EDITORIAL

Editorial over the Many Faces of Vitamin D in Chronic Kidney

Disease: from Mineral to Immune-Inflammatory Modulator

Patrick M. Honore

1,2

and Herbert D. Spapen

Vitamin D (vit D), whether produced in the skin or

absorbed from the diet, is first metabolized in the liver to

generate 25-hydroxyvitamin D (25OHD) and then hydrox-

ylated in the proximal renal tubule to 1,25-

dihydroxyvitamin D (1,25(OH)

D). 1,25(OH)

(calcitriol) is the major biologically active metabolite and

serves a paracrine/autocrine function. 1,25(OH)

Dformsa

complex with the vit D nuclear receptor which binds to vit

D response elements in the deoxyribonucleic acid (DNA).

Thousands of these binding sites regulate hundreds of

genes creating a multitude of genomic effects that modu-

late cell activation, proliferation, and differentiation within

the immune-inflammatory system [1]. This underpins the

biological rationale for a potential beneficial partnership of

vit D in a variety of immune-inflammatory conditions that

largely transcends its undisputed regulator y role in

calcium/phosphate homeostasis and bone mineralization

[2, 3].

Chronic kidney disease (CKD) is an intricate pathol-

ogy characterized by a state of accelerated cardiovascular

deterioration. Persistent inflammation has been recognized

as an important component of CKD a nd may in part

account for cardiovascular and all-cause mortality [4].

Low levels of both 25OHD and 1,25(OH)

D are observed

in patients with CKD and are associated with higher mor-

tality and faster progression of kidney disease [5]. In a

recent issue of Inflammation, Zhao et al. showed that

calcitriol significantly reduced tubulo-interstitial inflam-

mation in a rodent renal injury model [6]. The authors

linked this renoprotective effect to calcitriol-induced up-

regulation of zinc finger protein A20, a de-ubiquitinating

enzyme which causes disruption of nuclear factor kappa B

(NF-κB) dependent intracellular chemo- and cytokine pro-

duction and suppresses apoptotic pathways [7].

Whether this novel compelling insight into the cellu-

lar mechanism of action of vit D may change the current or

future therapeutic approach of CKD is uncertain. Factors

contributing to the progression of CKD are indeed not

limited to perturbed mineral metabolism, chronic inflam-

mation, and oxidative stress but also include protein-

energy wasting, pre-existing heart failure, arterial hyper-

tension, iron deficiency, and dialysis-related injury [8].

Patients with CKD often present a “leaky gut” and/or

profound alterations in gut microbial flora. Increased gut

wall permeability promotes translocation of bacteria and

endotoxin which continuously fuels an inflammatory state.

Changes in the intestinal microbiome are highly deter-

mined by intraluminal influx of urea, dietary constituents,

and occasional antimicrobial therapy [8, 9]. Of note is that

both intestinal leakage and microbial environment show

large interpatient variability and cannot be quantified. In

addition, accumulation of protein-bound toxins (e.g.,p-

cresyl sulfate and indoxyl sulfate) [10] and altered mucosal

defense mechanisms may also contribute to cardiovascular

events and sustain inflammation.

Despite robust in vitro arguments to support the

renoprotect ive potential of vit D su pplemen tation in

CKD, hard clinical outcome data are lacking. A meta-

analysis of randomized controlled trials showed that treat-

ment with paricalcitol, a selective activator of the vit D

receptor promoting sequestration of NF-κBsignaling[11],

lowered the risk of cardiovascular events in CKD patients

but failed to reduce proteinuria and to protect renal function

[12]. Vit D therapy neither improved vascular endothelial

function nor attenuated inflammation in patients with CKD

treated either with cholecalciferol or calcitriol for 6 months

[13]. Likely explanations of these negative outcomes are

ICU Department, Universitair Ziekenhuis Brussels, Vrije Universiteit

Brussel, 101 Laarbeeklaan, 1090 Brussels, Jette, Belgium

To whom correspondence should be addressed at ICU Department,

Universitair Ziekenhuis Brussels, Vrije Universiteit Brussel, 101

Laarbeeklaan, 1090 Brussels, Jette, Belgium. E-mail:

Patrick.Honore@az.vub.ac.be

0360-3997/17/0000-0001/0

2017 Springer Science+Business Media, LLC, part of Springer Nature

Inflammation (

2017)

DOI: 10.1007/s10753-017-0707-1

the use of different vit D dose regimens, attempted corre-

lations with 25OHD instead of active hormone plasma

levels, the effect of renal replacement therapy, and the

possible impact of other pathophysiological pathways that

are related with vit D. Among the latter, the renin-

angiotensin-aldosterone system (RAAS) stands out as a

crucial regulator of intravascular volume and blood pres-

sure in CKD. Calcitriol modulates the RAAS system by

suppressing renin gene and angiotensin-converting en-

zyme expression [14, 15]. Blocking RAAS with

angiotensin-converting enzyme inhibitors or angiotensin

receptor blockers controls arterial hypertension, reduces

proteinuria, and prevents or reverses endothelial dysfunc-

tion and atherosclerosis in patients with CKD [16].

Endothelin (ET)-1-induced signaling pathways in vascular

smooth muscle cells represent another attractive target for

improving cardiovascular morbidity in CKD. ET type A

receptor blockade reduced vascular inflammation and

smooth muscle cell differentiation in rats with CKD [17].

In experimental CKD models, the combination of RAAS

inhibition with ET receptor antagonism ameliorated pro-

teinuria, renal structural changes, and molecular markers of

glomerulosclerosis, renal fibrosis, or inflammation more

effectively than RAAS inhibitors or ET receptor antago-

nists alone [18].

Taken together, the findings of Zhao et al. confirm the

immune-inflammatory modulating capacity of vit D and

expand the molecular basis to further explore its therapeu-

tic potential in CKD. However, whether unveiling the role

of A20 in calcitriol’s renoprotection will lead to more

effective treatment remains to be proven.

Authors’ Contributions PMH and HDS designed and

wrote the paper. Both authors agree with the last version.

COMPLIANCE WITH ETHICAL STANDARDS

Conflict of Interest. The authors declare that they have

no competing interests.

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Many Faces of Vitamin D in Chronic Kidney Disease