods contain vitamin D and synthesis of vitamin D (specifically cholecalciferol) in the skin is the major natural source of the
vitamin. Dermal synthesis of vitamin D from cholesterol is dependent on sun exposure. Vitamin D obtained from the diet or dermal synthesis is biologically inactive. The activation of
vitamin D requires enzymatic conversion (hydroxylation) in the liver (25-hydroxylase) and kidney (1α-hydroxylase). The mitochondrial protein (24-hydroxylase) initiates the
degradation of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] by hydroxylation of the side chain to form calcitroic acids. In CKD, diabetic, increased
fibroblast growth factor 23 (FGF-23), and the use of active vitamin D decreases the activity of 25-hydroxylase and 1α-hydroxylase and increases the activity of 24-hydroxylase, resulting
in decreased endogenous 25(OH)D and 1,25(OH)2D production and increased 25(OH)D and 1,25(OH)2D degradation. In CKD patients with secondary hyperparathyroidism, a large dose of
active vitamin D may aggravate 25(OH)D deficiency, which may also deprive the need for 25(OH)D in other tissues or organs (skin, prostate, colon, brain, breast, lung, placenta, osteoblast,
parathyroid gland, pancreas, muscle, monocyte, T/B cells, etc.).
 Author's personal copy
138 W.-C. Liu et al. / Clinica Chimica Acta 450 (2015) 135–144
and increase the activity of 24-hydroxylase, resulting in a decrease in
endogenous 25(OH)D and 1,25(OH)2D production and increased
25(OH)D and 1,25(OH)2D degradation [40,41].
2.3.2.3. Influence of phosphaturic hormones. In CKD, FGF-23, a
phosphaturic hormone, is secreted to maintain normal serum phos-
phate homeostasis. As kidney function deteriorates, FGF-23 markedly
increases in individuals with CKD [42]. FGF-23 inhibits renal production
of 1,25(OH)2D by decreasing 1α-hydroxylase activity in renal proximal
tubules and simultaneously increasing the expression of 24-hydroxylase
and production of 24,25(OH)2D [43]. Therefore, FGF-23 decreases the
25(OH)D concentration.
2.3.2.4. Overusage of 1,25(OH)2D. 1,25(OH)2D is the most common drug
prescribed in CKD patients with secondary hyperparathyroidism.
Because 1,25(OH)2D, the end product of vitamin D, feedback inhibits
1α-hydroxylase and 25-hydroxylase, a large dose of 1,25(OH)2D may
aggravate 25(OH)D deficiency, which may decrease the providing of
25(OH)D in other tissues or organs (e.g., colon, brain, breast, osteo-
blasts, parathyroid gland, monocytes, immune cells) [44]. In addition,
the activity of 1α-hydroxylase and concentration of 25(OH)D have a
substrate-dependent relationship in CKD patients; the higher concen-
tration of 25(OH)D, the stronger the 1α-hydroxylase activity, and vice
versa [45].
3. Vitamin D and immune regulation
More than one hundred years ago, vitamin D was initially used to
treat infections and cod liver oil successfully helped tuberculosis [1]. Im-
mune cells carry VDR and 1α-hydroxylase, which profoundly influences
human health [36,46]. The immune system produces the active metab-
olite 1,25(OH)2D through local synthesis and heightens immunomodu-
latory properties [47,48]. Increasing evidence indicates that vitamin D
deficiency, as in CKD, not only causes dysregulation of the innate and
adaptive immune systems, but also promotes microinflammation [49].
In addition, epidemiological experiments have found that vitamin D de-
ficiency is closely related to autoimmune and infectious diseases
[50–53]. When serum vitamin D levels are adequate, the activation of
innate immunity is immediately enhanced when microbial pathogens
are presented, and the benefits of the adaptive immune response
prevent various autoimmune diseases and transplant rejection [1].
In addition, a cross-sectional analysis reported that severely ill septic
patients have significantly low serum 25(OH)D levels. The levels were
related to diminished concentrations of antimicrobial peptides, such
as cathelicidin and β-defensin 2[54–56]. Another randomized con-
trolled trial demonstrated that daily intake of 4000 IU cholecalciferol
over one year meaningfully reduces complications of infection,
pathogens in the nasal fluid, and antibiotic use [57]. Therefore, vitamin
D would upregulate antimicrobial peptide levels and be essential in
infection control.
4. Innate immune responses and vitamin D metabolism
4.1. Vitamin D promotes innate immunity
Innate immunity identifies PAMPs through TLRs and initiates
defense mechanisms in response to microorganisms [58]. Recently,
1,25(OH)2D was shown to enhance the effects of macrophages and
monocytes against pathogens by stimulating the differentiation of
monocytes into mature phagocytic macrophages [59–61]. During
infection, macrophages/monocytes are exposed to PAMPs, a small
molecular motif preserved within a class of microbes that activates
TLR 1/2 heterodimer. 1α-Hydroxylase activity and VDR expression are
then upregulated to produce 1,25(OH)2D [10,55]. Lipopolysaccharide
also induces TLR4, interferon-γ (IFN-γ), and CD14 activity to increase
1α-hydroxylase expression [1,62] (Fig. 2).
When serum 25(OH)D levels are N30 ng/ml (75 nmol/l), it can con-
vert to its active form, 1,25(OH)2D, via 1α-hydroxylase in macrophages
in an intracrine or autocrine manner [36]. 1,25(OH)2D enters the nucle-
us by binding VDR and complexes with retinoid X receptor (RXR),
directly signaling the transcription of cathelicidin and β-defensin 2
[33,54–56,63]. Both of these peptides cleave microbial membranes
and promote innate immunity in response to infectious agents, such
as bacteria, viruses, and fungi, in humans [64–66].
Compared to people with adequate serum levels of vitamin D, mac-
rophage function in vitamin D-deficient patients may deteriorate and
lead to a decreased bacterial killing effect [67]. However, some studies
have shown that, in contrast to renal 1α-hydroxylase, local production
of 1α-hydroxylase in macrophages is not inhibited by endocrine
1,25(OH)2D and is promoted by immune stimuli, such as interleukin-1
(IL-1) and IFN-γ [68,69].
Since 25(OH)D levels of individuals decide the capability of vitamin
D to influence normal human immunity, vitamin D insufficiency may
lead to a poor reaction to infection or innate immunity. In Swiss,
Sakem et al. found that almost two-thirds of healthy and older people
showed of Vitamin D insufficiency. They also noticed that low levels of
25(OH)D were directly related to levels of IgG2 and complement
component C4, in contrast, which were opposite associated with levels
of IgG1 and IgA and complement component C3. In other words, the
higher level of 25(OH)D will accompany with increasing C4 concentra-
tion but decreasing C3 concentration [70].
4.2. Vitamin D and antimicrobial peptides
4.2.1. Cathelicidin
Cathelicidin, the antimicrobial protein found in lysosomes, macro-
phages, and polymorphonuclear leukocytes, damages microbial mem-
branes and is increased in defense against infection [64]. In CKD
patients, low 1,25(OH)2D levels have been related to elevated mortality
rates caused by severe infections [71]. Thus, the vitamin D concentration
increases antimicrobial peptide levels and may be essential in the treat-
ment of infections. A study of African-Americans with lower levels of
25(OH)D found that, after providing 25(OH)D supplements, adequate
serum concentrations were achieved, rescuing TLR activation and in-
duction of cathelicidin mRNA [10]. Previous studies showed that
cathelicidin can be upregulated by 1,25(OH)2D via vitamin D response
element (VDRE) complexes [54]. Other experiments demonstrated
that VDR can increase cathelicidin transcription and 1,25(OH)2D can
build up cathelicidin levels in several types of cells, including
monocytes, macrophages, and neutrophils [54,72]. Liu et al. published
two important studies: the first one demonstrated that decreased
cathelicidin levels can diminish the monocyte capacity for killing
M. tuberculosis, and the second demonstrated that vitamin D supple-
mentation can enhance cathelicidin levels and promote antibacterial
activity [10].
4.2.2. Beta-defensins
Vitamin D binding to VDR can upregulate the expression of the
β-defensin 4A (DEFB4A) gene, which encodes the antibacterial
β-defensin 2 protein, during the innate immune response [54,55].
Compared to cathelicidin, vitamin D has less influence on DEFB4 expres-
sion because the functional ability of DEFB4–VDRE requires other stim-
uli to increase transcriptional activity [55]. Gastrointestinal epithelial
interleukin-1 (IL-1b) also enhances DEFB4 expression [73]. In addition,
DEFB4 is induced by 1,25(OH)2D through nucleotide-binding oligomer-
ization domain 2 (NOD2), an intracellular PRR that binds muramyl
dipeptide (MDP), a cell membrane product of bacteria [74]. The activa-
tion of immune cells induces the expression of IL-1 and suppresses ex-
pression of the IL-1 receptor antagonist, thereby enhancing intracrine
signaling by IL-1 and increasing nuclear factor кB (NF-кB) activity [75].
The NF-кB pathway also upregulates NOD2 signals to enhance DEFB4
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W.-C. Liu et al. / Clinica Chimica Acta 450 (2015) 135–144 139

Fig. 2. Vitamin-D, innate immunity (anti-infection), and autophagy. The activation of monocyte toll-like receptors (TLR1/TLR2) by pathogen-associated molecular patterns (PAMPs)
induces expression of the cytokine interleukin-1 (IL-1) and suppresses expression of the IL-1 receptor antagonist (IL-1RA), thereby enhancing intracrine signaling by IL-1 and increasing
nuclear factor кB (NF-кB) activity. The phagocytosis of pathogens increases intracellular concentrations of muramyl dipeptide (MDP), which can then bind to the intracellular pathogen-
recognition receptor NOD2. MDP-liganded NOD2 signaling increases NF-кB activity. In addition, the activation of monocyte TLR1/TLR2 by PAMP results in the transcriptional induction of
vitamin D receptor (VDR) and 1α-hydroxylase expression. Circulating 25-hydroxyvitamin D [25(OH)D] bound to serum vitamin D-binding protein (DBP) enters monocytes in its free form
and is converted to active 1,25-dihydroxyvitamin D [1,25(OH)2D] by mitochondrial 1α-hydroxylase, and then binds to VDR. 1,25(OH)2D bound to VDR is then able to act as a transcription
factor, leading to the induction of cathelicidin and β-defensin 4A expression and the promotion of autophagy by the formation autophagosomes. In concert with 1,25(OH)2D bound to VDR,
NF-кB also enhances the transcriptional induction of cathelicidin and β-defensin 4A. In the presence of increased cathelicidin, immune cells induce the activity of NOD2/CARD15-β-
defensin 2, autophagy-related protein 5 (ATG5), and BECLIN1, then induces autophagy. Antibacterial cathelicidin, β-defensin 4A, and the maturation of autophagosomes then cooperate
to enhance bacterial killing. Cytoplasm SNARE proteins mediate fusion between autophagosomes and lysosomes, and various lysosomal enzymes further hydrolyze proteins, lipids, and
nucleic acids. The digestive nutrients may be recycled and utilized by the cells. The net efficacy of such a response is highly dependent on vitamin D status, the availability of circulating
25(OH)D for intracrine conversion to active 1,25(OH)2D by the enzyme 1α-hydroxylase.

activity in a similar manner [76]. Therefore, vitamin D produces DEFB4 25D for intracrine conversion to active 1,25D by the enzyme
through NOD2 activation and NF-кB stimulation [77]. 1α-hydroxylase [65].

4.3. Vitamin D and autophagy 5. Vitamin D and adaptive immunity

In addition to bacterial killing agents, there are other essential fac-
tors that influence innate immune responses to pathogen invasion.
The cellular environment is also an important bactericidal location. It
is advantageous to kill pathogens when the merger of phagosomes
with lysosomes creates a phagolysosomal environment. Although the
mechanism is still unclear, autophagy, another aspect of cellular
immune function, may enhance the procedure of phagocytosed
pathogens.
In the presence of increased cathelicidin levels, immune cells induce
the activity of NOD2/CARD15-β-defensin 2, autophagy-related protein
5 (ATG5), and BECLIN1, which induce autophagy [76,78]. Autophagy is
not only the elimination of materials, but also acts as a dynamic
recycling system that yields new components and energy for cellular
renovation and homeostasis. Autophagy increases in response to sever-
al stimuli, such as infection and starvation [79]. Therefore, autophagy is
an important defense mechanism of macrophages against intracellular
pathogens [11]. Antibacterial cathelicidin, β-defensin 4A, and matura-
tion of autophagosomes cooperate to enhance bacterial killing. In addi-
tion, cytoplasm SNARE proteins mediate the fusion of autophagosomes
and lysosomes, and various lysosomal enzymes further hydrolyze
proteins, lipids, and nucleic acids. The digestive nutrients may be
recycled and utilized by the cells. The net efficacy of such a response
is highly dependent on vitamin D status, the availability of circulating
Decades ago, human lymphocytes were observed to present VDR
associating with vitamin D in extramineral reactions [80]. Evidence
indicates that VDR are presented in both activated T cells and B cells
[81,82] but not inactive cells. Thus, vitamin D plays a functional role in
modulating adaptive immunity. This process is set up by APCs, such as
DCs and macrophages, which present antigens to T lymphocytes and B
lymphocytes, leading to the production of antibodies and the regulation
of immunological memory [12].
5.1. Vitamin D and antigen presentation cells
The important distinction between innate and adaptive immunity is
the existence of APCs [77]. DCs, professional APCs, can express MHC
class II and have the necessary costimulatory signals to activate CD4+
T cells (helper T-cells). In contrast, most somatic cells present MHC
class I molecules and act as the targets of CD8+ T cells (cytotoxic
T-cells). In immature DCs, TLRs are stimulated by microbiological or
bacterial lipopolysaccharides to enhance DC maturity. Mature DCs
travel to lymph nodes to interact with T and B cells under the influence
of cytokines and chemokines.
In VDR knockout mice, Griffin et al. showed the important role of
VDR in DC maturation responses to vitamin D metabolites [83]. Later,
Piemonti et al. found that vitamin D leads to DC immaturity and results
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140 W.-C. Liu et al. / Clinica Chimica Acta 450 (2015) 135–144

in failed antigen presentation [84–86]. NF-кB signaling plays an impor-
tant role in the inhibitory effect of vitamin D on DC maturation [87,88].
There are two major reasons for immature DCs in vitamin D metab-
olism. First, 25(OH)D or 1,25(OH)2D suppresses the maturation of DCs
because of decreased expression of the co-stimulatory markers HLA-
DR, CD40, CD80, and CD86, which are necessary for antigen presenta-
tion and T cell proliferation [89–91]. 1,25(OH)2D also decreases the
level of IL 12, which can enhance the stimulation of T helper 1 (TH1)
cell development [92]. Second, the other pivotal characteristics of
vitamin D metabolism in DCs is that there is a relevant weakening of
the expression of VDR and ability of 1,25(OH)2D to bind the receptor
when the expression of 1α-hydroxylase and synthesis of 1,25(OH)2D
increases [91,93]. Because mature DCs have plenty of 1α-hydroxylase
to convert 25(OH)D to 1,25(OH)2D, which influences immature DCs
that express higher levels of the VDR than their mature counterparts.
In this paracrine mechanism, 1,25(OH)2D prevents the maturation of
DCs, thereby reducing antigen presentation and improving the T cell
tolerogenic immune response [77], preventing over-amplification of
adaptive immune responses [94].
5.2. Vitamin D and T cell proliferation and activation
1,25(OH)2D plays a key role in the proliferation and activation of T
cells. Vitamin D leans toward a tolerogenic immune status instead of
inflammation and promotes a T cell shift from Th1 to Th2 [95]. This
situation potentially damages tissue related to Th1 cellular immune
responses. Usually, vitamin D increases anti-inflammatory Th2 cytokine
(i.e., IL-3, IL-4, IL-5, and IL-10) production [96] and the efficiency of Treg
lymphocytes but suppresses the secretion of Th1 cytokines (i.e., IL-2,
IFN-γ, and TNF-α), which are potent stimulators of inflammation [90,
97,98] (Fig. 3). There are several mechanisms by which serum vitamin
D influences T cell function: endocrine, paracrine, and intracrine. Firstly,
systemic endocrine 1,25(OH)2D directly affects T cells. Secondly,
25(OH)D is converted to local 1,25(OH)2D within DCs acting on T cells
in a paracrine fashion. Thirdly, either the synthesis of 1,25(OH)2D in
an intracrine manner in DCs indirectly affects antigen presentation to
T cells or 25(OH)D directly converts to 1,25(OH)2D in T cells in an
intracrine manner [99].
Vitamin D also inhibits the development of Th17 (i.e., IL-17, IL-21),
which plays an essential role in the occurrence of autoimmune diseases
associated with tissue damage, inflammation, and host-graft rejection
[100]. Penna et al. demonstrated in an in vitro study that treatment of
non-obese diabetes (NOD) mice, a model of susceptible autoimmune
disease, with a synthetic analog of 1,25(OH)2D could reduce IL-17 ex-
pression [101]. Thus, vitamin D directly influences T cell proliferation
and cytokine production [102]. Patients on chronic hemodialysis (HD)
have impaired cellular and humoral immunity, and we have demon-
strated that Th2 differentiation correlates with age and serum
25(OH)D levels in patients [103]. We found that higher phosphate and
iPTH levels and longer dialysis duration increase Th17 cell differentia-
tion, especially in non-diabetic chronic HD patients [104].
5.3. Vitamin D and T regulatory cells (Treg cells)
Treg cells exhibit anti-inflammatory effects and reduce autoimmune
disorders by releasing cytokines IL-10 and TGF-β [105]. The suppression
of DC maturation by 1,25(OH)2D weakens the adaptive T lymphocyte
responses and augments immunosuppression affecting by Treg cells

Fig. 3. Mechanisms for adaptive immune responses to vitamin D. Dendritic cells (DCs) expressing 1α-hydroxylase and the vitamin D receptor (VDR) can utilize circulating
25-hydroxyvitamin D [25(OH)D] for intracrine responses via localized conversion to active 1,25-dihydroxyvitamin D [1,25(OH)2D]. In DCs, intracrine synthesis of 1,25(OH)2D inhibits DC
maturation, thereby modulating helper T (Th) cell function. Th responses to 25(OH)D may also be mediated in a paracrine fashion, with DC-generated 1,25(OH)2D acting on VDR-expressing
Th cells. VDR-expressing Th cells are also potential targets for systemic 1,25(OH)2D (endocrine effect). The action of vitamin D on DCs stimulates effector CD4+ cells to differentiate into one
of the four types of Th cells. Activated T cells also express VDR. Under normal conditions vitamin D increases Th2 cytokines (i.e., IL-10) and the efficiency of regulatory T (Treg) lymphocytes.
Vitamin D inhibits the development of Th1 cells, which are associated with the cellular immune response. In addition, vitamin D promotes Th2 cells associated with humoral (antibody)
mediated immunity. Thus, vitamin D promotes the T cell shift from Th1 to Th2 function. Vitamin D also inhibits the development of Th17 cells, which play an essential role in combating
certain pathogens and are linked to tissue damage and inflammation. The fourth group of CD4+ T cells, Treg cells, exerts suppressor function responses to vitamin D.
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W.-C. Liu et al. / Clinica Chimica Acta 450 (2015) 135–144
[106]. By inhibiting the maturation of DCs and increasing expression of
DC cytokines, such as CCL22, 1,25(OH)2D has the potential to suppress
Th1 cells and induce CD4+/CD25+ Treg cells [107], which are essential
for the induction of tolerogenic immune responses [108]. The influence
of vitamin D on Tregs can be direct through endocrine systemic calcitriol
effects or intracrine conversion of 25(OH)D to 1,25(OH)2D by Tregs
themselves, or indirect via APCs remaining in the immature status
while providing vitamin D supplementation, resulting in less antigen
expression [109]. Prietl et al. demonstrated that high doses of cholecal-
ciferol in the healthy population can significantly increase the percent-
age of Tregs in peripheral blood [110]. Ardalan et al. also found that
supplementing calcitriol upregulates the population of CD4+CD25+ T
cells in renal transplant recipients [111].
5.4. Vitamin D and B-cell function
1,25(OH)2D results in reduced proliferation and differentiation of B
lymphocytes and the production of immunoglobulin, leading to apopto-
sis because VDR can be expressed at higher levels in active B lympho-
cytes compared to resting B lymphocytes [112]. These effects are
probably indirectly mediated by T cells and macrophages [95,113].
This retardation of β-cell precursors into plasma cells is important in au-
toimmune diseases because plasma cells produce autoantibodies that
play a key role in the mechanisms underlying autoimmune disease
such as systemic lupus erythematosus (SLE) [32] and Crohn's disease
[114].
6. Immune dysfunction and role of vitamin D in CKD
6.1. Immune dysfunction in CKD
CKD patients usually have obvious immune dysregulation compared
to the general population. Due to the immune dysregulation, CKD pa-
tients have vascular calcification, atherosclerosis, impaired glucose tol-
erance, and hypercytokinemia [115,116]. Thus, they not only have a
higher rate of infection and malignancy, but also increased incidence
of cardiovascular events [117–119]. Many studies have shown that
both the innate and adaptive immune systems are impaired in patients
with advanced CKD and ESRD [4,5]. In CKD patients, immunity is usually
pre-activated to overproduce pro-inflammatory cytokines, such as TNF-
α, IL-1, and IL-6 [120,121], and the clearance of these hypercytokines is
impaired [122,123].
It is about 90% of health people who received hepatitis B vaccines
will achieve sufficient titers of anti-HBs antibodies but just 50–60% of
ESRD patients can obtain enough anti-HBs antibody titers [124]. Many
disturbances of immunity in CKD patients result in this impaired anti-
body response [117]. Zitt et al. conducted a research about anti-HBs an-
tibody titers and serum 25(OH)D levels in CKD 3–5D patients who
received hepatitis B vaccination, which performed that a lower antibody
titer is related to vitamin D deficiency. They assume that rising the levels
of 25(OH)D before hepatitis B vaccination has the possibility to increase
the titers of anti-HBs antibody and strengthen the immune responses
[125].
Furthermore, CKD attenuates the function of both DCs and macro-
phages because co-stimulatory molecules such as CD40, CD80, and
CD86 are impaired [30,126–128]. Consequently, CKD leads to a dimin-
ished response to infection and misapplied inflammatory response as
in a state of immune dysregulation and sustained inflammation [1]. In
addition, fewer peripheral CD4+ T lymphocytes, CD8+ T lymphocytes,
and B lymphocytes are present, but a higher level of soluble B lympho-
cyte markers is found in the blood of CKD patients [129,130]. Therefore,
the immune deterioration in CKD patients is a complex issue. Some
studies have demonstrated that uremic toxins lead to the accumulation
of pro-inflammatory cytokines and immunosuppression [3,131].
141
6.2. Role of vitamin D in immune dysfunction (crosstalk between innate
and adaptive immunity)
DCs are the key connector between the innate and adaptive immune
systems. In the innate response, DCs are activated by PRRs and sequen-
tially initiate the adaptive immune network [132]. Vitamin D plays a
role in the crosstalk between innate and adaptive immunity because it
has an essential influence on DCs (Fig. 4). In macrophages, 25(OH)D is
converted to local 1,25(OH)2D through 1α-hydroxylase, and this pro-
duction induces paracrine responses in monocytes and T or B lympho-
cytes. Activated monocytes further promote the differentiation of
macrophages via the paracrine effects of vitamin D, indicating that vita-
min D can enhance innate immunity. In contrast, vitamin D inhibits the
expression of MHC-II molecules and co-stimulatory molecules [133,
134]. Thus, local 1,25(OH)2D is assumed to have immunosuppressive
properties. In addition, the synthesis of vitamin D leads to the attenua-
tion of antigen presentation and enhances a tolerogenic immune
response. Vitamin D suppresses the maturation of DCs and promotes
the apoptosis of mature DCs [85], which inhibits adaptive immunity,
increasing the number of Th2 cells and Treg cells, and decreasing the
number of Th1 and Th17 cells [135].
Additionally, IFN-γ, produced by natural killer (NK) cells and T cells
[136], is a cytokine that is important for innate and adaptive immunity.
In innate immunity, IFN-γ increases the expression of 1α-hydroxylase
to augment local 1,25(OH)2D production and enhance macrophage
phagocytosis. T cells express IFN-γ through the stimulation of IL-15
secreted by DCs [137]. Therefore, a different mechanism in the adaptive
immune system can enrich the innate immune response to pathogens,
as increasing the activity of macrophage 1α-hydroxylase is indepen-
dent of PAMPs [77].
7. Conclusions
In CKD and ESRD patients, there is a tendency for immune dysfunc-
tion and infectious disorders due to vitamin D deficiency. Mounting
evidence indicates that the use of vitamin D goes beyond its traditional
roles, such as maintaining mineral homeostasis and dealing with
secondary hyperparathyroidism in CKD. Consequently, vitamin D has
received attention because of its pleiotropic actions in many chronic
diseases. However, it still needs more evidence to support the need for
vitamin D supplementation in improving immune function. Many
studies have established that extra-renal tissues and cells, such as im-
mune cells, contain vitamin D metabolizing enzymes (1-α hydroxylase)
to produce local biologically active forms of vitamin D in an intracrine/
paracrine manner.
Vitamin D promotes innate immune effects and inhibits adaptive
immune effects. In innate immunity, 1,25(OH)2D can be synthesized
by inflammatory cells during infection. Macrophages recognize PAMPs
via TLRs and increase the production of β-defensin 2 and cathelicidins
to fight against pathogens. In addition, cathelicidins induce the activa-
tion of autophagy, which is an important defense mechanism of macro-
phages to kill bacteria. In adaptive immunity, vitamin D can promote
the tolerogenic function of Treg cells and decrease autoimmune disease.
Recently, vitamin D has been shown to play an important role in the
crosstalk between the innate and adaptive immune systems. In other
words, vitamin D essentially influences DCs, which are the interface be-
tween innate and adaptive immunity. Collectively, vitamin D has a very
important role in maintaining normal immune function, and vitamin D
deficiency or insufficiency in CKD patients could result in a deterioration
of immune function and infectious disorders.
Conflict of interests
The authors declare that there is no conflict of interests regarding
the publication of this paper.
 Author's personal copy

142 W.-C. Liu et al. / Clinica Chimica Acta 450 (2015) 135–144

Fig. 4. Role of vitamin D in crosstalk between innate and adaptive immunity. Vitamin D plays a role in the crosstalk between innate and adaptive immunity because it has an essential
influence on macrophages and dendritic cells (DCs). DCs are the key connector between innate and adaptive immune systems. Local production of 1,25-dihydroxyvitamin D
[1,25(OH)2D] in paracrine responses also seems to have an effect on monocytes and immature DCs, which express higher levels of vitamin D receptor (VDR) than mature DCs. IFN-γ is
an important cytokine for innate and adaptive immunity. T cells express IFN-γ through the stimulation of DCs. IFN-γ increases the expression of 1α-hydroxylase to augment local
1,25(OH)2D production to enhance macrophage phagocytosis.

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