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© 2012 Revista Nefrología. Órgano Oficial de la Sociedad Española de Nefrología
FGF23 and mineral metabolism, implications
Mariano Rodríguez
, Ignacio López
, Juan Muñoz
, Escolástico Aguilera-Tejero
Yolanda Almaden
Servicio de Nefrología. Hospital Universitario Reina Sofía, REDINREN, IMIBIC. Córdoba
Departamento de Medicina y Cirugía. Facultad de Veterinaria. Córdoba
Nefrologia 2012;32(3):275-8
Correspondence: Mariano Rodríguez
Servicio de Nefrología.
Hospital Universitario Reina Sofía. REDINREN, IMIBIC, Córdoba.
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).
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 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).
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.
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.
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.
The endocrine ac-
tion of FGF23 is dependent upon its binding and activation
of the klotho-FGFR1 complex,
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
Mariano Rodríguez et al. FGF23 in CKD-MBD
Nefrologia 2012;32(3):275-8
together with calcifications. We should be aware that these
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-
FGF23 production by osteoblasts and osteocytes is stimulated
by high dietary intake of phosphate however the mechanisms
at the cellular level are unknown.
Experiments have failed to
show a direct effect of high extracellular phosphate concentra-
tion on FGF23 expression by bone cells.
The stimulation of
FGF23 production by 1,25(OH)2D3 is well defined. Liu S et
showed that 1,25(OH)2D3 up regulates FGF23 expression
by acting on VDR response elements of the FGF23 promoter.
Interestingly Carrillo et al.
have shown thatestrogens direct-
ly stimulate the production of FGF23.
Parathyroid tissue expresses a significant amount of klotho
FGF23 receptor. Thus it was reasonable to anticipate an effect
of FGF23 on the parathyroids. FGF23 acts on the parathyroid
FGF-Klotho complex
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
FGF23 also produces upregulation of parathyroid
1 alpha hydroxilase expression.
Canalejo et al.
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,
other authors
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.
Several publications have illustrated the important changes in
FGF23 levels in patients with CKD.
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.
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
There is a debate about which of the two phospha-
turic hormones, PTH or FGF23 increases earlier in CKD.
An study by Isakova T et al.
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.
FGF 23
Figure 1. Hormonal response to hypocalcemia.
Ca: calcium; P: phosphate; PTH: parathyroid hormone
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.
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.
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,
progression of renal disease
left ventricular hypertro-
vascular dysfunction,
renal transplant outcome
and experimental work have shown that FGF23 causes ven-
tricular hypertrophy directly.
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.
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.
Similar results were obtained by other group in another rat
model of renal insufficiency.
In parathyroid glands obtained
from patients with advanced secondary hyperparathyroidism
Klotho and FGFR1c expression decreased significantly partic-
ularly in glands with nodular hyperplasia.
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-
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
... The negative correlation of FGF23 with glomerular filtration is typical in patients with chronic kidney disease 16,24,27,28 . Although none of our patients enrolled in the study had significantly reduced glomerular filtration, we found significant negative correlation of cFGF23 and iFGF23 30 . ...
... A number of studies have focused on the association of FGF23 with bone metabolism 3,27,28,34 . ...
Full-text available
Background: Fibroblast growth factor-23 (FGF23) is a key regulator of urine phosphate excretion. The aim of the study was to investigate the perioperative (intraoperative and postoperative) changes of plasma intact and C-terminal FGF23 (iFGF23, cFGF23) concentrations in patients with primary hyperparathyroidism (pHPT) submitted to surgery. Materials and methods: Study involved 38 adult patients with pHPT caused by adenoma. PTH levels were investigated intraoperatively (just before the incision and 10 minutes after adenoma excision). cFGF23, iFGF23, phosphate, eGFR and P1NP were measured intraoperatively and postoperatively (next day after the surgery). Results: PTH levels decreased intraoperatively (13.10 vs. 4.17 pmol/L, P<0.0001). FGF23 levels measured intraoperatively were at the upper level of reference interval. cFGF23 decreased postoperatively compared with values measured just before the incision (cFGF23: 89.17 vs. 22.23 RU/mL, P<0.0001). iFGF23 decreased as well, but postoperative values were low. Postoperative inorganic phosphate values increased (1.03 mmol/L vs. 0.8 mmol/L, P=0.0025). We proved significant negative correlation of perioperative FGF23 with inorganic phosphate (cFGF23: Spearman r=-0.253,P=0.0065; iFGF23: Spearman r =-0.245, P=0.0085). We also found FGF23 values just before incision correlated with eGFR (cystatin C) (cFGF23: Spearman r=-0.499, P=0.0014; iFGF23: Spearman r=-0.413, P=0.01). Conclusion: Intraoperative iFGF23 and cFGF23 did not change despite PTH decreased significantly. cFGF23 and iFGF23 significantly decreased one day after parathyroidectomy and are associated with increase of inorganic phosphate in pHPT patients. cFGF23 and iFGF23 just before incision correlated with eGFR (cystatin C). The similar results found in both iFGF23 and cFGF23 suggest each could substitute the other.
... The effects of FGF23 are exerted by its biologically active form "intact FGF23" (iFGF23), which binds to the receptor complex FGFR/ α-Klotho and causes a down-regulation of the sodium-phosphate cotransporters Npt2a, Npt1 and Npt2c in renal proximal tubules, leading to increased phosphaturia [6][7][8]. Furthermore, iFGF23 markedly decreases plasma levels of 1,25(OH) 2 vitamin D levels by inhibiting 1α-hydroxylase and stimulating 24-hydroxylase in the kidney, which further reduces phosphate absorption [6,9,10]. ...
... Hence, upregulation of FGF23 was reported to lead to an increase in sodium retention, resulting in an expansion of plasma volume with consecutive arterial hypertension and left ventricular hypertrophy [39]. Additionally, FGF23 plays an important role in vitamin D homeostasis by reducing plasma levels of 1,25 (OH) 2 vitamin D via inhibition of 1α-hydroxylase and stimulation of 24-hydroxylase in the kidney [6,9,10]. Hereby, FGF23 is thought to induce secondary hyperparathyroidism [42], which is considered a key factor for calcification and thus represents a known risk factor especially in patients with advanced CKD [43]. ...
Introduction Serum levels of FGF23 have been associated with adverse outcomes in cardiovascular diseases in patients with and without impaired renal function. Hence, this study aimed to explore the prognostic relevance of intact FGF23 (iFGF23) and its derivate C-terminal FGF23 (cFGF23) in patients undergoing transcatheter aortic valve replacement (TAVR) with regard to renal function. Methods A total of 274 patients undergoing transfemoral TAVR were enrolled in this study. Blood samples were obtained preinterventionally and analyzed for iFGF23 and cFGF23 by means of enzyme linked immunosorbent assay (ELISA). Follow-up was obtained for 12 months. Results Serum levels of cFGF23 and iFGF23 both correlated positively with serum creatinine and inversely with estimated glomerular filtration rate (eGFR). Cox regression analysis revealed a significant association of cFGF23 with 1-year-mortality in patients with eGFR ≥45ml/min/1.73m², but not in patients with an eGFR <45ml/min/1.73m². A cut-off was calculated for cFGF23 (6.82 pmol/l) and patients with eGFR ≥45ml/min/1.73m² were retrospectively divided into two groups (above/below cut-off). Patients above the cut-off had a significantly worse 1-year-mortality than patients below the cut-off (33.3% vs. 19.6%; OR 2.05 (95%CI 1.03-4.07), p= 0.038). The association of cFGF23 with 1-year-mortality in patients with eGFR ≥45ml/min/1.73m² remained statistically significant even after correction for possible confounders in a multivariate Cox regression analysis. Conclusion cFGF23 could be an individual risk factor for mortality in patients undergoing TAVR with an eGFR ≥45ml/min/1.73m².
... Serum FGF-23 is increasingly being adopted as a marker of CKD-MBD in routine clinical practice. 15,16 In most of the sub-Saharan Africa, patients with CKD are either minimally or not evaluated for CKD-MBD at all, as majority of the patients pay out of pocket and thus add to the cost of care which is already not affordable by a large proportion of patients with CKD. 17,18 Most centres in Nigeria therefore adopt preventive strategies with dietary phosphate restrictions, use of phosphate binders and vitamin D (Vit D). 19 In addition, the indiscriminate use of phosphate binders and Vit D has been reported to be associated with low bone turn over (adynamic bone disease). ...
Full-text available
Background: Excess cardiovascular burden in patients with chronic kidney disease (CKD) has been attributed to the occurrence of CKD-Mineral Bone Disease (CKD - MBD). This study aimed to determine the spectrum of CKD-MBD among Nigerians with CKD using Fibroblast Growth Factor 23 (FGF 23) and intact Parathyroid Hormone (iPTH). Methods: Cross sectional survey of 105 patients with non-diabetic CKD and 104 controls. Information obtained were demographics, aetiology of CKD, features of CKD-MBD. Serum iPTH and FGF 23 were assayed. Results: The mean ages were 48.7±15.3 vs 48.6±17.4 years while 54.7% and 45.2% were males for cases and controls, respectively. The mean plasma FGF 23 (392.8±35.3 vs 133.8±22.7 RU/mL and plasma iPTH (289±25.6 vs 118±10.8 ng/L, respectively. The frequency of elevated FGF 23 (45.7% vs 24.0%, p<0.01) and abnormal iPTH (53.3% vs 14.1%, p- 0.01) were higher in cases. The prevalence of MBD were (59.0% vs 14.4%, p<0.01) in cases and controls while dialysis status OR 2.94, 95% CI (1.2803-5.3645), and elevated FGF 23 OR, 1.87, 95% CI (1.1782-5.4291) were associated with CKD-MBD. Conclusion: The study demonstrated high prevalence of CKD-MBD among patients with non-diabetic CKD while FGF23 and iPTH were useful assays in the diagnosis of CKD-MBD among Nigerians with CKD.
... The endocrine activity of FGF-23 requires its binding and the activation of its receptor complex containing a transmembrane protein Klotho [40,41]. The results of studies have indicated that the dysregulation of the FGF23-related compensatory mechanism in CKD patients is associated with Klotho deficiency [1]. ...
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Chronic kidney disease is a health problem whose prevalence is increasing worldwide. The kidney plays an important role in the metabolism of minerals and bone health and therefore, even at the early stages of CKD, disturbances in bone metabolism are observed. In the course of CKD, various bone turnover or mineralization disturbances can develop including adynamic hyperparathyroid, mixed renal bone disease, osteomalacia. The increased risk of fragility fractures is present at any age in these patients. Nutritional treatment of patients with advanced stages of CKD is aiming at prevention or correction of signs, symptoms of renal failure, avoidance of protein-energy wasting (PEW), delaying or prevention of the occurrence of mineral/bone disturbances, and delaying the start of dialysis. The results of studies suggest that progressive protein restriction is beneficial with the progression of renal insufficiency; however, other aspects of dietary management of CKD patients, including changes in sodium, phosphorus, and energy intake, as well as the source of protein and lipids (animal or plant origin) should also be considered carefully. Energy intake must cover patients’ energy requirement, in order to enable correct metabolic adaptation in the course of protein-restricted regimens and prevent negative nitrogen balance and protein-energy wasting.
... Renal phosphate excretion is stimulated by an interplay between FGF23 and PTH, both of which increase in response to increased serum phosphate. 22 FGF23, a bone-derived hormone, has been shown to be intricately involved in iron phosphate and vitamin D metabolism. 23 FGF23 regulates phosphate handling and is secreted as a response to increased calcitriol, PTH, hyperphosphataemia, or oral phosphate intake. ...
Third-generation intravenous (i.v.) iron preparations are safe and efficacious and are increasingly used in the treatment of iron-deficiency anaemia. Hypophosphataemia is emerging as an established side-effect following the administration of certain compounds. Symptoms of hypophosphataemia can be masked by their similarity to those of iron-deficiency anaemia and both acute and chronic hypophosphataemia can be detrimental. Hypophosphataemia appears to be linked to imbalances in the metabolism of the phosphatonin fibroblast growth factor 23. In this narrative review, we discuss the possible pathophysiology behind this phenomenon, the studies comparing third-generation i.v. iron compounds, and the potential implications of the changes in fibroblast growth factor 23 and hypophosphataemia. We also present an algorithm of how to approach such patients requiring i.v. iron in anticipation of hypophosphataemia and how the impact related to it can be minimized.
... La adecuada homeostasis del fosfato es fundamental para el normal desarrollo de numerosos procesos biológicos (1,2). El incremento sérico de fosfato, se asocia a un mayor riesgo de eventos cardiovasculares (cardiopatía isquémica, enfermedad cerebrovascular, insuficiencia cardíaca), tanto en individuos con Enfermedad Renal Crónica (ERC)(3), como en sanos (4). ...
... It is synthetized by osteocytes and mature osteoblasts. FGF23 primarily exerts its effect on target organs through activation of the FGFR-Klotho receptor [1][2][3]. ...
Fibroblast growth factor 23 (FGF23) increases phosphorus excretion and decreases calcitriol levels. FGF23 increases from early stages of renal failure. We evaluated whether strict control of phosphorus intake in renal failure prevents the increase in FGF23 and to what extent inflammation impairs regulation of FGF23. The study was performed in 5/6 nephrectomized (Nx) Wistar rats fed diets containing 0.2 to 1.2% phosphorus for 3 or 15 days. FGF23 levels significantly increased in all Nx groups in the short-term (3-day) experiment. However, at 15 days, FGF23 increased in all Nx rats except in those fed 0.2% phosphorus. In a second experiment, Nx rats fed low phosphorus diets (0.2 and 0.4%) for 15 days received daily intraperitoneal lipopolysaccharide (LPS) injections to induce inflammation. In these rats, FGF23 increased despite the low phosphorus diets. Thus, higher FGF23 levels were needed to maintain phosphaturia and normal serum phosphorus values. Renal Klotho expression was preserved in Nx rats on a 0.2% phosphorus diet, reduced on a 0.4% phosphorus diet, and markedly reduced in Nx rats receiving LPS. In ex vivo experiments, high phosphorus and LPS increased nuclear b-catenin and p65-NFkB and decreased Klotho. Inhibition of inflammation and Wnt signalling activation resulted in decreased FGF23 levels and increased renal Klotho. In conclusion, strict control of phosphorus intake prevented the increase in FGF23 in renal failure, whereas inflammation independently increased FGF23 values. Decreased Klotho may explain the renal resistance to FGF23 in inflammation. These effects are likely mediated by the activation of NFkB and Wnt/b-catenin signalling.
... Fibroblast growth factor-23 also reduces levels of 1, 25-dihydroxyvitamin D and reduces phosphate absorption in intestine. Furthermore, FGF23 inhibits the normal action of parathyroid glands (12)(13)(14)(15)(16)(17)(18)(19)(20). Fibroblast growth factor-23 level start to rise as glomerular filtration rate (GFR) declines below the normal level and continue to rise progressively as CKD progress and reaches to levels 100 to 1000 folds above normal in patients with end-stage renal disease (ESRD). ...
Introduction: Kidney transplantation restores many of the disorders accompanying endstage renal disease (ESRD). However, hypophosphatemia is common complication after renal transplantation. High levels of fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) are two suspected factors determining the hypophosphatemia after kidney transplantation. Objectives: This observational prospective study was carried out to clarify the role of mentioned factors in hypophosphatemia after kidney transplantation. Patients and Methods: Living donor kidney transplant recipients which admitted to the ward of the renal transplantation, enrolled to the study. Parameters of bone and mineral metabolism including FGF23 and intact PTH levels were assessed. Results: High FGF23 level before transplantation was related to lower phosphate levels at 3rd month after transplantation. PTH levels showed no relationship with hypophosphatemia after kidney transplantation. Conclusion: High levels of FGF23 in ESRD patients undergoing kidney transplantation is an important determinant of hypophosphatemia in long-term follow up.
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The aim of this paper is to review current knowledge about how calorie intake influences mineral metabolism focussing on four aspects of major interest for the renal patient: (a) phosphate (P) handling, (b) fibroblast growth factor 23 (FGF23) and calcitriol synthesis and secretion, (c) metabolic bone disease, and (d) vascular calcification (VC). Caloric intake has been shown to modulate P balance in experimental models: high caloric intake promotes P retention, while caloric restriction decreases plasma P concentrations. Synthesis and secretion of the phosphaturic hormone FGF23 is directly influenced by energy intake; a direct correlation between caloric intake and FGF23 plasma concentrations has been shown in animals and humans. Moreover, in vitro, energy availability has been demonstrated to regulate FGF23 synthesis through mechanisms in which the molecular target of rapamycin (mTOR) signalling pathway is involved. Plasma calcitriol concentrations are inversely proportional to caloric intake due to modulation by FGF23 of the enzymes implicated in vitamin D metabolism. The effect of caloric intake on bone is controversial. High caloric intake has been reported to increase bone mass, but the associated changes in adipokines and cytokines may as well be deleterious for bone. Low caloric intake tends to reduce bone mass but also may provide indirect (through modulation of inflammation and insulin regulation) beneficial effects on bone. Finally, while VC has been shown to be exacerbated by diets with high caloric content, the opposite has not been demonstrated with low calorie intake. In conclusion, although prospective studies in humans are needed, when planning caloric intake for a renal patient, it is important to take into consideration the associated changes in mineral metabolism.
Fibroblast growth factor 23 (FGF23) is a protein produced by mature osteoblasts involved in mineral homeostasis by binding to its receptor complex FGFR/Klotho located mainly in the kidneys. Although this protein participates in numerous biological processes, increase in the levels of FGF23 is responsible for many pathologies, such as X-linked hypophosphataemia (XLH), chronic kidney disease, cardiovascular disease or even mortality. For this reason, both FGF23 and its receptors have become elements of interest for the development of treatments. However, FGF23 can be altered for many other reasons, such as inflammatory processes, iron, hypoxia, heart failure or erythropoietin, that negatively affect mortality. This article will review the role of FGF23 in phosphate homeostasis, its relationship to mortality, fractures and chronic renal failure, and how the levels of this factor can be reduced.
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Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.
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A high level of the phosphate-regulating hormone fibroblast growth factor 23 (FGF-23) is associated with mortality in patients with end-stage renal disease, but little is known about its relationship with adverse outcomes in the much larger population of patients with earlier stages of chronic kidney disease. To evaluate FGF-23 as a risk factor for adverse outcomes in patients with chronic kidney disease. A prospective study of 3879 participants with chronic kidney disease stages 2 through 4 who enrolled in the Chronic Renal Insufficiency Cohort between June 2003 and September 2008. All-cause mortality and end-stage renal disease. At study enrollment, the mean (SD) estimated glomerular filtration rate (GFR) was 42.8 (13.5) mL/min/1.73 m(2), and the median FGF-23 level was 145.5 RU/mL (interquartile range [IQR], 96-239 reference unit [RU]/mL). During a median follow-up of 3.5 years (IQR, 2.5-4.4 years), 266 participants died (20.3/1000 person-years) and 410 reached end-stage renal disease (33.0/1000 person-years). In adjusted analyses, higher levels of FGF-23 were independently associated with a greater risk of death (hazard ratio [HR], per SD of natural log-transformed FGF-23, 1.5; 95% confidence interval [CI], 1.3-1.7). Mortality risk increased by quartile of FGF-23: the HR was 1.3 (95% CI, 0.8-2.2) for the second quartile, 2.0 (95% CI, 1.2-3.3) for the third quartile, and 3.0 (95% CI, 1.8-5.1) for the fourth quartile. Elevated fibroblast growth factor 23 was independently associated with significantly higher risk of end-stage renal disease among participants with an estimated GFR between 30 and 44 mL/min/1.73 m(2) (HR, 1.3 per SD of FGF-23 natural log-transformed FGF-23; 95% CI, 1.04-1.6) and 45 mL/min/1.73 m(2) or higher (HR, 1.7; 95% CI, 1.1-2.4), but not less than 30 mL/min/1.73 m(2). Elevated FGF-23 is an independent risk factor for end-stage renal disease in patients with relatively preserved kidney function and for mortality across the spectrum of chronic kidney disease.
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Secondary hyperparathyroidism (SHPT) is a challenge frequently encountered in the management of patients with chronic kidney disease (CKD). Downregulation of the parathyroid vitamin D and calcium-sensing receptors represent critical steps that lead to abnormalities in mineral metabolism: high phosphate, low calcium, and vitamin D deficiency. These imbalances result in parathyroid hyperplasia and contribute to vascular calcification. New studies have established a central role for fibroblast growth factor 23 (FGF-23) in the regulation of phosphate-vitamin D homeostasis. FGF-23 concentration increases in CKD and contributes to SHPT. Achieving current targets for the key mineral parameters in the management of SHPT set by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines can be challenging. This review summarizes the current understanding and evidence supporting strategies for SHPT treatment in CKD patients. Treatment should include a combination of dietary phosphorus restriction, phosphate binders, vitamin D sterols, and calcimimetics. Parathyroidectomy is effective in suitable candidates refractory to medical therapy and the standard against which new approaches should be measured. Future strategies may focus on the stimulation of apoptotic activity of hyperplastic parathyroid cells.
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In chronic kidney disease (CKD) patients, the ability to excrete a phosphate load is impaired. Compensatory increase in parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) promote phosphaturia. Serum FGF23 concentration is considered an early biomarker of excess phosphate load and high levels of FGF23 have been associated with increased mortality. In the present study, we have evaluated the changes in plasma FGF23 after treatment with the phosphate binder lanthanum carbonate in patients with CKD-3 and a normal serum phosphate concentration. Eighteen Caucasian CKD Stage 3a/3b patients with serum phosphate <4.5 mg/dL were recruited in a prospective longitudinal open-label study. Patients received a 4-week period of standardized phosphorus-restricted diet containing 0.8 g/Kg/day protein. Thereafter, the same diet was maintained and patients received lanthanum carbonate (750 mg with the three main meals) for 4 weeks. No significant changes were observed in serum phosphate, however, lanthanum carbonate significantly decreased urinary excretion of phosphate and fractional excretion of phosphate (P < 0.004). This was accompanied by a significant decrease in carboxyterminal FGF23 (median percent change from baseline -21.8% (interquartile range -4.5, -30%), P = 0.025). No changes were observed in PTH. In conclusion, lanthanum carbonate reduced phosphate load, as assessed by urinary phosphate excretion, and also reduced plasma FGF23 in CKD-3 patients. This occurs in the presence of unchanged normal serum phosphate levels.
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An increased circulating level of fibroblast growth factor 23 (FGF23) is an independent risk factor for mortality, cardiovascular disease, and progression of chronic kidney disease (CKD), but its role in transplant allograft and patient survival is unknown. We tested the hypothesis that increased FGF23 is an independent risk factor for all-cause mortality and allograft loss in a prospective cohort of 984 stable kidney transplant recipients. At enrollment, estimated GFR (eGFR) was 51 ± 21 ml/min per 1.73 m(2) and median C-terminal FGF23 was 28 RU/ml (interquartile range, 20 to 43 RU/ml). Higher FGF23 levels independently associated with increased risk of the composite outcome of all-cause mortality and allograft loss (full model hazard ratio: 1.46 per SD increase in logFGF23, 95% confidence interval: 1.28 to 1.68, P<0.001). The results were similar for each component of the composite outcome and in all sensitivity analyses, including prespecified analyses of patients with baseline eGFR of 30 to 90 ml/min per 1.73 m(2). In contrast, other measures of phosphorus metabolism, including serum phosphate and parathyroid hormone (PTH) levels, did not consistently associate with outcomes. We conclude that a high (or elevated) FGF23 is an independent risk factor for death and allograft loss in kidney transplant recipients.
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Circulating levels of fibroblast growth factor 23 (FGF23) are elevated in patients with early chronic kidney disease (CKD) and are postulated to cause low blood levels of 1,25-dihydroxyvitamin D, as well as normal phosphate levels. In order to provide more direct evidence for the pathophysiological role of FGF23 in the settings of mineral ion homeostasis typically seen in early CKD, we studied rats with progressive CKD treated with anti-FGF23 neutralizing antibody. Without antibody treatment, rats with CKD exhibited high circulating levels of FGF23 and parathyroid hormone, low 1,25-dihydroxyvitamin D, and normal serum phosphate levels, accompanied by increased fractional excretion of phosphate. Antibody treatment, however, lessened fractional excretion of phosphate, thus increasing serum phosphate levels, and normalized serum 1,25-dihydroxyvitamin D by increased 1α-OHase and decreased 24-OHase expressions in the kidney. These antibody-induced changes were followed by increased serum calcium levels, leading to decreased serum parathyroid hormone. Hence, our study shows that FGF23 normalizes serum phosphate and decreases 1,25-dihydroxyvitamin D levels in early-stage CKD, and suggests a pathological sequence of events for the development of secondary hyperparathyroidism triggered by increased FGF23, followed by a reduction of 1,25-dihydroxyvitamin D and calcium levels, thereby increasing parathyroid hormone secretion.
In the past 40 years, disordered mineral metabolism has been among the most intensely studied areas of nephrology. A June 2010 PubMed search for 'secondary hyperparathyroidism and kidney disease' yielded 5866 references. Among these are papers documenting the development and application of numerous therapeutic agents-including calcitriol, vitamin D analogs, phosphate binders, and cinacalcet-that remain in widespread use in the day-to-day management of dialysis patients worldwide. However, almost 6000 papers later, fundamental pathophysiological concepts remain unclear, particularly regarding the early pathogenesis of disordered mineral metabolism.
Fibroblast growth factor 23 (FGF-23) has emerged as a new factor in mineral metabolism in chronic kidney disease (CKD). An important regulator of phosphorus homeostasis, FGF-23 has been shown to independently predict CKD progression in nondiabetic renal disease. We analyzed the relation between FGF-23 and renal outcome in diabetic nephropathy (DN). DN patients participating in a clinical trial (enalapril+placebo versus enalapril+losartan) had baseline data collected and were followed until June 2009 or until the primary outcome was reached. Four patients were lost to follow-up. The composite primary outcome was defined as death, doubling of serum creatinine, and/or dialysis need. At baseline, serum FGF-23 showed a significant association with serum creatinine, intact parathyroid hormone, proteinuria, urinary fractional excretion of phosphate, male sex, and race. Interestingly, FGF-23 was not related to calcium, phosphorus, 25OH-vitamin D, or 24-hour urinary phosphorus. Mean follow-up time was 30.7±10 months. Cox regression showed that FGF-23 was an independent predictor of the primary outcome, even after adjustment for creatinine clearance and intact parathyroid hormone (10 pg/ml FGF-23 increase = hazard ratio, 1.09; 95% CI, 1.01 to 1.16, P=0.02). Finally, Kaplan-Meier analysis showed a significantly higher risk of the primary outcome in patients with FGF-23 values of >70 pg/ml. FGF-23 is a significant independent predictor of renal outcome in patients with macroalbuminuric DN. Further studies should clarify whether this relation is causal and whether FGF-23 should be a new therapeutic target for CKD prevention.