Nephrol Dial Transplant (2008) 23: 2733–2737
doi: 10.1093/ndt/gfn260
Advance Access publication 9 May 2008
Editorial Review
The bone-renal axis in early chronic kidney disease: an emerging
paradigm
John Danziger1
Renal Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Keywords: chronic kidney disease; FGF-23; parathyroid;
phosphaturia; phosphorus
Introduction
The prevailing paradigm of mineral metabolism in chronic
kidney disease (CKD) is based on two principles. First, as
the tradeoff hypothesis suggests, phosphate retention leads
to hyperparathyroidism, a response that maintains normal
levels of serum phosphorus until relatively late in the CKD
process [1–3]. In addition, it is believed that dietary deficiency of 25 hydroxylated vitamin D (25OHD) is important in early CKD, with the deficiency of the activated
version, 1,25-hydroxylated vitamin D (1,25OHD), developing only in the later stages. Since the hydroxylation to
1,25OHD is considered to be a renal-dependent mechanism,
the deficiency of this activated form is thought to reflect renal dysfunction. Various mechanisms have been impugned,
including loss of renal mass, hyperparathyroidism, hyperphosphatemia and uremic toxins. These two principles have
shaped the current KDOQI guidelines for the treatment of
mineral metabolism in CKD.
However, more recent data suggest that this approach to
mineral metabolism in CKD may not be wholly accurate.
A recent large trial has illustrated that 1,25OHD levels
begin to fall at the earliest stage of renal decline, before the
development of hyperparathyroidism, hyperphosphatemia
or any changes in renal mass [4].
Furthermore, although loss of 1-alpha hydroxylase has
been impugned as the cause of 1,25OHD deficiency, animal
data suggest that this enzyme is not decreased in CKD [5].
In addition, 1-alpha hydroxylase is expressed in diverse tissues beyond the kidney, potentially providing an extra-renal
source of 1,25OHD [6]. It seems that the 1,25OHD decline
in CKD is actually a much more complicated process than
originally proposed.
Correspondence and offprint requests to: John Danziger, 330 Brookline
Ave E/DA517, Boston, MA 02215, USA. Tel: +1-617-667-2147; Fax:
+1-617-667-5276; E-mail: [email protected]
1 Member of Genzyme’s Speaker Bureau.
The recent discovery of the phosphatonins, specifically
FGF-23, has added an interesting dynamic to our understanding of mineral metabolism, and in many ways, challenges the previous paradigm [7]. FGF-23 has important effects on phosphorus and vitamin D metabolism. Produced
by the bone, it induces renal phosphaturia, inhibits renal
production of 1,25OHD and down regulates PTH release.
In turn, the consequent fall in 1,25OHD modulates the
bone to reduce FGF-23 production, completing a feedback
loop. This newly recognized bone-renal axis helps maintain
phosphorus homeostasis.
How this bone-renal axis is affected by renal dysfunction
remains an area of great interest. Emerging data suggest that
FGF-23 levels begin to rise early in CKD, possibly before
changes in parathyroid levels, and may be the culprit for the
early decline of 1,25OHD. Several recent CKD trials have
illustrated the physiologic importance of this bone-renal
axis, and support the notion that FGF-23 is responsible for
the early 1,25OHD decline in CKD patients. This review
article summarizes the latest information on the bone-renal
axis, and how it is affected in CKD.
FGF-23
FGF-23 is a 251 amino acid protein, with a molecular
weight of 26 000 Da, and is cleaved into carboxyl-terminal
(aa 180–251) and amino-terminal portions (aa 1–24). It
is produced primarily in the femur, calvaria and teeth [8].
It binds to a family of FGF receptors, likely requiring a
transmembrane protein, klotho, to facilitate cell surface
interaction [9]. Although FGF receptors are ubiquitously
expressed, the downstream effects of FGF-23 have been
localized to the kidney, parathyroid and pituitary glands,
suggesting a primary role in these organs [10]. FGF-23
has two important and well-described effects on the kidney. Acting on the renal tubular epithelial cells, it down
regulates the activity of the type IIa sodium phosphate cotransporter (NaPi2a), preventing phosphate reclamation by
the tubules [11,12]. In addition, FGF-23 suppresses renal
1-alpha-hydroxylase expression, preventing 1,25OHD production by the kidney [13]. The net effect is an increase in
phosphaturia and decrease in renal production of activated
vitamin D. Recent animal data have shown a direct effect
C The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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2734
of FGF-23 on the parathyroid gland, decreasing both PTH
gene expression and secretion [14,15]. Whether this will
hold true in human studies remains uncertain, with some
finding a relationship between FGF-23 and PTH [16], and
others none [17].
The biochemical effects of FGF-23 explain the phenotype seen in several recently recognized clinical conditions of FGF-23 abnormalities. Tumor-induced osteomalacia, X-linked hypoposphatemia and autosomal dominant
hypophosphatemic rickets, all with markedly elevated FGF23 levels, are characterized by urinary phosphate wasting,
hypophosphatemia, reduced 1,25OHD levels and osteomalacia [18–20]. Conversely, mutations, either in FGF-23
itself [21] or its klotho coreceptor [22], lead to severe tumoral calcinosis, characterized by hyperphosphatemia, increased 1,25OHD levels and ectopic calcification. These
syndromes outline the importance of FGF-23 in maintaining normal physiologic balance.
The importance of FGF-23 in normal physiology
The mechanisms of phosphorus homeostasis in normal individuals remain an area of active research. Although the
difference between oral intake and renal and gastrointestinal
excretion will ultimately determine net phosphate balance,
how this relates to serum levels remains unanswered, and
there are few true ‘balance’ studies in the literature. Given
the multiple mechanisms that can influence serum phosphate, including acidosis, hypocalcemia and insulin release,
along with a large potential depot of phosphate within the
skeleton, serum phosphate levels may not reflect net phosphate homeostasis. And interestingly, although initial studies suggested that increasing serum phosphate levels, by inducing hypocalcemia, triggered a PTH-driven phosphaturic
response, more recent data suggest that these phosphaturic
responses occur independently of changes in serum phosphate levels. Slatopolsky has shown that dietary phosphate
can stimulate PTH release without any changes in serum
calcium. This occurs with the duodenal infusion of phosphonoformate, a nonabsorbable phosphate analog, suggesting a direct signaling mechanism from the gastroinstestinal
tract to the kidney [23]. In a similar manner, Kumar and
colleagues have shown that dietary phosphate induces renal
phosphaturia independently of serum calcium, phosphate,
PTH and FGF-23 [24], further supporting the notion of an
entero-renal axis.
The role of FGF-23 in phosphorus metabolism of normal individuals has recently been investigated. In the most
recent study, Wolf and colleagues illustrated that a 500-mg
phosphorus meal leads to an immediate phosphaturic response, yet without changes in FGF-23 [25]. Others have
also suggested that the phosphaturic response to increased
dietary intake is independent of FGF-23 [26,27]. However,
Portale and colleagues showed that longer periods of high
phosphate intake lead to increasing FGF-23 production. In
a well-performed inpatient dietary study, 9 days of a high
phosphate diet lead to an increase of FGF-23, along with a
decline of 1,25OHD [16]. Others have also found that several days of high phosphate intake, rather than one meal,
lead to increased FGF-23 levels [17]. Interestingly, in both
these studies, the FGF-23 increase was associated with de-
J. Danziger
Fig. 1. Normal phosphate homeostasis. Phosphate balance depends on
multiple systems of regulation. Dietary phosphorus stimulates an enterorenal axis, parathyroid release of parathyroid hormone and skeletal release
of FGF-23, all resulting in phosphaturia. The stimulation of these axes can
occur independently of serum phosphorus levels.
creasing 1,25OHD, supporting the in vitro data that FGF-23
regulates 1,25OHD production. This reduction in 1,25OHD
likely decreases further absorption of dietary phosphate,
completing an important feedback loop and reestablishing
homeostasis.
In summary, the normal response to oral phosphate intake involves multiple pathways of response, involving the
parathyroid gland, bone and the GI tract itself. As seen in
Figure 1, phosphate intake stimulates the entero-renal axis,
PTH release and skeletal production of FGF-23, without
requiring changes in serum levels of phosphate or calcium.
The timing and relative importance of each axis in the
daily control of phosphate balance remains uncertain at
this point, with some suggesting that the entero-renal is
the first response system, with FGF-23 changes occurring
only after longer exposure to high phosphate intake. Nevertheless, FGF-23 adds another important component to our
emerging understanding of phosphorus control. How FGF23 is affected by changes in renal function is reviewed
below.
FGF-23 in early CKD
FGF-23 levels are markedly elevated in ESRD, yet the effect of subtle changes of renal function is not fully known
[28]. Studies of FGF-23 in early CKD are limited by the
difficulty of accurately estimating GFR in mild renal dysfunction. In addition, the C-terminal portion of FGF-23
may be filtered by the kidney, suggesting that the loss of renal filtration could lead to FGF-23 accumulation. Whether
this is true for the intact larger molecule remains unanswered [17]. Currently, there are two types of assays. Both
are ELISA tests: one detects only the C-terminal portion of
FGF-23 and is usually reported in RU/ml, whereas the other
assay detects the intact peptide and is reported in pg/ml. At
this point, there is no reliable relationship between these
different measurements, and the normal ranges in different
populations have not been fully elucidated.
Nevertheless, despite these caveats, several recent studies give insight as to when FGF-23 levels begin to increase
in CKD. Shigematsu and colleagues, using 24-h urine collections and cystatin-C measurements, suggest that FGF-23
levels begin to increase as the GFR falls to between 30 and
80 ml/min [29]. A more recent study by Wolf and colleagues
FGF-23 is important in early chronic kidney disease
suggests that FGF-23 levels increase once the GFR falls below 60 cc/min [30]. The most recent study of FGF-23 in
CKD provides a slightly different timeline, suggesting that
FGF-23 levels do not change until stage IV CKD [31]. The
relative paucity of diabetic CKD patients in this study, and
a potential relationship of FGF-23 to glucose metabolism,
might explain these differences to the above studies [32].
Nevertheless, despite such differences in the exact timeline of when FGF-23 levels begin to increase in CKD and
how that change may be affected by comorbidities such as
diabetes, it is apparent that FGF-23 levels do increase in
early CKD.
Effect of increasing FGF-23 on 1,25OHD levels
Ultimately, the recognition that FGF-23 levels rise early in
CKD, combined with its inhibition of 1,25OHD production,
suggests that FGF-23 may have an important clinical role
in vitamin D metabolism. Admittedly, this field remains
an area of uncertainty, and research is confounded by a
relatively short half-life of the 1,25OHD molecule, large
variations in serum levels and lack of consensus regarding
the definition of ‘normal’ 1,25OHD levels. At this point,
it is unknown how changes in serum 1,25OHD relate to
biologic activity of the vitamin D axis, and the emerging
importance of local, paracrine activation of 25OHD further
complicates this issue [33]. Nevertheless, despite the uncertainty of how to interpret 1,25OHD levels, emerging data
have shown that these levels begin to change early in CKD,
challenging the traditional teaching that places 1,25OHD
deficiency as a relatively late complication. There is little
data as to exactly how renal 1-alpha-hydroxylase inactivity
develops; yet although this was traditionally attributed to
loss of renal mass [34], recent animal data find that enzyme
activity remains relatively unaffected by loss of renal tissue
[5].
In a recently published large cross-sectional study of
>1800 CKD patients, the timeline of 1,25OHD decline has
been revisited [4]. Levin et al. have shown that 1,25OHD
levels actually begin to decline at the very mildest decrements of eGFR. This decline precedes measurable abnormalities of PTH, calcium or phosphorus. Although some
have suggested that this decline in the activated 1,25OHD
might be related to deficient 25OHD substrate [35], Levin
found no statistical relationship between the two forms, as
suggested by previous investigators [36]. Of the patients
with low 1,25OHD, ∼45% had normal 25OHD stores and
PTH levels. This large study suggests that the decline in
1,25OHD begins early in the course of CKD, and precedes
PTH elevations.
In the studies of FGF-23 in early CKD, both Shigematsu and Wolf found that the rise in FGF-23 levels was
associated with a decline in 1,25OHD. Indeed, in multivariate analysis, FGF-23 was the strongest determinant of
1,25OHD levels, and adjusting for FGF-23 extinguished
the association between renal function and 1,25OHD levels. Furthermore, even in healthy individuals, the FGF-23
increase induced by a prolonged high phosphorus diet is
associated with a decline in 1,25OHD levels [16,17]. Thus,
although some have suggested that 1-alpha hydroxylase
is suppressed by various metabolic abnormalities seen in
2735
Fig. 2. FGF-23 in early CKD. In early CKD, both PTH and FGF-23 levels
begin to rise. Although the clinical effects of secondary hyperparathyroidism are known, the clinical sequelae of increased FGF-23 are not
clear. Emerging data suggest that FGF-23 may have direct effects on the
vasculature, and by its ability to inhibit 1,25OHD production, may contribute to early bone disease.
CKD, such as metabolic acidosis [37], uremic toxins [38]
or hyperphosphatemia [39], these are unlikely to account
for the initial 1,25OHD decline when the GFR is relatively
well preserved. Given these inconsistencies, and the welldocumented inhibitory effect of FGF-23 on 1,25OHD production, it seems plausible that FGF-23 may be primarily
responsible for the decrement of 1,25OHD levels in early
CKD.
In summary, with a mild decrement of renal function,
skeletal release of FGF-23 increases, presumably to maintain phosphate balance (Figure 2). Ultimately however,
because of impaired renal phosphate clearance, FGF-23
production continues unabated, leading to 1,25OHD deficiency. Further studies to assess whether reducing FGF-23
levels in early CKD might prevent 1,25OHD deficiency are
needed. Initial animal data suggest that although the use
of phosphate binders reduces FGF-23 levels, it does not
improve 1,25OHD levels [40]. This question has not been
evaluated in human studies.
Systemic effects of FGF-23 elevation and 1,25OHD
deficiency
The ramifications of FGF-23 elevation and 1,25OHD deficiency seen in early CKD are just beginning to be explored, yet emerging data suggest that these changes may be
clinically significant. FGF-23 acts through a downstream
signal, early growth response (Egr)-1, a novel molecule
recently found to have widespread influence on atherosclerosis [9,41]. In addition, since FGF-23 modulates type II
sodium phosphate (NaP) transporters expression in the kidney, it might also influence the ubiquitously expressed type
III NaP transporters. These potential mechanisms could
link FGF-23 to vascular calcification, and might explain
why calcification begins so early in CKD [42,43], prior to
the development of hyperphosphatemia. One recent study
suggests that FGF-23 levels predict the presence of vascular calcification independently of calcium, phosphate or
PTH [44]. FGF-23 levels have also been correlated with
progression of renal disease [45]. Ultimately, answering
whether FGF-23, acting directly, through downstream signals or by inhibiting 1,25OHD production, has effects on
vascular calcification will require further studies.
2736
Although FGF-23 provides a mechanistic link between
the skeleton and the kidneys, there is a paucity of data investigating whether the FGF-23 elevation seen in early CKD
is associated with underlying bone disease. A single study
has found no relationship between FGF-23 levels and bone
mass in ESRD, yet this study relied on bone densitometry
and circulating biomarkers rather than histology [46], making the results difficult to interpret. Ultimately, given the
small number of clinical studies that obtain bone histology
in early CKD, combined with the existing literature with
widely disparate findings about bone disease in early CKD
[47,48], it is difficult to make any conclusions about FGF23’s relationship to underlying bone histology. However,
a recent clinical study has suggested that 1,25OHD, rather
than PTH, bests correlates with loss of bone density in early
CKD [49]. Furthermore, treatment with activated vitamin D
prevents further bone loss [50]. These findings suggest that
FGF-23’s inhibition of 1,25OHD formation may be more
clinically important than previously recognized.
Conclusion
FGF-23 has emerged as an important moderator in the
physiology of phosphate homeostasis. Dietary phosphate
stimulates an entero-renal axis, PTH and FGF-23, which
in turn, induces phosphaturia. FGF-23 decreases 1,25OHD
production, preventing further dietary phosphate absorption, thus helping to reestablish phosphorous homeostasis.
This axis is disturbed in the early stages of CKD, and the
potential downstream effects of FGF-23 elevation and early
1,25OHD deficiency remain not fully described.
This phosphate centric paradigm is in keeping with the
idea that phosphate homeostasis can be independent of calcium and phosphate levels, as well as the parathyroid gland,
and raises further questions as to how the body regulates
and responds to this important anion. Phosphate has multiple biologic activities, and subtle changes in serum levels
seem to have widespread physiologic consequence [51].
Although the exact sensing mechanisms remain unknown,
with a potential phosphate receptor hitherto undiscovered,
the manner in which phosphate regulates FGF-23 may ultimately provide insight into phosphate’s control of other
biologic systems.
In addition, the emergence of this bone-renal axis will
undoubtedly raise therapeutic questions, and challenge the
current principles of mineral metabolism in early CKD.
Although vitamin D therapy remains the mainstay of therapy in early CKD, the importance of dietary phosphate
in stimulating FGF-23 release, and thus in perpetuating
1,25OHD deficiency, suggests that phosphate restriction
might be the most appropriate early intervention. As increasing attention shifts to early CKD management, an understanding of the full spectrum of mineral metabolism will
require further careful studies of FGF-23 and its clinical
effects.
Acknowledgements. I would like to thank Drs Stewart Lecker and Marc
Cohen for their expertise in the preparation of this manuscript.
Conflict of interest statement. None declared.
J. Danziger
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Received for publication: 7.4.08
Accepted in revised form: 15.4.08