www.kidney-international.
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Phosphate—a poison for humans?
Hirotaka Komaba1,2,3 and Masafumi Fukagawa1
1
Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan; 2Interactive Translational
Research Center for Kidney Diseases, Tokai University School of Medicine, Isehara, Japan; and 3The Institute of Medical Sciences, Tokai
University, Isehara, Japan
Maintenance of phosphate balance is essential for life, and
mammals have developed a sophisticated system to
regulate phosphate homeostasis over the course of
evolution. However, due to the dependence of phosphate
elimination on the kidney, humans with decreased kidney
function are likely to be in a positive phosphate balance.
Phosphate excess has been well recognized as a critical
factor in the pathogenesis of mineral and bone disorders
associated with chronic kidney disease, but recent
investigations have also uncovered toxic effects of
phosphate on the cardiovascular system and the aging
process. Compelling evidence also suggests that increased
fibroblastic growth factor 23 and parathyroid hormone
levels in response to a positive phosphate balance
contribute to adverse clinical outcomes. These insights
support the current practice of managing serum phosphate
in patients with advanced chronic kidney disease, although
definitive evidence of these effects is lacking. Given the
potential toxicity of excess phosphate, the general
population may also be viewed as a target for phosphate
management. However, the widespread implementation of
dietary phosphate intervention in the general population
may not be warranted due to the limited impact of
increased phosphate intake on mineral metabolism and
clinical outcomes. Nonetheless, the increasing incidence of
kidney disease or injury in our aging society emphasizes
the potential importance of this issue. Further work is
needed to more completely characterize phosphate toxicity
and to establish the optimal therapeutic strategy for
managing phosphate in patients with chronic kidney
disease and in the general population.
Kidney International (2016) 90, 753–763; http://dx.doi.org/10.1016/
j.kint.2016.03.039
KEYWORDS: chronic kidney disease; fibroblastic growth factor 23;
phosphate; parathyroid hormone
Copyright ª 2016, International Society of Nephrology. Published by
Elsevier Inc. All rights reserved.
Correspondence: Masafumi Fukagawa, Division of Nephrology, Endocri-
nology and Metabolism, Tokai University School of Medicine, 143
Shimo-Kasuya, Isehara 259-1193, Japan. E-mail: fukagawa@tokai-u.jp
Received 18 January 2016; revised 3 March 2016; accepted 24 March
2016; published online 7 June 2016
Kidney International (2016) 90, 753–763
review
S
ince the discovery of phosphate by Hennig Brand in
1669 using a preparation from urine,1 the essential role
of phosphate in living organisms has been well estab-
lished. Phosphate serves as a structural component of nucleic
acids, adenosine triphosphate, and the phospholipids of
membranes. Phosphate also plays a critical role in cellular
signaling through phosphorylation reactions. For these rea-
sons, phosphate is essential for life, and the intake of
phosphate-containing products is crucial for all animals.
During the course of evolution, animals have acquired
“bone” that serves as a reservoir for life-essential phosphate
and calcium. This evolutionary event has likely eliminated the
need to store phosphate in extracellular fluids. Because
extremely high phosphate concentrations can have toxic
effects,2,3 animals have developed a system to excrete excess
phosphate through the kidneys and thereby maintain extra-
cellular phosphate concentrations within physiologically
acceptable ranges. In mammals, parathyroid hormone (PTH)
and fibroblastic growth factor 23 (FGF23) both play an
important role in regulating extracellular phosphate concen-
trations by stimulating urinary phosphate excretion.4
In this way, mammals have developed a sophisticated
system to tightly regulate phosphate homeostasis. However,
due to the dependence of phosphate elimination on urinary
excretion by the kidneys, patients with decreased kidney
function are likely to be in a positive phosphate balance.
The resulting hyperphosphatemia has been shown to be
independently associated with increased risks of death and
cardiovascular complications in patients with chronic kidney
disease (CKD),5,6 with the most pronounced associations being
observed in patients undergoing dialysis.7–9 Phosphate excess
has also been shown to be associated with vascular calcification
and cardiovascular events in individuals with normal kidney
function.10–12 Of importance, individuals consume large
amounts of phosphate through processed foods that are rich
in phosphate additives,13,14 and there is a growing interest
in restricting dietary phosphate as a matter of public health.
In this review, we outline disorders of phosphate meta-
bolism and the adverse effects of hyperphosphatemia with
a primary focus on CKD, address more general aspects of
phosphate toxicity, and discuss future directions for the
management of phosphate balance in individuals with normal
and impaired kidney function.
Phospate omeostatis
In humans, w85% of the total phosphate is in the bone and
teeth, 10% to 15% is in soft tissues, and <1% is in extracellular
753
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fluids. Phosphate homeostasis is maintained by a delicate
balance between intestinal absorption, renal excretion, and
influx to and efflux from bone (Figure 1).
Regulation of intestinal absorption. Phosphate is abundant
in the human diet, with daily dietary phosphate intake
reaching $1500 mg. Approximately 40% to 80% of total
ingested phosphate is absorbed through the intestine. There are
the following 2 mechanisms of intestinal phosphate absorp-
tion: a passive paracellular pathway through tight junctions and
an active transport pathway through the sodium-dependent
phosphate cotransporter Npt2b.15 Active transport of phos-
phate is regulated by calcitriol (1,25-dihydroxyvitamin D),
which induces the expression of Npt2b on the apical mem-
brane of intestinal epithelial cells.16 Low-phosphate diets also
upregulate Npt2b expression independent of calcitriol,17
although the detailed mechanism of this regulation remains
unclear.
In addition to these intrinsic factors, the type of the
diet also has a considerable impact on intestinal phosphate
absorption. The modern diet often contains high levels of
phosphate in the form of preservatives and additive salts that
are readily absorbed by the intestine and can contribute to an
individual’s phosphate burden.13,14 In contrast, phosphate in
plants is primarily in the form of phytic acid and is generally
not bioavailable to humans because humans do not have the
digestive enzyme phytase that degrades phytic acid.18
Regulation of urinary excretion. In humans with normal
kidney function, urinary excretion of excess phosphate is
primarily responsible for maintaining phosphate balance.
After glomerular filtration, the majority of phosphate is
reabsorbed in the proximal tubule. Phosphate transport
across the proximal tubule cells is mediated by Npt2a and
Parathyroid
Dietary glands
phosphate intake
1500 mg/day
Stimulates
PTH
secretion
Extracellular
Phosphate phosphate
absorption
Intestine 900 mg/day
Formation
Fecal
phosphate
600 mg/day
Resorption
Bone
Figure 1 | Phosphate homeostasis in normal physiology. In healthy adults, phosphate homeostasis is maintained by a delicate balance
between intestinal absorption, renal excretion, and influx to and efflux from bone. Fibroblast growth factor 23 (FGF23) and parathyroid
hormone (PTH) play a central role in the regulation of phosphate homeostasis.
754
H Komaba and M Fukagawa: Phosphate—a poison for humans?
Npt2c.19 The amount of Npt2a expressed on the apical
membrane of the tubule cells is primarily regulated by
PTH20,21 and FGF23.22,23 PTH decreases Npt2a expression in
the proximal tubule by driving internalization of Npt2a from
the apical membrane and by decreasing Npt2a gene tran-
scription. On the other hand, the detailed mechanisms by
which FGF23 regulates Npt2a expression in the proximal
tubule are not clear. FGF23 exerts its biological functions by
binding to its cognate FGF receptor in the presence of Klo-
tho, which acts as an obligate cofactor.24,25 However, it is
unknown why FGF23-mediated phosphate excretion takes
place in the proximal tubules even though Klotho is pre-
dominantly expressed in the distal tubular cells.26 One pre-
vious study detected a robust induction of phosphorylated
ERK1 only within Klotho-expressing distal tubule cells
following an FGF23 injection,27 suggesting that FGF23-
mediated intracellular signaling is initiated in the distal tu-
bule. However, the targeted deletion of Klotho in the distal
tubule28 yielded a significant but subtle change in phenotype
relative to that of kidney-specific Klotho-deficient mice.29
Furthermore, a recent study showed that Klotho is also
expressed in proximal tubular cells and that FGF23 directly
downregulates Npt2a in the proximal tubule.30 Further work
is needed to completely elucidate the independent or inter-
active roles of proximal and distal tubular cells in mediating
the actions of FGF23.
In addition to its role as a coreceptor for FGF23, the
extracellular domain of Klotho can be cleaved and released
into circulation where it may function as an endocrine fac-
tor.31 One possible action of this secreted Klotho is to
promote urinary phosphate excretion by suppressing the
expression of Npt2a.32 However, the physiological importance
PTH
Kidney
Npt2a/2c
Filtration
Reabsorption
Stimulates
FGF23
secretion Urinary
phosphate
excretion
900 mg/day
FGF23
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H Komaba and M Fukagawa: Phosphate—a poison for humans?
of this effect remains to be elucidated and deserves further
investigation.
Phosphate-sensing mechanisms. Although putative
phosphate-sensing mechanisms have been shown in Escher-
ichia coli and yeast, it is unclear how mammals sense changes
in extracellular phosphate. Given that FGF23 and PTH are the
2 major hormones that regulate phosphate metabolism, bone
cells and parathyroid cells are the most likely candidates for
sensing extracellular phosphate. Indeed, a series of studies
have shown that high extracellular phosphate levels increase
PTH gene expression and secretion.33,34 However, it remains
unclear how parathyroid cells sense changes in extracellular
phosphate. Several studies have also shown that FGF23 pro-
duction is increased by prolonged dietary phosphate
loading35–37; however, such findings were not evident in a
study of the effects of acute phosphate infusion38 and were
not reliably reproducible in cell culture experiments.39,40
Thus, it is unknown whether bone cells per se sense changes
in extracellular phosphate or whether there are other organs
involved in this phosphate-sensing mechanism.
Of interest, a recent study performed in rats showed that
infusion of phosphate into the duodenum generated a rapid
increase in urinary phosphate excretion without changes in
PTH or FGF23. Furthermore, the infusion of extracts from
duodenal homogenates increased urinary phosphate excre-
tion.41 These data led to the hypothesis that the intestine has
a phosphate sensor that regulates the secretion of an as-yet
undefined intestine-derived phosphaturic factor. Further
Liver
Fetuin A
Removal
by reticulo-
Fetuin-mineral
endothelial
complex
system
(calciprotein
particles)
Bone
Figure 2 | Compensatory mechanisms to maintain phosphate balance in early to moderate chronic kidney disease (CKD). In patients
with early to moderate CKD, increased fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) stimulate urinary phosphate
excretion to maintain phosphate balance. In addition to the increased phosphate excretion induced by FGF23 and PTH, fetuin-A also plays an
important role in the prevention of ectopic calcification. Fetuin-A inhibits the precipitation of calcium phosphate by forming soluble colloidal
protein-mineral nanoparticles called fetuin-mineral complexes or calcitropin particles. These particles are removed by phagocytic cells of the
reticuloendothelial system.
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review
work is needed to determine the primary organs that sense
the phosphate balance in the body and the biological nature
of these sensing mechanisms.
Hyperphosphatemia in CKD and other diseases
Phosphate metabolism in early to moderate CKD. Hyper-
phosphatemia occurs in a variety of disorders, among which
the most common is CKD. Urinary excretion of excess
phosphate is the primary mechanism for maintaining a
neutral phosphate balance; however, serum phosphate levels
are normal in the vast majority of patients in the early and
intermediate stages of CKD, presumably due to a compen-
satory reduction in tubular resorption mediated by increased
levels of FGF23 and PTH42,43 (Figure 2). Emerging data
suggest that increased FGF23 develops earlier than the in-
crease in PTH and that it plays a more important role in
maintaining phosphate balance in patients with CKD.44 The
precise mechanism by which FGF23 levels are increased in
this stage of the disease is unclear. A recent study found that
the kidney plays a key role in FGF23 metabolism,45 but
additional research is required to clarify the mechanisms
involved in the regulation of circulating FGF23 levels for
maintaining a neutral phosphate balance.
Several factors have been identified that modify the rela-
tive importance and roles of FGF23 and PTH in patients with
CKD. A recent study found that in patients with vitamin D
deficiency, PTH levels were markedly elevated relative to
those of FGF23.46 This suggests that the phosphaturic role of
Kidney
Decreased
kidney function
Npt2a/2c
Insufficient
phosphate excretion
Compensation by
stimulating
Positive phosphate excretion
phosphate
balance
Parathyroid
glands
Stimulates
Stimulates
FGF23
PTH
secretion
secretion
PTH
FGF23
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FGF23 is less pronounced when PTH secretion is stimulated
in response to vitamin D deficiency. Another recent study
showed that proteinuria impairs urinary phosphate excretion
by inhibiting the effects of FGF23, which is likely caused by
decreased Klotho expression.47 Therefore, patients with
proteinuria have increased levels of both FGF23 and PTH,
presumably to maintain a normal phosphate balance.
In addition to maintaining phosphate balance, the body
uses a variety of mechanisms to prevent ectopic mineral
precipitation. Emerging research has identified fetuin-A, a
hepatocyte-derived glycoprotein, as a major systemic inhibi-
tor of calcification.48 Fetuin-A inhibits the precipitation of
calcium phosphate by forming soluble colloidal protein-
mineral nanoparticles, which have been called fetuin-
mineral complexes or calcitropin particles (CPPs).49 If
supersaturated conditions persist even after primary CPP
formation, the particles develop crystalline structures to form
elongated particles called secondary CPPs,50 through which
continuous inhibition of ectopic mineral deposition may be
achieved. Removal of CPPs from the circulation has recently
been shown to be predominantly mediated by phagocytic cells
of the reticuloendothelial system51 (Figure 2).
Phosphate metabolism in advanced CKD. In patients with
advanced stages of CKD, progressive reductions in the
number of functional nephrons leads to insufficient phos-
phate excretion even with the compensatory mechanisms of
FGF23 and PTH.44 This results in a positive phosphate bal-
ance and almost universally produces hyperphosphatemia in
patients with end-stage renal disease.
In addition to a reduction in urinary phosphate excre-
tion, abnormal bone metabolism can also contribute to
hyperphosphatemia in patients with CKD through the
effects of disordered bone remodeling characterized by
excess bone resorption relative to the rate of bone forma-
tion. This theory is supported by a recent observational
study showing that higher serum PTH levels are associated
with a higher risk of the development of hyper-
phosphatemia.52 In addition, clinical studies have shown
that the treatment of secondary hyperparathyroidism, using
either cinacalcet hydrochloride53,54 or surgical para-
thyroidectomy,55,56 leads to sustained reductions in serum
phosphate and FGF23 levels, which may in part explain the
potential survival benefit of these interventions.57–59 A
more recent study also showed that velcalcetide, a novel
long-acting calcimimetic agent, attenuated the rise in
serum phosphate levels during the interdialytic period.60 In
future research, it would be interesting to examine whether
treatment of high-turnover bone disease leads to improved
survival through better control of hyperphosphatemia in
patients with CKD.
Secondary hyperparathyroidism. The role of phosphate
retention in the development and progression of secondary
hyperparathyroidism in patients with CKD has been well
established. Traditionally, it has been thought that phos-
phate retention causes a reciprocal decrease in serum cal-
cium, which in turn stimulates PTH secretion, thereby
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H Komaba and M Fukagawa: Phosphate—a poison for humans?
maintaining a normal phosphate balance.61 After the iden-
tification of FGF23, it is now thought that FGF23 is
increased in early CKD, presumably to maintain a neutral
phosphate balance, which in turn results in reductions in the
renal production of calcitriol, thereby stimulating PTH
secretion.62 FGF23 is also known to inhibit PTH secretion,63
but this effect is less pronounced in ESRD because of the
downregulation of the Klotho-FGF receptor 1 complex in
the parathyroid.64,65 Studies performed before the identifi-
cation of FGF23 also suggested that phosphate directly
suppresses renal calcitriol production, thereby causing sec-
ondary hyperparathyroidism.66 The validity of this hypoth-
esis remains to be determined because a recent study has
shown that a phosphate-deficient diet did not increase but
rather decreased serum calcitriol levels in FGF23-knockout
mice.67
In addition to these indirect effects, several studies have
shown that high phosphate levels also directly stimulate PTH
secretion.33,34 This effect has been shown to be mediated by a
posttranscriptional mechanism that regulates the stability of
PTH mRNA.68 High phosphate levels have also been shown
to stimulate parathyroid cell proliferation, which involves the
enhanced expression of transforming growth factor-a.69
However, as mentioned earlier, there is no evidence suggest-
ing the existence of a phosphate sensor on parathyroid cells,
and little is known regarding the initial steps involved in these
phosphate-induced effects.
Hyperphosphatemia in other diseases. Hyperphosphatemia
also occurs in several other diseases (Table 1). Among these,
familial tumoral calcinosis is clinically uncommon but
informative for understanding the critical role of the FGF23-
Klotho system in regulating phosphate homeostasis. This
genetic disorder is caused by an inactivating mutation in the
GALNT3,70 FGF23,71–73 or Klotho74 genes, any of which can
lead to the functional impairment of FGF23. The GALNT3
gene encodes a glycosyltransferase that likely prevents the
degradation of FGF23 through a mucin-type O-glycosylation
at the processing site; thus, an inactivating mutation in the
GALNT3 gene can cause enhanced processing of FGF23,
thereby decreasing circulating levels of biologically active full-
length FGF23.75,76
Table 1 | Major causes of hyperphosphatemia
Phosphate overload
Phosphate-containing enemas
Vitamin D toxicity
Excess bone resorption
Immobilization
Extracellular sift
Tumor lysis syndrome
Rhabdomyolysis
Acidosis
Decreased renal excretion
Kidney disease
Hypoparathyroidism
Pseudohypoparathyroidism (renal resistance to PTH)
Familial tumoral calcinosis
PTH, parathyroid hormone.
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Toxicity of excess phosphate
Vascular calcification. A number of observational studies
have shown associations between hyperphosphatemia and an
increased risk of death in patients with CKD.5–9 One of the
most likely mechanisms linking hyperphosphatemia to higher
risks of mortality is vascular calcification. A growing body of
in vitro studies has shown that the process of vascular
calcification is not merely a passive deposition of calcium-
phosphate crystals but an actively regulated process
resembling osteogenesis in bone.77,78 In support of these
findings, a key osteogenic factor, core binding factor a-1,
which is also known as runt-related transcription factor 2,
was shown to be expressed in calcified arteries from end-stage
renal disease patients.79 A more recent study showed that the
targeted deletion of core binding factor a-1/runt-related
transcription factor 2 in arterial smooth muscle cells in mice
prevented the vascular calcification induced by high-dose
calcitriol treatment,80 indicating that core binding factor
a-1/runt-related transcription factor 2 plays a critical role in
the transition of vascular smooth muscle cells to an osteo-
genic phenotype. High phosphate levels also induce apoptosis
in vascular smooth muscle cells, which in turn triggers
vascular calcification through the release of apoptotic
bodies.81,82 In addition, a recent experimental study showed
that in rats with adenine-induced CKD, high-phosphate diets
induced inflammation both locally in the artery and sys-
temically,83 which may also play a role in the pathogenesis of
the vascular calcification associated with hyperphosphatemia.
Although the effects of high phosphate levels on vascular
smooth muscle cells are considered to be mediated via the
uptake of phosphate through the sodium-dependent phos-
phate cotransporter Pit1,84 recent experimental data suggest
the possibility that calcium phosphate crystals, rather than
increases in free phosphate ions, contribute to the patho-
genesis of vascular calcification.85,86 However, it is unknown
whether these nanocrystals are present in the human circu-
latory system where fetuin-A serves as a systemic inhibitor of
calcium phosphate precipitation. It is also unknown whether
CPPs, which are produced during this process, contribute to
the pathogenesis of vascular calcification.50 Although clinical
studies have identified associations between serum CPP levels
and vascular calcification87 and aortic stiffness,88 it remains to
be determined whether serum CPP level is merely a marker of
the propensity for vascular calcification or whether they are
directly involved in the pathogenesis of this process.
Several investigators have also explored the possibility that
vascular calcification associated with hyperphosphatemia
might, in part, be mediated by FGF23. However, there are
conflicting reports on whether vascular calcification can
either be potentiated or inhibited by FGF23.89–91 These
inconsistent results may suggest the relative importance of
phosphate per se rather than FGF23 in vascular calcification.
Endothelial dysfunction. Endothelial dysfunction is
another consequence of hyperphosphatemia, and it can also
lead to an increased risk of cardiovascular disease. Several
experimental studies have shown that high phosphate
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concentrations impair endothelium-dependent vasodilation
by inhibiting nitric oxide production.92–94 High phosphate
levels also induce apoptosis in endothelial cells, thereby
impairing endothelial integrity.92,93 Supporting these experi-
mental data, recent clinical studies have shown that dietary
phosphate loading lowered flow-mediated dilation in healthy
men,94 whereas treatment with the phosphate binder seve-
lamer improved flow-mediated dilation in predialysis CKD
patients.95 The effects of high phosphate levels on endothelial
cells appear to be direct and mediated via phosphate uptake
through Pit1.92,93 It is unknown whether calcium phosphate
nanocrystals induce endothelial cell dysfunction, as has been
shown in the experiments on vascular smooth muscle cells.
Left ventricular hypertrophy. Left ventricular hypertrophy
(LVH) is another common manifestation of cardiovascular
disease in patients with CKD, which may also mediate the
association between hyperphosphatemia and the higher risk
of death in this population. Observational studies96,97 and
animal studies98,99 have shown associations between hyper-
phosphatemia and LVH. However, the direct causal role of
phosphate in the pathogenesis of LVH is still not completely
understood.
Recently, increasing attention has been devoted to the
possibility that FGF23 can cause pathologic LVH. This pos-
sibility was first raised based on clinical observations showing
associations between elevations in FGF23 levels and the
prevalence of LVH100 and the future risk of new-onset
LVH.101 These associations were subsequently proven in cell
culture experiments and animal studies.101 As cardiomyocytes
do not express Klotho, it was suggested that the hypertrophic
effects of FGF23 are mediated via Klotho-independent
signaling through FGF receptors. A follow-up study from
the same group further demonstrated that FGF23 exerts hy-
pertrophic effects by activating FGF receptor 4 and that a
specific inhibition of this receptor inhibits the FGF23-induced
hypertrophy of isolated cardiac myocytes and attenuates LVH
in rats with CKD.102 Another recent study showed that FGF23
increases renal sodium reabsorption by upregulating the
Naþ:Cl cotransporter in the distal tubules via a Klotho-
dependent pathway.103 This could also induce LVH through
volume expansion and hypertension. In addition to the
pathogenic roles of FGF23 in LVH, previous studies have
shown that PTH also exerts hypertrophic effects on car-
diomyocytes.104 Collectively, it is likely that LVH associated
with hyperphosphatemia in patients with CKD is, at least in
part, mediated through elevated FGF23 and PTH levels.
Kidney disease progression. Acute hyperphosphatemia, as
encountered in patients treated with phosphate-containing
enemas, can cause acute or subacute kidney injury, which is
referred to as acute phosphate nephropathy.105 Although the
detailed mechanisms of this process are not fully understood,
it is generally accepted that an elevated intratubular phos-
phate concentration results in the precipitation and tissue
deposition of calcium phosphate salts, which causes luminal
obstructions and tubular epithelial injury. Similar pathologic
processes can occur in CKD rats,106 and several animal107,108
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and human109 studies have suggested that a low phosphate
diet slows the progression of CKD. Epidemiologic studies also
suggested that higher serum phosphate110 or FGF23111–113
levels predict a more rapid decline in kidney function in the
CKD population. These data raise the possibility that high
phosphate intake together with a decreased number of
nephrons can result in an elevated intratubular phosphate
concentration, which induces tubular damage and renal
fibrosis. Of note, a recent cohort study of the general popu-
lation showed that higher FGF23 levels were independently
associated with higher risks of the development of end-stage
renal disease, but that it was not as predictive of the incidence
of CKD.114 These findings may suggest that enhanced phos-
phaturia, predominantly mediated by elevated FGF23 levels,
exposes tubules to intraluminal phosphate concentrations
that are sufficiently high to induce tubular toxicity in those
with established CKD but not in those with normal kidney
function.115
Bone disease. Hyperphosphatemia is one of the major
contributors to the development of secondary hyperparathy-
roidism; thus, excess phosphate can cause high-turnover bone
disease through the stimulation of PTH secretion. Indeed, in
rodent models of CKD, a high-phosphate diet is known to
induce high-turnover bone disease, and treatment of hyper-
phosphatemia by sevelamer hydrochloride has been shown to
improve high-turnover bone disease.116 This may also be the
case for humans, although previous studies focused on
comparisons between different phosphate binder clas-
ses,117,118 and no placebo-controlled trials have evaluated the
impact of phosphate-lowering therapy on bone histology.
Several lines of experimental evidence also suggest that FGF23
directly affects bone metabolism,119,120 but conflicting results
have been reported regarding the associations of serum
FGF23 levels with fracture risk in older individuals.121,122
Aging and cytotoxicity. The toxic effects of excess phos-
phate have been well characterized in genetically modified
animal models. Klotho-deficient (kl/kl) mice26 and FGF23-
knockout mice23 are 2 major mouse models that have pro-
vided instructive information on the effects of phosphate
toxicity. Klotho was originally identified as an antiaging gene,
as complex phenotypes resembling those observed in human
aging were shown to develop in kl/kl mice.26 An identical
phenotype was also observed in FGF23-knockout mice.23 It is
currently accepted that, for the most part, these premature-
aging features are caused by severe hyperphosphatemia as a
result of impaired function of the FGF23-Klotho system.
Indeed, it has been shown that the lethal phenotypic effects
observed in kl/kl mice and FGF23-knockout mice were
attenuated by feeding them a low-phosphate diet.67,123 In
addition, genetic ablation of Npt2a has also been shown to
rescue the phenotype of Klotho-knockout mice124 and
FGF23-knockout mice.125 More importantly, in Klotho/
Npt2a double knockout mice, the aging phenotype was
restored when the mice were fed a high-phosphate diet.126
These data suggest the hypothesis that phosphate toxicity
can accelerate the mammalian aging process. Of interest,
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H Komaba and M Fukagawa: Phosphate—a poison for humans?
phosphate overload has also been shown to shorten life spans
in nonmammalian species such as Drosophila,127 suggesting
that the toxic effect of excess phosphate is evolutionarily
conserved across diverse species.
The mechanisms by which hyperphosphatemia accelerates
aging are largely unknown, but several possibilities exist.
Probably one of the most reasonable mechanisms is that the
vascular calcification induced by hyperphosphatemia is
responsible for the observed age-related effects. Although
there is no direct evidence, alterations in systemic or regional
hemodynamics due to vascular calcification may induce
cellular damage and stress in the perfused tissue, which may
accelerate the aging process. From the perspective of cellular
metabolism, it is possible that excess phosphate, if taken up
intracellularly, might cause dysregulation of the
phosphorylation-dependent signaling pathways.2 In addition,
recent studies have shown that elevated extracellular phos-
phate concentrations cause mitochondrial oxidative stress by
increasing the mitochondrial membrane potential, leading to
caspase activation and the subsequent induction of
apoptosis.128 Another recent study showed that high phos-
phate levels directly induce systemic inflammation,83 which
may cause accelerated aging and vascular calcification. Finally,
a high-phosphate diet has also been shown to stimulate the
growth of lung tumors,129 suggesting that excess phosphate
may induce tumorigenesis in the aging process.
Possible toxicity of compensatory mechanisms. Observa-
tional studies have shown associations between higher serum
phosphate levels and poor clinical outcomes in patients with
predialysis CKD.5,6 Epidemiologic studies of the general
population have also shown associations of serum phosphate
with cardiovascular events and vascular calcification.10–12
However, it should be noted that serum phosphate levels
associated with adverse outcomes are within or only slightly
above the normal range and are much lower than those used
to induce pathologic calcification in experimental models.
There are 3 possibilities that could explain these findings.
First, the slight increase in serum phosphate level may reflect
an elevated intratubular phosphate concentration, which can
cause kidney injury, as described previously. This may be
clinically relevant because impaired kidney function is a
powerful predictor of mortality and cardiovascular events.130
Second, it is possible that a single measurement of serum
phosphate provides only a partial assessment of total phos-
phate balance and its associated calcification risk. This pos-
sibility is supported by the observation that serum CPP levels,
a potential marker of calcification propensity, begin to rise
before the appearance of hyperphosphatemia in those
with CKD.87,88 Third, the homeostatic response to maintain
phosphate balance may be responsible for the associations
between higher serum phosphate levels and adverse out-
comes. As discussed previously, a growing body of evidence
suggests causal roles for FGF23 and PTH in the pathologic
development of LVH.100–104 Previous and recent studies have
also suggested a link between FGF23 or PTH and renal
anemia131,132 and between these molecules and immune
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dysfunction.133,134 Furthermore, a very recent study showed
that in 5/6 nephrectomized mice, PTH induced adipose tissue
browning and cachexia and, thereby, presumably induced
skeletal muscle atrophy.135 Thus, there are multiple mecha-
nisms linking the physiological response for maintaining
phosphate homeostasis with adverse clinical outcomes. A
schematic representation of the toxic effects of phosphate per
se and the compensatory mechanisms involved are provided
in Figure 3.
Future directions for phosphate management
The importance of controlling hyperphosphatemia has
already been well recognized for the management of dialysis
patients.136 However, it should be stressed that the current
approach is not based on definitive evidence. Although recent
observational studies have shown independent associations of
phosphate binder use with improved survival,137–139 no ran-
domized trials have yet proved whether the management of
serum phosphate actually improves clinical outcomes. The
ideal target level of serum phosphate also remains to be
determined. In this regard, clinical trials comparing the sur-
vival of intensive versus conventional serum phosphate con-
trol are urgently needed and would be appropriate as the next
step for research in this field of study.
Observational data linking higher serum phosphate levels
with adverse outcomes in predialysis CKD patients suggest
the potential benefit of managing phosphate in this popula-
tion.5,6 Several lines of evidence suggest that elevations in
FGF23 and PTH levels are responsible for the adverse effects
of excess phosphate, but the inhibition of these compensatory
mechanisms is clinically impracticable because it leads to
detrimental alterations in mineral metabolism.140,141 Thus, an
adequate approach may be dietary phosphate restriction and
the administration of phosphate binders. Testing this
approach, several recent studies compared the effects of
phosphate binders versus those of placebos on intermediate
endpoints for cardiovascular disease.142,143 However, these
studies found no significant benefit of phosphate binders.
One possible reason for these null findings may be a
compensatory upregulation of Npt2b in the intestine, which
could counteract the effects of phosphate binders. This pos-
sibility has recently been demonstrated in an experimental
study using Npt2b-deficient mice144 and will be addressed by
the COMBINE study.145 This clinical study will examine the
effects of lanthanum carbonate plus nicotinamide, which
decreases Npt2b expression, on serum phosphate and FGF23
levels in patients with stage 3-4 CKD.
Emerging data on the general toxicity of excess phosphate
also highlight the importance of subjects with normal kidney
function as potential targets for phosphate management.
However, several caveats should be addressed. First, if kidney
function is normal, dietary phosphate overload causes only a
slight increase in serum phosphate levels, if any at all, and this
is unlikely to exert any cytotoxic effects. Second, because
healthy subjects have a sufficient number of nephrons, in-
creases in intratubular phosphate concentration that are high
enough to induce kidney injury may not occur. Third, the
increases in serum FGF23 or PTH in response to phosphate
overload are much smaller in the general population than
they are in patients with CKD.35–37 Therefore, a physiological

Vascular calcification • Dysregulation of cell signaling

Endothelial dysfunction • Oxidative stress
Direct cell • Apoptosis
toxicity • Inflammation
Induces osteogenic
differentiation
Phosphate High intratubular
?
phosphate

Stimulates PTH
Fetuin-mineral Stimulates secretion Kidney disease
complex FGF23 progression
(calciprotein particles) secretion

FGF23 Stimulates bone Secondary

resorption PTH hyperparathyroidism
Induces hypertrophy
of cardiomyocytes

Browning of
Inhibits adipose tissue
Left ventricular sodium excretion
hypertrophy
Volume Immune Muscle atrophy
expansion dysfunction
Inhibits Renal
calcitriol production anemia

Figure 3 | Schematic representation of phosphate toxicity. Excess phosphate exerts toxic effects through a variety of pathways. High
phosphate levels directly potentiate vascular calcification and endothelial dysfunction, promote the progression of kidney disease, and induce
cell stress and apoptosis. High phosphate levels also contribute to adverse outcomes through increases in the levels of fibroblast growth factor
23 (FGF23) and parathyroid hormone (PTH), including left ventricular hypertrophy, renal anemia, immune dysfunction, adipose tissue browning,
and skeletal muscle atrophy.

Kidney International (2016) 90, 753–763 759

review
increase in FGF23 or PTH would not generate harmful effects
because the off-target effects of FGF23 and PTH require
marked elevations in their circulating levels.100–104 Taken
together, our current knowledge does not convincingly sup-
port the idea that increased phosphate intake within the usual
dietary range causes adverse outcomes. One possible excep-
tion is in cases in which de novo kidney disease or injury has
occurred. In this situation, dietary phosphate overload, as
reflected by elevated FGF23 levels, may accelerate the pro-
gression of kidney damage until the disease is identified.
CONCLUSIONS
Recent investigations have uncovered the toxic effects of
excess phosphate on the cardiovascular system and the aging
process. Compelling evidence also suggests that elevated
FGF23 and PTH levels in response to a positive phosphate
balance contribute to these adverse clinical outcomes. These
insights support the current practice of managing serum
phosphate in patients with advanced CKD. However, defini-
tive evidence is lacking, and clinical trials to determine the
benefit of phosphate management are desperately needed and
should be strongly encouraged.
Given the potential toxicity of excess phosphate, the gen-
eral population may also be viewed as a target for phosphate
management. However, a widespread implementation of di-
etary phosphate intervention in the general population may
not be warranted because the impact of increased phosphate
intake on mineral metabolism and clinical outcomes is much
less pronounced in individuals with normal kidney function.
Nonetheless, the increasing incidence of kidney disease or
injury in our aging society146 emphasizes the potential
importance of this issue. Further work is needed to more
completely characterize phosphate toxicity and to establish
the optimal therapeutic strategy for managing phosphate in
patients with CKD and in the general population.
DISCLOSURE
HK has received honoraria, consulting fees, and grant/research
support from Kyowa Hakko Kirin. MF has received honoraria,
consulting fees, and/or grant/research support from Bayer Yakuhin,
Kyowa Hakko Kirin, and Torii Pharmaceutical.
ACKNOWLEDGMENTS
This work was supported in part by a Grant-in-Aid for Scientific
Research (C) (25461257) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
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