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5 Modifications of FGF23 and Calcitriol When the Glomerular Filtration Rate Declines

5 Modifications of FGF23 and Calcitriol When the Glomerular Filtration Rate Declines

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D. Prié

PTH exceeds the capacity of the kidney to eliminate phosphate. Subsequently

plasma phosphate concentration augments, aggravating FGF23 production that further decreases calcitriol levels and worsens secondary hyperparathyroidism. This

mechanism is supported by experimental data. In rats with CKD, injection of antibodies blocking the action of FGF23 induced a rapid and significant increase in

plasma calcitriol concentration, associated to a rise of calcium levels that reduces

PTH production. The consequence is a rise of plasma phosphate concentration and

the increase in vascular and tissue calcification and in mortality of the animals [38,

39]. In many but not all studies, a decline of αklotho expression paralleled the rise

of plasma FGF23 concentration. This additional aftermath may contribute to the

augmentation of FGF23 [40].

In summary during CKD, phosphate accumulation is the poison, FGF23 is the

antidote and the decrease in calcitriol and the secondary hyperparathyroidism, and

potentially the decrease in αklotho expression, are the side effects of the antidote.

Contributions of FGF23 and calcitriol to adverse outcomes in CKD.

High circulating FGF23 concentrations are associated with increased mortality

in CKD patients and have deleterious cardiac effects. Experimental studies showed

that at elevated concentration FGF23 could directly stimulate FGFR in the absence

of αklotho on cardiomyocytes, inducing heart hypertrophy, and alteration of cardiac

functions [41]. Low plasma vitamin D levels have been associated with similar

adverse cardiovascular outcomes in CKD patients. It is unclear if low calcitriol levels have deleterious effects on heart independently of FGF23 in CKD patients.

Studies assessing the effects of treatment with vitamin D analogs on cardiovascular

mortality or morbidity led to conflicting results in CKD patients before or during

dialysis. These discrepancies between studies could depend on the consequences of

vitamin D treatment on FGF23 and αklotho levels. We can hypothesize, on the basis

of the findings mentioned above, that beneficial impacts on survival could be

observed mainly in patients with no further increase in FGF23 plasma concentration

or with significant stimulation of αklotho expression. Indeed, many experimental

and observational data suggest that low levels of αklotho expression have deleterious consequences on heart function. The identification of parameters that could

predict a beneficial effect of vitamin D treatment would permit to target a subpopulation of CKD patients.

Low vitamin D or αklotho levels or high FGF23 plasma concentrations have

been also associated with susceptibility to infection, modifications of the immune

system, insulin resistance, or anemia. The relative weight of each factor when considered altogether has not yet been assessed in particular in CKD.


Perspectives for the Treatments of CKD Patients

Based on these findings several strategies can be proposed to control FGF23

and prevent secondary hyperparathyroidism. Treatment with calcitriol, or its

analogs, has been used for decades. Calcitriol is efficient to prevent secondary

10 Vitamin D and FGF23 in Chronic Kidney Disease


hyperparathyroidism however it also stimulates FGF23 production. The ideal calcitriol analog for the treatment of secondary hyperparathyroidism in CKD should

be able to stimulate intestinal calcium absorption and αklotho expression without

stimulating intestinal phosphate absorption and FGF23 production. Such an analog

has not been identified to date. A more promising possibility is blocking of FGF23

effect in patients on dialysis. In these patients the lack of calcitriol production by the

kidneys is very likely more due to FGF23 overproduction than to the destruction of

the renal parenchyma. By contrast to the situation before dialysis, FGF23 does not

participate anymore to phosphate elimination by the kidney in dialysis patients. In

this condition high FGF23 has deleterious consequences without beneficial effects.

Consequently the use of anti-FGF23 antibodies or FGFR antagonists in patients on

dialysis might be able to increase calcitriol production and reverse secondary hyperparathyroidism. Anti-FGF23 antibodies are already on trials in human with X-linked

hypophosphatemic rickets and are efficient to hinder FGF23 effects [42].

In non-dialysis CKD patients, diminishing FGF23 production to tackle low

plasma calcitriol concentration and secondary hyperparathyroidism might be

achieved by combining several approaches: decreasing intestinal phosphate absorption, preventing calcitriol-induced phosphate absorption in the intestine, increasing

phosphate excretion in urine. Phosphate binders have shown interesting but limited

results on plasma FGF23 and vitamin D concentrations on dialysis patients. This

might be due to the fact that any diminution in FGF23, following the reduction of

phosphate absorption, induces a slight increase in calcitriol secretion that stimulates

intestinal phosphate absorption that in turn triggers FGF23 production. Inhibitors of

the intestinal sodium-phosphate co-transporter could prevent the calcitriol-induced

increase of phosphate reabsorption in this context. Nicotinamide is already available and pharmacological inhibitors could be designed for use in human in a near

future. Inhibition of renal sodium- phosphate co-transporters can be also interesting.

The diminution of renal phosphate reabsorption could lower plasma FGF23 concentration and consequently stimulate calcitriol synthesis. Again the association to

molecules that inhibits intestinal sodium phosphate co-transporters would prevent a

subsequent increase in intestinal phosphate absorption. These inhibitors however

are not yet available for clinical use.


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D. Prié

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D. Prié

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Chapter 11

Wnt/Sclerostin and the Relation with Vitamin

D in Chronic Kidney Disease

Mugurel Apetrii and Adrian Covic

Abstract The skeleton, while strong, isn’t made of static tissue. It is a highly

dynamic organ that constantly undergoes changes and regeneration. A continuous

change is taking place, as osteoclasts degrade bone and osteoblasts rebuild new

bone. This ongoing skeletal adaptation is greatly influenced by the amount of

mechanical strain that the skeleton senses as a result of everyday movement and

physical activity. However, many burning questions were, at least until recently,

without an answer. In particular, was how does the skeleton “feel” mechanical strain

and maybe most importantly how does it turn this information into the act of making

more or less bone?

Keywords Bone • Osteoporosis • Sclerosteosis • Calcium • Phosphate • BMD

• Vascular calcification • Vitamin D • FGF23



The skeleton, while strong, isn’t made of static tissue. It is a highly dynamic organ

that constantly undergoes changes and regeneration. A continuous change is taking

place, as osteoclasts degrade bone and osteoblasts rebuild new bone. This ongoing

skeletal adaptation is greatly influenced by the amount of mechanical strain that the

skeleton senses as a result of everyday movement and physical activity. However,

many burning questions were, at least until recently, without an answer. In particular, was how does the skeleton “feel” mechanical strain and maybe most importantly how does it turn this information into the act of making more or less bone?

The answer to this question seems to be related to the nerve-like osteocyte network embedded throughout bone acting as a mechano sensor that allows the skeleton

M. Apetrii, MD, PhD (*)

Nephrology Unit, Dr CI Parhon University Hospital, Iasi, Romania

e-mail: mugurelu_1980@yahoo.com

A. Covic, MD, PhD, FRCP (London), FERA

Nephrology and Internal Medicine, University “Grigore T. Popa”, Iasi, Romania

e-mail: acccovic@gmail.com

© 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_11



M. Apetrii and A. Covic

to “feel” and respond to mechanical strain. This network produces a powerful and

cryptic inhibitory signal which most likely represents a master regulator of the skeleton. This master regulatory molecule, called sclerostin, is a glycoprotein (22 kDa)

product of the SOST gene, which is localized at chromosome region 17q 12-p21

[1]. Inactivating mutations of this gene lead to a rare genetic disease characterized

by high bone mass, namely sclerosteosis. The tremendous increase in bone mass

and bone mineral density (BMD) that is observed in these patients is similar to what

is seen in another autosomal recessive, inherited high bone mass disorder, Van

Buchem disease. In the Van Buchem disease SOST itself is not mutated; however,

there is a 52-kb deletion in the downstream region of the SOST gene that results in

the absence of postnatal sclerostin production. Thus, both sclerosteosis and Van

Buchem disease are causes by sclerostin deficiency, leading to the conclusion that

sclerostin must be a natural brake for bone formation, preventing the body from

making too much bone. When mechanical forces are applied to the bone, the osteocytes stop secreting sclerostin and bone formation is initiated on the bone surface.

Wnt/B-catenin signaling pathway is a critical regulator of skeletal development and

mass, working in part through the stimulation of Runx2 gene expression. Activation

of the canonical Wnt signaling involves the formation of a complex between Wnt

proteins, frizzled and low density lipoprotein receptor-related protein 5 (LRP5) or

LRP6 receptors. Osteocytes are the predominant cellular source of the Wnt antagonist

sclerostin, a limiting factor for osteoblast generation and bone mass accrual that mediates the homeostatic adaptation of bone to mechanical loading. Sclerostin is a negative

regulator of Wnt signaling. It binds to both LRP5 and LRP6 and prevents activation of

the Wnt receptor complex, resulting in inhibition of bone formation. In addition to

sclerostin, the DKK family members, particularly DKK-1 (Dickkopf-1), inhibit the

Wnt pathway by binding to the LPR-5/6 receptor. Wnt signaling can also be blocked

by other proteins, such as soluble frizzled-related protein, that bind to Wnt ligands.

Osteocytes effectively act as mechanoreceptors for bone formation, and sclerostin was shown to play a key role in the development of osteoporosis associated with

lack of mechanical stimulation, as observed in weightless astronauts or in patients

confined to bed for a long period of time. Most studies, in both the general and the

osteoporotic populations, sustain this hypothesis by reporting a positive association

between circulating sclerostin levels and bone mineral density (BMD).

Several clinical and biological variables have been described as determinants of

sclerostin secretion. Among the most important of them, age and CKD have been

found to be directly associated with increased circulating sclerostin concentrations,

whereas an inverse correlation has been observed between circulating sclerostin and

parathyroid hormone (PTH) levels and other bone biomarkers [2].


Sclerostin in CKD

In the setting of CKD, circulating sclerostin concentrations clearly increase as glomerular filtration rate (GFR) decreases reaching an almost four times higher serum

sclerostin level in predialysis patients with CKD stage V than in participants with


Wnt/Sclerostin and the Relation with Vitamin D in Chronic Kidney Disease


normal renal function [3]; whether this is due to reduced renal clearance, increased

skeletal production, or both is still a subject of debate. Recently, Cejka et al. showed

that excretion of sclerostin increases with declining renal function [4] thus invalidating the hypothesis that increasing serum levels of sclerostin in CKD patients are

related only to renal retention. The reason for increased circulating levels of sclerostin

is therefore linked to an increase in its production; this hypothesis has been also suggested by previous research of Sabbagh et al. using immunohistochemical staining of

sclerostin in bone biopsies from CKD patients [5]. Thus, in an experimental study of

mice experiencing progressive CKD, the repression of the Wnt/b-catenin pathway and

its inhibitor sclerostin was associated with increased osteoclast activity and repression

of bone formation suggesting a possible implication in pathogenesis of renal osteodystrophy [5]. However, the exact underlying mechanism of increased production of

sclerostin in CKD is still a matter of debate. It has been suggested that PTH, which is

a known repressor of SOST gene expression and an inhibitor of sclerostin production

in normal situations [6] might have a role. Indeed, it is well known that uremia is

associated with a renal and skeletal resistance to the actions of PTH [7], which may in

some extent be related to the increased production of sclerostin in CKD patients. This

finding may open new possible therapeutic strategies in which anti-sclerostin antibodies which are currently in development [8], might ameliorate bone formation rates

especially in elderly osteoporotic subjects with some degree of renal impairment.

However, the PTH-sclerostin correlation is not consistent through all the studies.

Thus, Kanbay et al. suggest a possible role of other factors including phosphorus

and FGF23 in the regulation of sclerostin through a PTH-independent mechanism

in CKD patients treated by hemodialysis (HD) [9]. Moreover, sclerostin at least

partly regulates bone matrix mineralization through a signaling pathway involving

phosphate regulators—the phosphate regulating neutral endopeptidase on chromosome X (PHEX) and the matrix extracellular phosphoglycoprotein (MEPE) axis

[10]. However, the mechanism underlying the positive association between serum

sclerostin levels and serum phosphate levels remains unclear. They seem to interact

via another phosphate regulator like FGF23, PHEX or MEPE and thus regulating

bone turnover, bone mineralization, and renal mineral homeostasis [10, 11].

In peritoneal dialysis patients, as in HD patients, there is also a higher than normal serum level of sclerostin which is inversely correlated with the degree of bone

formation rate [12]. According to the KDIGO (Kidney Disease Improving Global

Outcome) guidelines [13] and other studies [12], the most frequent pattern of renal

osteodystrophy in PD is characterized by a low bone turnover, with the leading

entity being adynamic bone disease. Sclerostin is therefore one potential “actor”

that may play a role in the pathophysiology of adynamic bone disease.

In renal transplanted patients, sclerostin acknowledge a rapid decrease to normal

or even subnormal values shortly after transplantation in contrast with the persistent

elevation of PTH and FGF23 [14]. This decrease of sclerostin is probably due to the

improvement of renal function, increased physical activity and use of glucocorticoids. Subsequently, in the first year after renal transplantation there is a gradual

increase in serum sclerostin levels towards normal values; this rise is not influenced

by the GFR, but paralleled the reduction of PTH and the normalization of serum

calcium, phosphate and vitamin D concentrations [14].


M. Apetrii and A. Covic

Although preliminary data suggest that sclerostin may be a promising biomarker

in assessing bone health in CKD patients, it is not clear whether it has any added

value compared with existing bone biomarkers in predicting bone turnover and/or

BMD. Its clinical utility in determining hard clinical end points such as fracture is

unknown. Indeed, given that global bone strength is determined both by qualitative

changes in bone (for instance, mineralization and turnover) and by quantitative

changes in bone volume and density it is perhaps unrealistic to expect a single biomarker to predict such outcomes. Therefore the biological significance and interpretation of circulating sclerostin levels in CKD remain uncertain.


Sclerostin and Vascular Calcification in CKD

Vascular calcifications (VCs) are recognized as a strong predictor of all-cause and

cardiovascular mortality in CKD patients [15]. The discovery of CKD bone-vascular

axis, addressing the complex interactions between bone and vessel which share

similar underlying mechanisms, let bone turnover inhibitors emerge as potential

risk factors for VC. More recently, attention has focused on sclerostin, a novel candidate for the bone-vascular axis.

Vascular smooth muscles cells undergo osteo/chondrogenic transdifferentiation

in a pro-calcifying environment. In the late phase of VC, sclerostin is expressed.

This can be interpreted as a defensive response that aims to block the Wnt pathway

in order to reduce the mineralization in the vascular tissue. Sclerostin may spill over

to the circulation and may reciprocally inhibit bone metabolism [16].

Several studies report a positive association between sclerostin and VC [15, 17]

(Table 11.1); furthermore, expression of sclerostin has also been demonstrated in

the vascular wall, in the calcification site [18]. However, once again other authors

reported discordant results describing an inverse correlation between sclerostin and

VC. Thus, in a cohort of hemodialyzed patients, those with more severe aortic calcifications had significantly lower serum sclerostin levels. In addition, low levels of

sclerostin remained a significant predictor of cardiovascular outcome even after

adjusting for age and gender, suggesting that Wnt/β-catenin signaling plays an additional role in uremic VC beyond aging [19].


Sclerostin and Mortality in CKD

Even if experimental and clinical studies suggest that the Wnt pathway may also

play a role in atherosclerosis and vascular calcification, the association between

sclerostin and mortality in CKD patients remains so far inconsistent (Table 11.2).

In a post-hoc analysis in 100 prevalent HD patients, Viaene et al. [16], found a

positive association between higher circulating sclerostin levels (defined as values

superior to the median) and survival after a median follow-up time of 637 days.


Wnt/Sclerostin and the Relation with Vitamin D in Chronic Kidney Disease


Table 11.1 Association between sclerostin with vascular calcification

Trial, (year)

Qureshi et al.

(2015) [31]




Claes et al.

(2013) [32]



Desjardins et al.

(2014) [33]

Balci et al.

(2015) [34]

CKD stages


Prevalent HD

Yang et al.

(2015) [19]

Prevaent HD

Pelletier et al.

(2015) [35]

Prevalent HD

Kim et al.

(2011) [36]

Prevalent HD

Delanaye et al.

(2014) [21]

Prevalent HD

Scl as independent determinant in vascular calcification


(Higher sclerostin levels were found with epigastric and

coronary artery calcification)


(Patients with aortic calcifications had higher sclerostin

levels, but in multivariate analysis, the association became




(Sclerostin level was significantly important in AVF

calcification but it was not independent predictor of AVF



(Lower sclerostin levels were associated with the severity of

aortic calcification)


(Serum sclerostin was associated with a 33 % increase of

severe AAC risk for each 0.1 ng/ml rise in serum sclerostin,

p < 0.001)


(Sclerostin and FGF-23 were independently associated with



(The clinical interest of sclerostin to assess vascular

calcifications in HD is limited, no association between

sclerostin and calcification score in the univariate analysis,

but association became significant and negative in the

multivariate model)

The authors link this survival benefit to the possible attenuation of the progression

of VC in the setting of high sclerostin [16]. However, within a fully adjusted model

including bone-specific alkaline phosphatase the association between survival and

sclerostin lost statistical significance [16]. In the same line, a very recent prospective study, from The (Netherlands) (the NECOSAD cohort), Drechsler et al. found

that high or intermediate levels of circulating sclerostin were strongly associated

with lower risk factor for future all-cause and cardiovascular mortality in 637 incident dialysis patients, particularly in the short term follow-up (18 months) [20].

The results were quite impressive, cardiovascular mortality being 70 % lower in

patients of the highest tertile of sclerostin within 18 months when compared with

patients of the lowest tertile. In addition, compared with Viaene et al. study, these

results remained consistent even in the fully adjusted model. In contrast with the

results previously reported, our group [9] found in 173 non-dialyzed patients with

CKD stages 3–5 that higher sclerostin values were associated with fatal and nonfatal cardiovascular events after a mean follow-up of 26 months even after multiple


et al. (2014)


Kanbay et al.

(2014) [9]


et al. (2015)


Nowak et al.

(2015) [22]

Trial, (year)


et al. (2014)


Viaene et al.

(2013) [16]















68 ± 14




67 ± 12



63 ± 14

68 ± 13






42 ± 19




CKD (2–5

including 5D)


(93 %)

Peritoneal dialysis

(7 %)

CKD (nondialysis)



Renal status and

dialysis duration,



829 days

26 months

4 years

1461 days

637 days

Follow up


10 years

Table 11.2 Studies reporting the correlation between circulating sclerostin levels and mortality






Scl as


determinant in

CV events







Scl as


determinant in

CV mortality







Scl as


determinant in





M. Apetrii and A. Covic

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