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5 Systemic and Indirect Effects of Vitamin D on Vascular Calcification

5 Systemic and Indirect Effects of Vitamin D on Vascular Calcification

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predictive of death [86]. Recently, the upregulation of mitogen-activated protein

kinase phosphatase-1 by vitamin D was identified as a novel pathway by which

vitamin D inhibits lipopolysaccharide (LPS)-induced p38 activation and cytokine

production by monocytes and macrophages [87]. In accordance with this observation, treatment with vitamin D and its analogues was shown to lower serum levels

of CRP, TNF-α, IL-1β and IL-6 in haemodialysis patients [88–91]. As discussed

above, TNF-α is a strong inducer of Pi-induced VSMCs calcification and is also

involved in the onset of valve myofibroblast calcification. In addition to the direct

protective effect of calcitriol on the TNF-α-induced osteogenic transition in VSMCs,

VDRAs are known to act in a paracrine manner to promote a pro-calcific to anticalcific phenotypic transition in macrophages. The latter phenotype is characterized

by low production of TNF-α and elevated levels of osteopontin (an inhibitor of calcification), which strongly reduces the VSMC calcification induced by co-culture

with macrophages [92]. IL-1β was shown to promote MMP expression in calcific

aortic valve stenosis [93]. Furthermore, mice lacking the IL-1β inhibitor IL-1Ra

were shown to develop aortic stenosis and proximalis calcification [94]. IL-6 is a

strong inducer of RANKL, and vice versa [95]. Neutralization of IL-6 reversed the

RANKL-dependent regulation of osteopontin, runx2 and BMP2 in cultured VSMCs

isolated from ApoE–/– OPG–/– mice [95]. In cultured human VICs, high Pi was associated with greater IL-6 secretion [96]. Pi-induced mineralization was strongly

dependent on IL-6 expression in the latter study, since IL-6 blockade by siRNA

decreased VICs calcification. Indeed, IL-6 increased the expression of osteoblastic

genes (including runx2 and osteopontin) in cultured human VICs. Thus, by modulating the vascular response to inflammation, vitamin D sterols might interfere with

vascular calcification. To address this question, Guerrero et al. evaluated the impact

of vitamin D supplementation on systemic inflammation and the resulting vascular

calcification in uraemic rats fed with high-phosphorus diet. Treatment with LPS

increased plasma levels of TNF-α, monocyte chemotactic protein-1 and

interleukin-1α, and induced calcification. Concomitant treatment with paricalcitol

resulted in more marked anti-inflammatory effects than treatment with calcitriol. In

contrast to calcitriol, paricalcitol prevented vascular calcification [77]. These results

demonstrate that the potential anti-inflammatory effects associated with vitamin D

supplementation might interfere with the process of cardiovascular calcification and

therefore should not be neglected. Furthermore, they demonstrate that supplementation with various vitamin D analogues may affect vascular calcification to differing

extents.

The phosphaturic hormone FGF23 and its co-factor klotho have an essential role

in the control of phosphate and vitamin D metabolism. The klotho/FGF receptor-1

complex forms a specific receptor for FGF-23 signalling and mediates (in part)

FGF-23’s action [97]. In CKD, circulating levels of FGF23 increase dramatically as

renal function decreases, whereas tissue levels of klotho decline. Since klothodeficient mice and FGF23-null mice were shown to exhibit soft tissue calcification,

some researchers have suggested that dysregulation of the FGF23–klotho axis may

impact the progression of vascular calcification [98]. FGF23’s putative direct effect



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on VSMCs calcification is still subject to debate, since the hormone was shown to

induce or, in contrast, inhibit VSMCs calcification in different models [99, 100].

Uraemic, transgenic mice overexpressing klotho had greater phosphaturia, better

renal function and much less calcification than wild-type mice with CKD. This

klotho – associated reduction in vascular calcification might result from (i) a better

control of renal function and serum phosphate and also (ii) a local protective effect,

since klotho has been shown to suppress high-Pi-induced VSMCs mineralization

and the osteogenic transition in vitro [101]. VDRAs were shown to stimulate FGF23 and klotho production through the action of 1,25D-VDR/RXR on VDREs. In

VDR knock-out mice, circulating levels of FGF-23 decreased more than klotho

levels – suggesting that the production of FGF23 depends more tightly than klotho

production on VDR activation [102]. Under calcifying conditions, VDR activation

was shown to raise klotho levels and restore the VSMCs’ responsiveness to FGF23’s inhibitory effects on calcification [99]. Intraperitoneal injection of VDRAs in

CKD mice fed with a high-Pi diet was shown to increase serum and urinary levels

of klotho. These effects were associated with an increase in vascular osteopontin

expression and a decrease in aortic calcification [47].

Chronic stress factors (including pro-inflammatory TNF-α, dysregulated mineral

levels, and uraemia) drive arterial klotho deficiency, which in turn is associated with

the osteogenic transition of VSMCs [99]. Given that (i) pro-inflammatory factors

were shown to be partly responsible for CKD-driven klotho deficiency and (ii) calcitriol reduces inflammation [90, 91], we cannot rule out the possibility that the

calcitriol-driven restoration of serum and vascular klotho levels is also due to calcitriol’s anti-inflammatory effects.

To distinguish between local and systemic effects of calcitriol, Lomashvili et al.

grafted wild type mice with aorta from VDR knock-out mice or other wild-type

mice, and then induced uraemia by feeding the animals on a high-adenine diet

[103]. The researchers did not observe any intergroup differences in aorta calcification – suggesting that indirect effects of VDRAs are essential for modulating vascular calcification. However, the respective involvements of direct and indirect effects

of VDRAs have not been established.



21.6



Conclusions



The link between vitamin D status and cardiovascular calcification is complex, in

view of (i) the dual local and systemic effects of vitamin D products (Fig. 21.1) and

(ii) the U-shaped relationship between the dose of vitamin D and cardiovascular

calcification (Fig. 21.1). This complexity has major repercussions on the choice and

monitoring of the dose of vitamin D prescribed to prevent and/or treat cardiovascular calcification in CKD. Future research into the role of vitamin D in cardiovascular

calcification must take account of local vs. systemic effects and the U-shaped

response curve.



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Chapter 22



Calciphylaxis and Vitamin D

Vincent M. Brandenburg and Pablo A. Ureña Torres



Abstract Calciphylaxis (calcific uremic arteriolopathy, CUA) is a rare disease that

typically occurs in chronic dialysis patients. Clinically CUA is characterized by the

stepwise development of superficial painful sensations and cutaneous lesions similar to livedo reticularis. Skin necrosis and ulceration represent the full-blown, “late”

clinical picture. The aetiology of CUA is incompletely understood. Disturbances in

bone and mineral metabolism as frequently seen in dialysis patients presumably

play a role. Previous treatment with vitamin K antagonists for oral anticoagulation

therapy is considered as a triggering and risk factor. Unfortunately, evidence-based

therapeutic options are absent, since controlled treatment trials have not been conducted yet. Treatment strategies should aim at pain relief, wound care, and minimizing pro-calcifying factors. In the absence of controlled prospective trials registry

studies such as the German CUA registry (www.calciphylaxis.net) are valuable

tools in order to increase our understanding of the disease.

Keywords Calciphylaxis • Dialysis • Mortality • Calcitriol • Hyperparathyroidism •

Sodium thiosulfate • Vitamin K antagonist



22.1



Introduction



Calciphylaxis (Calcific uremic arteriolopathy) is a rare disease primarily affecting

patients on chronic hemodialysis. Exceptionally, patients without severe kidney

disease are affected. Only rough estimates can be made upon the true incidence and

prevalence of CUA in nephrology patient cohorts and no reliable statement can be

V.M. Brandenburg (*)

Department of Cardiology and Center for Rare Diseases (ZSEA),

RWTH University Hospital Aachen, Aachen, Germany

e-mail: vmbrandenburg@aol.com; Vincent.Brandenburg@post.rwth-aachen.de

P.A. Ureña Torres, MD, PhD

Ramsay-Générale de Santé, Service de Néphrologie et Dialyse, Clinique du Landy,

Saint Ouen, France

Department of Renal Physiology, Necker Hospital, University of Paris V, René Descartes,

Paris, France

© Springer International Publishing Switzerland 2016

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

DOI 10.1007/978-3-319-32507-1_22



379



380



V.M. Brandenburg and P.A. Ureña Torres



made if these figures are changing over time. The diagnosis of CUA might be overlooked in patients with mild or abortive disease. Recent data from the US point

towards an increase in incidence [1]. However, such speculations need to take into

account the phenomenon of a potential pseudo-increase in incidence based on better

awareness of the disease or changes in medical coding systems. Based on our experience from the German calciphylaxis registry we cannot confirm changes in incidence over time since our registry records a stable rate of 25–35 de novo CUA

patients per year in Germany (2007–2014). This translates into low incidence figures clearly below those previously reported which exceeded one percent in dialysis

patients [2]. Overall, calciphylaxis qualifies as a truly rare disease and is officially

acknowledged (Orphanet number ORPHA280062).



22.2



Historical Perspective



Based on Hans Selye’s (1907–1982) early work in the 1960s he coined the term

calciphylaxis which then first appeared in human medicine. Selye’s basal concept

about the pathophysiology of calciphylaxis is not without obvious discrepancies to

what we consider typical in CUA development nowadays. Selye’s rodent experiments did not induce small-artery or arteriolar calcifications, although extensive

soft-tissue calcifications were present. Nevertheless, Selye’s theory is still very useful to concisely summarize our growing understanding about CUA [3]: CUA development obviously requires chronically disturbed background conditions, i.e. the

breeding ground in the sense of Selye’s “sensitization” factors. Chronic disturbances

in mineral metabolism homeostasis (e.g. hyperparathyroidism) qualify as such

latent sensitization factors. These factors need to be present for a certain latency or

critical period, but CUA requires the occurrence of a final trigger or a second hit –

according to Selye a “challenging” factor. Based on this theory, only the coincidence of sensitization plus challenging factor can provoke the outbreak of the full

blown disease. Chronic kidney disease (CKD) or end-stage renal disease (ESRD)

apparently qualify as a sensitization factor: CKD/ESRD is present in more than

90 % of all cases of calciphylaxis, both go along with disturbances in bone and mineral metabolism as well as with a chronic inflammatory state thus preparing the field

for the second hit. But what exactly is the “second hit”? This issue is still unsolved

and a matter of ongoing research.

CUA is not just part of the extra-osseous calcification continuum which characterizes patients with CKD/ESRD. It is noteworthy that virtually all long-term ESRD

patients present with some degree of arterial calcification (both arteriosclerotic and

atherosclerotic), calcific valvular disease and/or other forms of soft tissue calcifications. In sharp contrast, CUA, however, is not such a highly prevalent, creeping,

slowly evolving condition – it is a more dichotomic event (i.e. present or absent).

This aspect also indirectly supports the two-hit theory with some kind of acute

injury as necessary additional trigger.



22 Calciphylaxis and Vitamin D



381



Severely impaired prognosis for CUA patients in terms of survival [4] plus a

dramatically reduced quality of life [5] together with a high expenditure for the

health system (e.g. due to long-term hospitalizations) clearly deserve our attention

as caregivers and scientists in charge. Mortality rates among calciphylaxis patients

were noted to be 2.5–3 times higher than average mortality rates for chronic hemodialysis patients [1].



22.3



The Clinical Picture of Calciphylaxis



The clinical picture of calciphylaxis exhibits some unique features. In many cases

CUA presents with a mixture of large retiform ulceration with thick eschar surrounded by violaceous, indurated, tender, retiform plaques (Fig. 22.1). Some early

or minor forms present like livedo reticularis (Fig. 22.2) or even as single indurated

plaque. The latter may also occur as milder forms of CUA especially at the extremities (Fig. 22.3). Large, deep fat tissue ulcerations typical for the proximal form are

associated with a particularly poor prognosis. Septicemia is a formidable consequence of ulcerative calciphylaxis. However, such ulcerations may also occur in the

distal form of CUA. Superficial, often burning pain is virtually always part of the

initial clinical picture with zoster neuralgia being a typical differential diagnosis.

Therefore, pain management constitutes an integral part of adjunctive therapy in

CUA patients [6]. On palpation, skin and soft tissue surrounding the necrotic areas

often have a characteristic plaque-like hardening not seen in other forms of gangrene. There is a central form of calciphylaxis seen mainly at the trunk and the

upper legs in obese patients which can be separated clinically from a more distal

form, predominantly at the lower legs [5]. It remains unclear if these two forms are

distinct but, local factors in adipose tissue such as inflammation or tissue hypoxia

most likely contribute, particularly to the central form. The distal form appears to

have a milder course with lower mortality rates [6].



Fig. 22.1 Right leg: large

retiform ulceration with

thick eschar surrounded by

violaceous, indurated,

tender, retiform plaques



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