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5 Modifications of FGF23 and Calcitriol When the Glomerular Filtration Rate Declines
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 .
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 . 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 .
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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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
A. Covic, MD, PhD, FRCP (London), FERA
Nephrology and Internal Medicine, University “Grigore T. Popa”, Iasi, Romania
© Springer International Publishing Switzerland 2016
P.A. Ureña Torres et al. (eds.), Vitamin D in Chronic Kidney Disease,
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
. 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 .
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 ; 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  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 . 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 . 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  might have a role. Indeed, it is well known that uremia is
associated with a renal and skeletal resistance to the actions of PTH , 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 , 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) . 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
. 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 . According to the KDIGO (Kidney Disease Improving Global
Outcome) guidelines  and other studies , 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 . 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 .
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 . 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 .
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 . 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 .
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. , 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
Qureshi et al.
Claes et al.
Desjardins et al.
Balci et al.
Yang et al.
Pelletier et al.
Kim et al.
Delanaye et al.
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
(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
The authors link this survival benefit to the possible attenuation of the progression
of VC in the setting of high sclerostin . However, within a fully adjusted model
including bone-specific alkaline phosphatase the association between survival and
sclerostin lost statistical significance . 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) .
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  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.
et al. (2015)
Nowak et al.
et al. (2014)
Viaene et al.
68 ± 14
67 ± 12
63 ± 14
68 ± 13
42 ± 19
Renal status and
Table 11.2 Studies reporting the correlation between circulating sclerostin levels and mortality
M. Apetrii and A. Covic