FGF23 and mineral metabolism, implications in CKD-MBD

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275
http://www.revistanefrologia.com
© 2012 Revista Nefrología. Órgano Oficial de la Sociedad Española de Nefrología
FGF23 and mineral metabolism, implications
in CKD-MBD
Mariano Rodríguez
1
, Ignacio López
2
, Juan Muñoz
1
, Escolástico Aguilera-Tejero
2
,
Yolanda Almaden
1
1
Servicio de Nefrología. Hospital Universitario Reina Sofía, REDINREN, IMIBIC. Córdoba
2
Departamento de Medicina y Cirugía. Facultad de Veterinaria. Córdoba
Nefrologia 2012;32(3):275-8
doi:10.3265/Nefrologia.pre2012.Mar.11415
Correspondence: Mariano Rodríguez
Servicio de Nefrología.
Hospital Universitario Reina Sofía. REDINREN, IMIBIC, Córdoba.
juanm.rodriguez.sspa@juntadeandalucia.es
T
he regulation of mineral metabolism is achieved trough
a complex interaction of hormonal factors and target
organs. Before the discovery of FGF23 we believed
that the regulation of serum calcium and phosphate was main-
ly the result of changes in PTH and vitamin D acting on bone,
kidneys and intestine. Parathyroids and kidneys were respon-
sible for the production of PTH and 1,25(OH)2D3 respective-
ly. Presently we know that FGF23 is produced by bone so the
bone is not longer just a target organ but an active endocrine
organ that participate in the regulation of mineral metabolism
by sending signals through FGF23. Nephrologists are
knowledgeable about the regulation of calcium and phos-
phate otherwise it is difficult to understand and manage the
disturbances of mineral metabolism that are always present
in patients with CKD. Changes in mineral metabolism in
CKD are now described as chronic kidney disease-mineral
and bone disorders (CKD-MBD).
1
The pathology derived
from CKD-MBD includes not only bone abnormalities but
cardiovascular disease with a devastating prevalence of vas-
cular calcification. The severity of CKD –MBD is associated
with increased mortality in CKD patients.
THE REGULATION OF SERUM PHOSPHATE
The regulation of calcium and phosphate was only partially un-
derstood until the discovery of FGF23. FGF23 increases phos-
phaturia a reduces the production of 1,25(OH)2D3 (Figure 1).
Let’s think in a situation of hypocalcemia; the parathyroids re-
spond promptly to a decrease in serum calcium, elevated PTH
acts on bone to increase the exit of calcium, but the calcium re-
lease from bone is also accompanied by the release of phos-
phate. The PTH acts also in kidneys increasing the tubular re-
absorption of calcium so the calcium released by bone is kept
in the extracellular space. The PTH produces phosphaturia so
the phosphate released by bone does not build up in the extra-
cellular space. This may not be sufficient to bring the calcium
up to normal, therefore the elevated PTH stimulatesrenal pro-
duction of 1,25(OH)2D3 which in turn stimulates intestinal
calcium absorption. This regulatory system appears to be ade-
quate to control serum calcium, however 1,25(OH)2D3 not
only increase gut absorption of calcium but also the absorption
of phosphate. It does not seem logical that a synchronized hor-
monal response to correct hypocalcemia had to be concluded
with an excess of phosphate. FGF23 modulates the production
of 1,25(OH)2D3 and the accumulation phosphate. Both high
phosphate and 1,25(OH)2D3 stimulate the production of
FGF23 which feeds back on the production of1,25(OH)2D3
and induces phosphaturia. Thus the presence of FGF23 enables
the system to restore the serum calcium without the trouble of
phosphate accumulation (Figure 2).
PRODUCTION AND ACTIONS OF FGF23
FGF23 is a 32-kDa (251 amino acid) protein produced by os-
teocytes and osteoblasts which makes the bone an endocrine
organ that communicates with other organs involved in miner-
al homeostasis. FGF23 acts on its receptor complex, klotho-
FGFR1, in the kidney to cause phosphaturia and to decrease
calcitriol synthesis.
2-5
FGF23 induces phosphaturia by sup-
pressing the expression ofthe Na-Pi cotransporters 2a and 2c
in the brush border of renal proximal tubules. FGF23 suppress-
es renal production of 1,25(OH)2D3 by inhibiting 1α-hydrox-
ylase (CYP27B1) activity which produces 1,25(OH)2D3 from
25(OH)D and also by increasing 24-hydroxylase activity
which inactivates the 1,25(OH)2D3.
3,6
Therefore the lack of
FGF23, as in the FGF23 null mouse (FGF23
-/-
) causes hyper-
phosphatemia and high levels of 1,25(OH)2D3 a situation
that produces extraosseous calcification.
7
The endocrine ac-
tion of FGF23 is dependent upon its binding and activation
of the klotho-FGFR1 complex,
5
therefore the absence of
klotho as in the klotho
-/-
mouse produces a phenotype similar to
the FGF23
-/-
mouse, elevation of phosphate and 1,25(OH)2D3

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Mariano Rodríguez et al. FGF23 in CKD-MBD
Nefrologia 2012;32(3):275-8
together with calcifications. We should be aware that these
FGF23
-/-
rodents are teaching us what has been clinically evi-
dent in uremic patient: excessive doses of Calcitriol in com-
bination with hyperphosphatemia carries the risk of calcifi-
cation.
FGF23 production by osteoblasts and osteocytes is stimulated
by high dietary intake of phosphate however the mechanisms
at the cellular level are unknown.
8
Experiments have failed to
show a direct effect of high extracellular phosphate concentra-
tion on FGF23 expression by bone cells.
8
The stimulation of
FGF23 production by 1,25(OH)2D3 is well defined. Liu S et
al.
9
showed that 1,25(OH)2D3 up regulates FGF23 expression
by acting on VDR response elements of the FGF23 promoter.
Interestingly Carrillo et al.
10
have shown thatestrogens direct-
ly stimulate the production of FGF23.
THE INTERRELATIONSHIP FGF23-PTH
Parathyroid tissue expresses a significant amount of klotho
11
and
FGF23 receptor. Thus it was reasonable to anticipate an effect
of FGF23 on the parathyroids. FGF23 acts on the parathyroid
FGF-Klotho complex
12
causing activation ofthe MAPK path-
way through ERK1/2 phosphorylation and increasein early
growth response 1 mRNA levels. In vivo and in vitro experi-
ments demonstrate that FGF23 decreased PTH mRNA and PTH
secretion.
12-14
FGF23 also produces upregulation of parathyroid
1 alpha hydroxilase expression.
13
Canalejo et al.
14
investigated
the effect of FGF23 on two main parathyroid receptors that in-
hibit parathyroid function: the calcium sensing receptor and the
vitamin D receptor. In vivo and in vitro studies demonstrated that
FGF23 increased gene expression and protein levels of both cal-
cium sensing and Vitamin D receptors. Finally the same authors
showed that FGF23 decreased parathyroid cell proliferation. All
these results strongly suggest that FGF23 inhibits parathyroid
function in normal parathyroids. The expression of FGF23 re-
ceptor and klotho in parathyroids have been investigated. Some
experiments have shown that administration of FGF23 produces
upregulation of parathyroid klotho,
12
other authors
14
observed
that FGF23 produced an increase in klotho that did not reach sig-
nificance. High extracellular calcium was able to increase in both
parathyroid klotho and FGF receptor expression in normal
parathyroid glands.
14
FGF23 IN PATIENTS WITH CHRONIC KIDNEY
DISEASE. THE PATHOGENESIS OF SECONDARY
HYPERPARATHYROIDISM
Several publications have illustrated the important changes in
FGF23 levels in patients with CKD.
15-18
Some authors have
shown that in early stages of CKD serum levels of FGF23 are
elevated even when PTH is not significantly increased. For
many years accumulation of phosphate and vitamin D defi-
ciency were considered the key factors in the development of
secondary hyperparathyroidism.
18
The increase in serum PTH
in CKD not only promotes urinary excretion of phosphate but
also maintains serum calcium levels and stimulate the failing
kidney to produce 1,25(OH)2D3. The increased production of
FGF23 in CKD patients is most likely due to the increase in
body burden of phosphate (not necessarily accompanied by
hyperphosphatemia). FGF23 induces phosphaturia, which
may explain why serum levels of phosphate are maintained in
early stages of CKD. However FGF23 decreases de produc-
tion of 1,25(OH)2D3 and accelerates its metabolism by aug-
menting 24(OH) asa activity. Thus, the decrease in
1,25(OH)2D3 seen in early CKD may be attributed not only
to the decrease in renal mass but also to the early increase in
FGF23.
19
There is a debate about which of the two phospha-
turic hormones, PTH or FGF23 increases earlier in CKD.
20-22
An study by Isakova T et al.
22
showed that in a group CKD
patients with an average GFR of 41 ml/min had normal serum
levels of calcium, phosphate and PTH, however FGF23 were
already elevated and 1,25(OH)2D3 levels significantly re-
duced. Progressive loss of nephrons will make both FGF23
and PTH non-operative and then serum phosphate concentra-
tion will increase.
Figure 2. Hormonal response to hypocalcemia and the
role of FGF23 to maintain phosphate balance.
Ca: calcium; FGF23: fibroblast growth factor 23;
P: phosphate; PTH: parathyroid hormone.
 Ca
Ca
Calcitriol
Phosphaturia
FGF 23
 P
 P
 P
Figure 1. Hormonal response to hypocalcemia.
Ca: calcium; P: phosphate; PTH: parathyroid hormone
 Ca
 P
Calcitriol
 PTH
 P
 P
 Ca





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Mariano Rodríguez et al. FGF23 in CKD-MBD
Nefrologia 2012;32(3):275-8
Nephrologists frequently ask whether or not it is advantageous
to have elevation of FGF23. Certainly FGF23 helps to control
phosphate balance but contributes to vitamin D deficiency. Fur-
thermore recent experiments demonstrate a direct negative ef-
fect of FGF23 on the cardiovascular system.
23
The fact that
FGF23 is elevated indicates that the failing kidney needs the
”help” of a phosphaturic hormone able to handle the phosphate
load. Therefore the increase in FGF23 implies inadequate phos-
phate control. In patients with CKD a better control of phosphate
is associated with a decrease in FGF23.
24
Another question is
whether FGF23 is a clinical usefultool to assess phosphate bal-
ance in CKD patients. FGF23 levels may not reflect acute
changes in dietary phosphate; however high serum level of
FGF23 may reveal a long period of positive phosphate balance.
Certainly, clinical studies will have to be performed to prove the
usefulness of FGF23 as a marker of phosphate balance.
A considerable amount of clinical studies have shown that a
high FGF23 level is independent predictor of mortality,
25-27
progression of renal disease
28,29
left ventricular hypertro-
phy,
30,31
vascular dysfunction,
32
renal transplant outcome
33
and experimental work have shown that FGF23 causes ven-
tricular hypertrophy directly.
23
FGF23 IN ADVANCED SECONDARY
HYPERPARATHYROIDISM
In dialysis patients serum FGF23 levels are markedly in-
creased and they are positively correlated with serum PTH
levels and with serum levels of phosphate.
16
One may assume
that the sustained accumulation of phosphate is the cause of
a direct correlation between PTH and FGF23. Nevertheless,
given the fact that FGF23 inhibits parathyroid function it is
unexpected to observe a parallel increase in the serum con-
centrations of FGF23 and PTH.
Experimental work in uremic rats with secondary hyper-
parathyroidism revealed that administration of FGF23 did not
reduce serum levels of FGF23 in uremic rats; and, in vitro hy-
perplastic parathyroid glands from uremic rats did not respond
to FGF23. Further experiments showed that hyperplastic
parathyroid glands presented low expression of both FGF re-
ceptors and klotho. This results suggests a resistance of hyper-
plastic parathyroid gland to the inhibitory action of FGF23.
14
Similar results were obtained by other group in another rat
model of renal insufficiency.
34
In parathyroid glands obtained
from patients with advanced secondary hyperparathyroidism
Klotho and FGFR1c expression decreased significantly partic-
ularly in glands with nodular hyperplasia.
35-37
FGF23 AFTER RENAL TRANSPLANT
After renal transplant many patients maintain high FGF23
levels suggesting that FGF23 may be the cause of of post-
transplant hypophosphatemia with a relative vitamin D defi-
ciency.
38-40
Before transplantation FGF23 levels are very high
and after kidney transplantation the excess of FGF23 acts to
promote phosphaturia and suppress 1,25(OH)2D production.
It is not clear why FGF23 secretion is maintained after trans-
plantation despite hypophosphatemia.
Conflict of interest
The authors declare potential conflicts of interest.
Grants: Amgen, Abbott, Fresenius.
Presentation honoraria: Amgen, Abbott, Fresenius, Shire,
Genzyme, Roche, Vifor.
Consultant honoraria: Amgen, Abbott, Fresenius, Shire,
Genzyme, Roche, Vifor.
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Enviado a Revisar:25 Feb. 2012 | Aceptado el: 25 Mar. 2012