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3 Possible Role of Vitamin D Deficiency in the Immune Dysfunction of CKD

3 Possible Role of Vitamin D Deficiency in the Immune Dysfunction of CKD

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dose-dependent manner, 1,25(OH)2D induces autophagy in monocyte-derived macrophages, and this has been shown to reduce the intracelluar replication of HIV and

Mycobacterium tuberculosis. In human macrophages, TLR8 activation induces the

expression of cathelicidin, VDR and CYP27B1. Experiments using interfering

RNAs, inhibitory chemicals and vitamin D-depleted culture media have shown that

it is through vitamin D and cathelicidin-dependent autophagy that TLR8 agonistes

inhibit HIV cell infection in this model [17].

Altogether, these results suggest that vitamin D could play an important role in

the first line of defence against pathogens.



17.3.1.2



Vitamin D in Adaptive Immunity



The literature on vitamin D and T cell function supports the assumption that vitamin

D deficiency is a risk factor for the onset and a poorer evolution of autoimmune

diseases, the strongest example being multiple sclerosis. It is widely admitted that

vitamin D decreases the differentiation and proliferation of dendritic cells, favors

the production of Th2, rather than Th1 cytokines, decreases the CD4/CD8 ratio, and

induces the differentiation of regulatory T cells (Treg), while it prevents the differentiation of Th17 cells and inhibits differentiation and antibody production in B

cells [14, 18].

At first sight, all these actions of vitamin D appear contrary to mounting a good

response against pathogens, but this should probably be nuanced for two reasons.

First, it has been shown, in CKD patients, that vitamin D deficiency is associated

with a low T-cell proliferation ability, corrected by the addition 1,25(OH)2D, and

furthermore that the vitamin D-VDR system is active in the signal transduction

through the T cell receptor in naïve T cells [19]. This suggests that vitamin D plays

a role in primary T cell activation, upstream to cytokine orientation. Second, it has

been shown in a mouse model [20] that Tregs play an important role in T CD8 cell

priming. While Tregs are widely known for suppressing autoimmune responses,

their depletion induces activation and expansion of CD8+ cells with low avidity for

the antigen, due to an overproduction of the CCL-3/4/5 chemokines, which stabilize

the interactions between dendritic cells and low avidity T cells. In the absence of

Tregs, antigen avidity of the primary immune response remained low, resulting in

an impaired memory response to Listeria monocytogenes. These results suggest that

Tregs are important regulatory agents of T CD8 cell homeostasis and priming, conditioning high avidity primary response and strong memory response.



17.3.1.3



Vitamin D and Inflammation



Vitamin D deficiency has been associated with inflammation. In patients having

performed a coronary angiography, vitamin D deficiency was associated with higher

mortality, but also with higher levels of cell adhesion molecules, of oxidative stress

markers and of inflammatory markers such as C-reactive protein (CRP) and



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interleukin 6 (IL-6) [21]. In a placebo-controlled study in patients with heart failure,

vitamin D supplementation induced a decrease of TNF-α levels and an increase in

the level of the anti-inflammatory cytokine interleukin 10 (IL-10) [22]. In a large

general population cohort, low 25(OH)D levels were associated with higher levels

of coagulation activation markers, plasminogen tissue activator and D-dimers [23].

Higher concentrations of these markers of inflammation and coagulation activation

have been associated with mortality in persons living with HIV showing good control of viral replication on treatment [24]. Vitamin D deficiency has been associated

with poorer clinical outcomes in persons with treated or untreated HIV infection

[25, 26], with ongoing inflammation [27], with an increase over time of inflammatory markers and a poorer CD4 cell count restoration [28]. Finally, in a small trial in

virologically controlled HIV-infected persons, vitamin D supplementation allowed

to obtain a decrease of CD8 cell activation markers [29]. In the setting of tuberculosis, vitamin D supplementation, added to anti-tuberculous drugs, was associated

with a much faster correction of immune/inflammation parameters than antituberculous drugs alone [30].

A reasonable conclusion is that vitamin D could not only favour a stronger innate

immune response (and possibly a stronger adaptive cell responses) to pathogens, but

could also reduce inflammation and cell activation linked to the presence of pathogens, particularly in subacute or chronic infections. It can be hypothesized that this

would also apply to other conditions, such as CKD/ESRD, where chronic inflammation, which is not triggered by a specific pathogen, has also been associated with

higher mortality [31].

However, interestingly, a recent study in a mouse model of systemic Candida

infection showed that animals receiving low doses of 1,25(OH)2D3 had a lower fungic

load and a longer survival than controls, while animals receiving high doses of

1,25(OH)2D3 had poorer outcomes: these surprising results suggest that low vitamin

D doses favors beneficial inflammatory response (e.g. by targeting the IFN-ϒ gene),

while high doses would reduce the inflammatory response to the point of being detrimental [32]. This indication of a bimodal influence of vitamin D on host responses

adds complexity but might help interpreting apparently conflicting results of supplementation trials.

Recent studies indicate that vitamin D could also play a role in the interplay

between the microbiome and immune dysregulation and inflammation, by modulating the microbiome and intestinal permeability [33, 34].



17.3.2



Contribution of Low Vitamin D in Immune Impairment

in CKD



As summarized above, immune dysfunction in CKD concerns both innate and adaptive immunity, and persistent inflammation. From the description of the immunological effects of vitamin D, it is reasonable to speculate that vitamin D deficiency

may be involved in the immune impairment of CKD and that supplementation could



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reinforce innate immunity and decrease inflammation in CKD patients, while it

would certainly be much more difficult to anticipate its effects on adaptive

immunity.

As a matter of fact, it has been recently shown that treating peritoneal macrophages from patients on peritoneal dialysis with vitamin D ex vivo increased mRNA

expression of cathelicidin, and that supplementing patients with vitamin D had the

same effect (after adjustment for cell population number) [35]. Interestingly, the

same study showed that vitamin D (ex vivo treatment and administration to patients)

decreased the synthesis of hepcidin, which normally inhibits ferroportin, the only

known exporter of intracellular iron to date. Since many bacteria use iron for growth,

depletion of intracellular iron could be another, indirect, vitamin-D induced antibacterial effect.

Another factor of immune dysregulation has been proposed in CKD patients, in

relation with vitamin D metabolism and phosphocalcic homeostasis. Bone-derived

fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that inhibits

CYP27B1 and induces 1,25(OH)2D inactivation, and serum levels of FGF23 are

increased in CKD. Recent studies indicate that FGF23 could also have immune

regulatory functions. Treatment of monocytes (from blood of healthy donors or

from peritoneal dialysis effluents of uremic patients) with FGF23 decreased

CYP27B1 mRNA expression in these cells [36]. This could interfere negatively

with the intracrine system responsible for the production of bactericidal peptides

and contribute to an increased susceptibility to infections.



17.4



Observational Studies in CKD



One recent large study from the HEMO cohort of hemodialysis patients [37] examined the association between yearly serum levels of 25(OH)D, 1,25(OH)2D and

FGF23 and clinical cardiovascular and infectious outcomes using time-dependent

Cox regression models, after controlling for important covariates.

Correlations between vitamin D, FGF23 and inflammation markers were also

examined. 25(OH)D levels correlated positively with serum calcium, 1,25(OH)2D,

FGF23, and inversely with PTH, hsCRP and IL-6. FGF23 levels also correlated

positively with serum phosphorus, PTH, and 1,25(OH)2D, but there was no correlation with hsCRP or IL-6.

After a median follow-up of 3 years, 582 deaths were reported in 1,340 participants, and 499 participants were hospitalized or died because of an infection.

Patients with 25(OH)D levels in the highest quartile had the lowest risk of infectious

events (hazard ratio [HR]: 0.66 vs lowest quartile, 95 % CI: 0.49–0.89), cardiovascular events (HR: 0.71, 95 % CI: 0.53–0,96) and all-cause mortality (HR: 0 0.46,

95 % CI: 0.34–0.62). No significant association of 1,25(OH)2D with clinical outcomes was observed. In contrast, patients with FGF23 in the highest quartile had the

highest risk of infection (HR: 1.57, vs lowest quartile, 95 % CI: 1.13–2.18), cardiovascular events (HR: 1.49, 95 % CI: 1.06–2.08) and all-cause death (HR: 1.50, 95 %



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CI: 1.07–2.12). Interestingly, the addition of inflammation markers (including also

TNF-α and IFN-Y) in the models did not attenuate the associations.

This important study underlines that high 25(OH)D levels, as a time-dependent

variable had a graded relationship with the decreased risk of events, in particular

infections, and that this was independent of systemic inflammation. As frequently

debated, this can generate two series of hypotheses: the first one would evoke the

direct immunological effects of vitamin D, the second one would view high 25(OH)

D levels only as a marker of better general health. Of particular interest, however, is

the finding that higher FGF23 levels were predictive of infections, and this was also

independent of inflammation. The inhibitory effect of FGF23 on 1,25(OH)2D synthesis in monocytes, resulting in decreased bactericidal abilities, is a plausible

explanation.



17.5



Intervention Trials in CKD



To our knowledge, there is no convincing data from large cohorts or randomized

controlled trials assessing whether vitamin D supplementation could reduce infectious diseases morbidity or mortality in CKD. However, meta-analyses have been

produced examining its effects on all-cause mortality or cardiovascular deaths, and

we can hypothesize that infectious events would follow the same trends (as in ref

[37]). One meta-analysis of observational cohorts [38] concluded that vitamin D

supplementation and a protective effect on all-cause mortality (HR: 0.71, 95 % CI:

0.57–0.89, in a time-dependent Cox model). A meta-analysis of randomized,

placebo-controlled trials found no significant effect [39]. The heterogeneity of trials, particularly in terms of vitamin D dosing and duration of supplementation, is a

recurrent difficulty for analysis. In addition, another meta-analysis examined

whether the effect of drugs (vitamin D compounds, phosphate binders, cinacalcet,

biphosphonates, calcitonin) on PTH, calcemia and phosphoremia were associated

with all-cause and cardiovascular deaths: only PTH levels were significantly, but

loosely, negatively associated with mortality [40]. This is important to keep in mind,

because there is probably no direct relationship between bone/mineral-related endpoints and other, extra-skeletal (e.g. immunoregulatory, anti-infectious) effects of

vitamin D.



17.6



Conclusions



In CKD, as in other chronic conditions, vitamin D deficiency could act as an aggravating factor of immune dysregulation and inflammation. Since vitamin D supplementation is easy, unexpensive and well tolerated, it is of great interest to determine

whether it can translate into the correction of immunological abnormalities and ultimately into clinical benefit, e.g. the prevention of infections. Controlled trials are



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needed but one should not underestimate the difficulties pertaining due to the

selection of adequate at-risk populations, the definition of relevant and realistic outcomes, the numbers of participants necessary to reach a valid conclusion, and the

definition of the dosing and timing of vitamin D supplementation. The latter issue

should not be overlooked, because, there is no agreement on desirable target vitamin D levels when examining non-skeletal outcomes, and some effects of vitamin

D, particularly in the field of inflammation, might follow a “U” curve.

Studying the effects of vitamin D supplementation on especially relevant biological markers, in carefully designed trials, may still represent an unavoidable

intermediate step on the basis of current knowledge.



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Chapter 18



Vitamin D and Inflammation in Chronic

Kidney Disease

Javier Donate-Correa, Ernesto Martín-Núđez, and Juan F. Navarro-González



Abstract Vitamin D deficiency, defined by low serum levels of 25-hydroxyvitamin

D, is prevalent in patients with chronic kidney disease, a disorder characterized by

a state of chronic low-grade inflammation. This inflammatory state is especially

marked in end-stage renal disease and it has been disclosed as an important factor

contributing to the progression of renal disease and the high cardiovascular morbidity and mortality found in these patients. This chapter highlights clinical and experimental studies that could potentially explain the link between vitamin D and

inflammation. Whether correction of vitamin D deficiency and the associated

improvement of inflammatory markers has beneficial effects on cardiovascular outcomes should be investigated in controlled clinical trials.

Keywords Chronic kidney disease • Vitamin D • Inflammation • Vitamin D receptor • Cardiovascular disease • Inflammatory cytokines • RAAS • Vitamin D receptor

activators • Paricalcitol • Immunomodulation



18.1



Introduction



Inflammation is recognized as an important factor contributing to the progression of

chronic kidney disease (CKD) as well as a hallmark of the high cardiovascular (CV)

morbidity and mortality present in these patients. Vitamin D deficiency, defined by

low serum levels of 25-hydroxyvitamin D, is especially prevalent in CKD patients

who present a dysregulation of vitamin D and mineral metabolism [1].



J. Donate-Correa, PhD (*) • E. Martín-Núđez

Research Unit, University Hospital Nuestra Sora de Candelaria,

Santa Cruz de Tenerife, Spain

e-mail: jdonate@ull.es

J.F. Navarro-González, MD, PhD, FASN

Research Unit and Nephrology Service, University Hospital Nuestra Señora de Candelaria,

Santa Cruz de Tenerife, Spain

e-mail: jnavgon@gobiernodecanarias.org

© Springer International Publishing Switzerland 2016

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

DOI 10.1007/978-3-319-32507-1_18



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Vitamin D has important roles in many physiological processes although is

primarily involved in calcium and phosphorus homeostasis and bone metabolism.

However, beyond these regulatory capabilities, experimental and clinical data

suggest beneficial effects of vitamin D on proteinuria, blood pressure, inflammation, and cardiovascular outcomes. Different epidemiological studies have shown

an association between vitamin D deficiency with inflammatory disorders such as

rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematous,

while has been also considered as a risk factor for developing cancer, cardiovascular

disease, hypertension, and diabetes [2]. Importantly, in animal models for some of

these diseases, vitamin D supplementation has showed therapeutic effects [3].

The active form of vitamin D, also called calcitriol or 1-alpha,25-dihydroxyvitamin

D3 (1,25(OH)2D3) is primarily synthesized in the kidneys from 25(OH)D (calcidiol)

by the action of the enzyme 1α-hydroxylase. This active form binds posteriorly to

the vitamin D receptor (VDR) to exert its functions. However, there is increasing

evidence that the kidneys are not unique in its ability to generate calcitriol. Many

tissues possess 1α-hydroxylase activity, suggesting a paracrine role for 1,25(OH)2D3,

which is not well understood. However, in vitro experiments indicate that

1,25(OH)2D3 may be involved in diverse physiological functions, including regulation of cytokines, inflammatory and/or fibrotic pathways, the renin-angiotensinaldosterone system (RAAS), vascular and cardiac cell function, modulation of

immune response, cell growth and differentiation, and others [4–12].

The existence of this wide range of physiological actions is enhanced by the

ubiquitous distribution of the VDR in the human body (intestine, kidney, bone, parathyroid glands, immune system, smooth muscle, and myocardium),which is responsible for the pleiotropic effects of VDR activation [4].

Therefore, despite its classical actions in mineral metabolism homeostasis, vitamin D may play important roles on the cardiovascular system, systemic inflammation, oxidative stress, and immune regulation [13]. Importantly, epidemiological

studies suggest an inverse association between vitamin D levels and inflammatory

markers [14–16]. This chapter highlights clinical and experimental studies that

could potentially explain the link between vitamin D and inflammation in the renal

patient.



18.2



Inflammation in CKD Patients



Among the many complications of CKD that contribute to the high morbidity and

mortality observed in these patients, systemic low-grade inflammation has a

prominent role as one of the most typical features and major contributors to the

uremic phenotype in advanced stages of CKD. This chronic low-grade inflammation

is almost universally present in CKD patients and is fuelled by several independent

mechanisms, including accumulation of advanced glycation end products and

advanced oxidative protein products, enhanced lipid oxidation, elevation of

pro-inflammatory cytokine levels, and stimulated T-cells [17, 18]. Although the



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prevalence of inflammation is variable and depends of multiple factors like residual

renal function, geographic and genetic differences, and dialysis therapy [19], is particularly elevated in end stage renal disease (ESRD) patients, where inflammatory

cytokines are associated with higher all-cause and CV mortality [19–21].

Systemic inflammation in these patients is intrinsically linked not only to renal

dysfunction but also to other factors, including a state of acquired immune dysfunction, metabolic and nutritional derangements, and protein-energy wasting [22].

Inflammation is an underlying phenomenon in atherosclerosis and vascular disease,

and the inflammatory status strongly correlates with increased CV morbidity and

mortality. Recent evidence suggests that persistent inflammation is also a major

cause of premature general and vascular aging [23]. In addition, inflammation is

thought to play a major role in the pathophysiology and progression of renal dysfunction [24].

In these patients, C-reactive protein (CRP) and pro-inflammatory cytokines such

as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6 are elevated [19–21].

In a prospective study involving patients on hemodialysis (HD), Jung et al. [25]

used computed tomography imaging to demonstrate that elevated CRP was a strong

and independent predictor of progression of coronary artery calcification, even after

adjusting for baseline calcification. Likewise, Zocalli et al. demonstrated in this

population that IL-6 captures almost entirely the prediction power of the overall

inflammation burden, and therefore, IL-6 seems to be an almost ideal indicator of

the severity of inflammation [26]. Since inflammatory parameters are sensitive predictors of the outcomes, inflammation appears to be a logical target for preventive

and therapeutic interventions in patients with CKD [27, 28].

Many therapeutic strategies can be addressed for treating inflammation in renal

patients by targeting inflammatory pathways at different levels, including treating

the source of inflammation, changing lifestyle and nutritional habits, and implementing therapeutic strategies commonly used in these patients, which may induce

pleiotropic beneficial effects. From this point of view, therapy with vitamin D may

be considered as a common therapeutic approach in patients with CKD with additional positive impact on systemic inflammation.



18.3



Vitamin D in Cardiovascular Disease



There is increased recognition that vitamin D deficiency plays a role in the development of CV disease. In addition to regulating mineral metabolism homeostasis and

skeletal health, vitamin D plays important metabolic roles which are important for

renal and CV protection [29]. Observational studies in general population showed

that vitamin D deficiency is associated with classical CV risk factors [30] as well as

with clinical events such as congestive heart failure, coronary artery disease, peripheral artery disease, and stroke [31–33], an association that persists in prospective

studies [34–36]. Importantly, in one of this observational studies [37] it was shown

that low levels of circulating 25(OH)D were significantly correlated with two



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markers of inflammation (CRP and IL-6), suggesting a link between low vitamin D

levels and inflammation. Posteriorly, a study conducted in middle-aged and older

healthy volunteers [38] revealed that vascular endothelial cells from subjects with

25(OH)D deficiency showed increased expression levels of the inflammatory cytokine IL-6 and the pro-inflammatory transcription nuclear factor kappa B (NF-kB).

More recently, an inverse correlation between 25(OH)D and CRP and IL-6 levels

was described in 182 patients (ages 5–21) with CKD stages 2–5, an association that

remained significant after adjusting for the severity of CKD [39].

Animal studies point to vitamin D as an important regulator of the RAAS. In a

very interesting study, Xiang et al. [40] showed that VDR knockout mice shared

hypertension with cardiac hypertrophy and, importantly, up-regulation of the cardiac RAAS. In this model, 1,25(OH)2D3 acted as an endocrine suppressor of renin

biosynthesis. Conversely, treatment with VDR activators (VDRAs) like paricalcitol

attenuated the development of left ventricular hypertrophy (LVH) in Dahl saltsensitive [41] and uremic rats [42]. Likewise, amelioration of cardiac hypertrophy

and, cardiac remodeling, and an improvement of left ventricular diastolic measures

have been observed in uremic rats and in rats with spontaneous hypertension treated

with vitamin D analogs [43].

Clinical studies also point to the cardio-protective effects of vitamin D. HD

patients treated with intravenous calcitriol [44] or with oral cholecalciferol [45, 46]

shared reduced cardiac hypertrophy accompanied by a decrease in the levels of

inflammatory markers [45, 46]. Administration of cholecalciferol to ESRD patients

was found to reduce circulating IL-8, IL-6, and TNF-α levels by approximately

55 %, 30 %, and 60 %, respectively [47]. Similarly, one study showed that vitamin D

deficiency in HD patients who did not received therapy with vitamin D receptor

agonists was associated with an increased risk of all-cause mortality [48]. However,

in the recent multicenter double-blinded, randomized, placebo-controlled PRIMO

study, treatment with paricalcitol did not alter left ventricular mass index or improve

measures of diastolic dysfunction in patients with CKD [49]. Therefore, the impact

of vitamin D therapy on long-term outcomes in patients with CKD, and its potential

relationship with modulation of inflammation, needs to be evaluated in prospective

adequately designed and powered studies.



18.4



Mechanisms Linking Vitamin D and Inflammation



As discussed above, inflammation has been associated with vitamin D deficiency in

CKD patients. Several mechanisms have been recently proposed to explain this link.

The active form of the vitamin D generates biological responses both by regulating gene transcription (genomic responses) and by rapidly activating a variety of

signal transduction pathways (rapid responses). Vitamin D regulates the expression

of diverse genes in a variety of tissues. These genomic actions are mediated by the

VDR, a kind of nuclear receptor which, after heterodimerization with the retinoid X

receptor (RXR) to form the VDR/RXR/co-factor complex, interacts with specific



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3 Possible Role of Vitamin D Deficiency in the Immune Dysfunction of CKD

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