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Hyperphosphatemia of Chronic Kidney Disease
Keith A Hruska, M.D.
1,2
, Suresh Mathew, M.D.
1
, Richard Lund, M.D.
3
, Ping Qiu
4
, and
Raymond Pratt
4
1
Renal Division, Department of Pediatrics, Washington University, St Louis, Missouri
2
Renal Division, Department of Medicine, Washington University, St Louis, Missouri
3
Creighton University, Omaha, Nebraska
4
Shire Pharmaceuticals, Wayne, PA
Abstract
Observational studies have determined hyperphosphatemia to be a cardiovascular risk factor in
chronic kidney disease. Mechanistic studies have elucidated that hyperphosphatemia is a direct
stimulus to vascular calcification, which is one cause of morbid cardiovascular events contributing
to the excess mortality of chronic kidney disease. This review describes the pathobiology of
hyperphosphatemia that develops as a consequence of positive phosphate balance in chronic kidney
disease and the mechanisms by which hyperphosphatemia acts on neointimal vascular cells that are
stimulated to mineralize in chronic kidney disease. The characterization of hyperphosphatemia of
chronic kidney disease as a distinct syndrome in clinical medicine with unique disordered skeletal
remodeling, heterotopic mineralization and cardiovascular morbidity is presented.
Introduction
Hyperphosphatemia is associated with significant pathophysiology in chronic kidney disease
(CKD). This pathophysiology contributes to the high rates of mortality observed in CKD (1).
Approximately 11–15% of Americans have CKD (2–4), and their risk of death due to a
cardiovascular event related cause is higher than their risk of surviving and needing renal
replacement therapy for end stage kidney disease (ESKD) (1,2,4). The mortality rates of
patients surviving CKD and receiving hemodialysis are extremely high such that a 30 year old
patient with ESKD has a life expectancy similar to a ninety year old with normal renal function
(2). The mechanisms of this excess risk of cardiovascular disease are not completely
understood. The well characterized risks of cardiovascular disease in the general population
do not explain the increased risk in CKD (1,3). Observational studies suggest that the well
known propensity of ESKD patients to develop heterotopic mineralization of soft tissues
including the vasculature is an important component of the cardiovascular risks of ESKD (5,
6). Furthermore, several observational studies demonstrate that hyperphosphatemia is an
independent cardiovascular risk factor in CKD (7–9). Hyperphosphatemia has been linked to
vascular calcification (5,10)(11).
Pathogenesis
To consider the pathogenesis of hyperphosphatemia in CKD, it is useful to review the
mechanisms of phosphate homeostasis (Figure 1). We ingest approximately 1000–1200 mg of
Corresponding Author: Keith A Hruska, M.D., Division of Pediatric Nephrology, Department of Pediatrics, Washington University,
McDonnell Pediatric Research Bldg, Room 5109, Campus Box 8208, 660 S. Euclid Avenue, St. Louis, Mo 63110, Ph 314-286-2772,
Fax 314-286-2894, Hruska_k@kids.wustl.edu.
NIH Public Access
Author Manuscript
Kidney Int. Author manuscript; available in PMC 2009 August 31.
Published in final edited form as:
Kidney Int. 2008 July ; 74(2): 148–157. doi:10.1038/ki.2008.130.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
phosphorus in the average American diet of 2007. Of this, a net of about 800 mg is absorbed
into the exchangeable phosphorus pool. This pool consists of intracellular phosphorus (70%),
the skeletal mineralization front (29%) and the serum phosphorus (<1%). Exit from the
exchangeable pool is through skeletal deposition, renal excretion, and intestinal secretion
(Figure 1). Exit from the exchangeable pool into the skeleton is matched by entry from the
skeleton into the pool in adulthood, and therefore, we do not normally think of the skeleton as
a key contributor to the level of phosphorus concentration in the pool, but in chronic kidney
disease, as we will show below, it is very important. Regulation of phosphorus excretion by
the kidney is the key mechanism of maintaining phosphate balancein normal day to day life.
Kidney injury impairs the ability of mammals to maintain phosphorus balance, and in human
chronic kidney disease, phosphorus homeostasis is lost and positive phosphate balance occurs
in the later stages (4 and 5) of kidney diseases (12,13). Loss of phosphorus homeostasis due
to excretion failure in chronic kidney disease results in hyperphosphatemia (14) due to positive
balance increasing the concentration in the exchangeable phosphorus pool, often when the pool
size is reduced as in the adynamic bone disorder (Figure 2). Surprisingly and not generally
adequately considered, the skeleton contributes to hyperphosphatemia in CKD and ESKD
through the effects of disordered bone remodeling. There are multiple skeletal remodeling
disorders discussed below in CKD, but all of them are associated with excess bone resorption
compared to bone formation. Thereby, they contribute to hyperphosphatemia and effectively
block the skeleton from exerting its normal reservoir function when positive phosphate balance
occurs.
The normal function of the skeleton as a reservoir when phosphate balance is positive is seen
in several syndromes of hyperphosphatemia in mammalian pathophysiology (Table 1). All of
these except immobilization and chronic kidney disease are associated with increased skeletal
mass and mineralization due to phosphorus deposition into the skeletal storage reservoir (see
section on “Other Hyperphosphatemic Syndromes”). In chronic kidney disease, there is a
complex set of losses and adaptations in skeletal function that produce bone disorders that
complicate the state (see section on “Renal Osteodystrophy”). Recent discoveries characterize
all forms of skeletal function disorder in chronic kidney disease as having excess bone
resorption rates compared to bone formation rates (see section on “Osteoporosis in chronic
kidney disease”). Therefore, the skeleton is contributing to hyperphosphatemia in chronic
kidney disease, and the reservoir function of the skeleton that is supposed to act in the presence
of positive phosphorus balance is blocked. The outcome of this change in physiology to a new
pathophysiology requires that a new phosphate reservoir for the positive balance is established.
This new reservoir is soft tissue organs including the vasculature (Figure 2). The problem with
establishing the new reservoirs of phosphate storage is that they produce disease.
Regulation of phosphate balance during CKD before loss of balance occurs is complex. Loss
of calcitriol production capacity is an important factor leading to a decrease in Ca absorption,
hypocalcemia and stimulation of parathyroid hormone (PTH) secretion (Figure 3). The increase
in PTH levels reduces the fraction of the filtered phosphate load and maintains phosphate
excretion at normal levels despite the reduction in the filtered load of phosphorus due to the
decrease in glomerular filtration. The decrease in calcitriol production also represents a
decrease in the signal to the osteocytes and osteoblasts for the production of fibroblast growth
factor 23 (FGF23) (15). However, the tendency for decreased production is overcome by the
fact that FGF23 is normally catabolized by glomerular filtration and proximal tubular
degradation. Thus, the protein levels increase in CKD as the GFR decreases (16,17). This is a
second potent stimulus to phosphorus excretion as kidney function is diminished. The relative
contributions PTH and FGF23 make to phosphate homeostasis during CKD have not been
determined, but in the absence of either homeostasis is lost. A third stimulus for increased
phosphate excretion is phosphate itself which also potently inhibits the activity of the proximal
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tubular sodium dependent Pi transport proteins (Na/Pi co-transporters, NaPi2a and NaPi2c
(18)(19)).
The sodium dependent phosphate transport protein, NaPi2a (approximately 70% of proximal
tubular phosphate transport), is regulated mainly by endocytic vesicle cycling in an out of the
apical membrane of the epithelial cell (20,21)(19). It is directly regulated by Pi concentrations
(20,21)(18). Low Pi increases decreases vesicular retrieval from the plasma membrane while
high Pi concentrations stimulate it (20). A late effect of Pi concentration is a slight change in
gene transcription of NaPi2a with greater effects on protein levels, and stimulation of
transcription of NaPi2a associated proteins (such as (diphor-1) by low and inhibition by high
Pi (20,22). Similar experiments have not been performed for the minor, but very important
NaPi2c of the proximal tubule. NaPi2b of the duodenal enterocyte is a transcriptional target of
the vitamin D receptor (VDR) and dietary phosphorus (23), but calcitriol deficiency or
hyperphosphatemia in CKD do not result in decreased intestinal phosphate absorption, because
the decrease in active duodenal transport is compensated by passive transport through
enterocyte paracellular pathways in the rest of the intestine.
One of the new reservoirs for phosphate deposition established when excretion is no longer
sufficient to maintain balance, the vasculature (Figure 2), is especially disease causing.
Vascular calcification in CKD is not well tolerated as it produces blood vessel stiffness (Figure
4). There are two forms of vascular calcification prominent in CKD, calcification of
atherosclerotic neointimal plaques and arterial medial calcification. CKD markedly stimulates
both forms. The atherosclerotic calcification is especially appreciated in the coronary arteries
as it is measured by the increasingly popular imaging techniques for determining coronary
artery calcification (24,25). However, arterial medial calcification is as clinically important,
as it is the likely the most important factor in vascular stiffness and increased pulse pressure
in CKD.
In order to study the mechanisms of CKD stimulated vascular calcification, we developed a
translational animal model. We started with a model of atherosclerosis that develops cardiac
valvular and atherosclerotic neointimal plaque calcification, the low density lipoprotein
receptor deficient mouse (LDLR−/−) fed a high fat diet. To the model we added ablation
induced kidney failure, and demonstrated marked stimulation of aortic atherosclerotic
calcification (26). We discovered that bone morphogenetic protein-7 (BMP-7) prevented the
development of CKD stimulated vascular calcification (26). Furthermore, the high fat fed CKD
mice exhibited hyperphosphatemia that was corrected by BMP-7 (27). In investigating the
mechanism of hyperphosphatemia correction by BMP-7 we found that bone formation was
stimulated correcting the adynamic bone disorder that complicates the kidney failure in these
mice (27). Renal phosphate excretion was not increased, and we questioned how much of the
BMP-7 effect on vascular calcification was due to bone formation induced correction of
hyperphosphatemia. To examine this, we added phosphate binders to the high fat diet in an
attempt to isolate hyperphosphatemia correction as a single entity separate from the other
actions of BMP-7. To our surprise, phosphate binders were very effective in preventing
vascular calcification. We first used CaCO3 (27), but subsequently have studied sevelamer
carbonate (Figure 5) (28) and LaCO3 with similar results.
The LDLR−/− high fat fed mouse is characterized by obesity, hypertension and insulin
resistance that progresses to diabetes and severe hypercholesterolemia. Thus, the mouse model
is relevant to the human metabolic syndrome, and the development of kidney disease in obese
diabetics. Even the renal osteodystrophy complicating CKD, the adynamic bone disorder, is
the same as observed in patients with diabetic nephropathy. The vascular calcification of the
model was discovered by Towler and Semenkovich (29). They found that osteoblastic
transcriptional activity was present in the aorta, and their model is the starting point to which
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we add CKD. At the beginning, in other words our high fat fed sham operated animals,
expressed BMP-2, BMP-4, Runx2, Msx2, osteocalcin and osteopontin in the vasculature,
especially the aorta. This is relevant because several investigators have demonstrated that the
vasculature of patients with CKD/ESKD expresses osteoblastic markers (30–33). However,
our high fat fed sham operated animals had a low level of vascular calcification that was
stimulated two to four fold by the induction of CKD (26).
To further investigate mechanisms of atherosclerotic calcification, we developed an in vitro
model to study in cell culture with the strategy of confirming discoveries made in vitro using
our animal model. We began by obtaining primary cultures of human vascular smooth muscle
cells (hVSMC) from areas of aortic atherosclerotic plaques, which were expanded and then
exposed to an increase in media phosphorus concentrations (Figure 6). We demonstrated that
the starting tissue and the primary cultures in regular media expressed BMP-2, BMP-4, Runx2,
Msx2, osteocalcin and osteopontin. Thus, it appeared that BMP-2 and 4 as bone morphogens
were stimulating an osteoblastic differentiation program in vascular cells directed by the
osteoblast specific transcription factors. This data is in agreement with other investigators
(34), including those who reported increased levels of BMP-2 and 4 in atherosclerotic lesions
(35,36). However, the primary hVSMC cultures did not mineralize the extracellular matrix as
osteoblast cultures do (Figure 6) (37). When media phosphorus was increased by 1 or 2 mM
to 2 or 3 mM (equal to a serum phosphorus of 6 to 9 mg/dl), heavy matrix mineralization
ensued. Analysis of the osteoblastic transcription program revealed that the very low levels of
osterix expression in the starting cultures were increased several fold by the increase in media
phosphorus. Blocking the increase in osterix expression in high phosphate media prevented
matrix mineralization (38). Both our translational model in vivo and our cell culture model in
vivo represent mineralization due to the atherosclerotic process. We observe mainly neointimal
calcification in vivo, and the medial calcification we observe is in proximity to atherosclerotic
plaques.
When we examined our high fat fed LDLR−/− aortas from the various groups of animals, we
found that the sham operated high fat fed animals had low or undetectable levels of osterix
expression that were increased several fold when CKD was induced (38). Most importantly,
treatment of CKD high fat fed hyperphosphatemic animals with phosphate binders inhibited
osterix expression (Figure 7) (38). As expected without a critical osteoblastic transcription
factor, matrix mineralization (neointimal calcification) was severely compromised similar to
results shown in Figure 5.
The mechanism of phosphorus stimulation of matrix mineralization in vitro has been studied
by Jono et al (39) and Li et al (40) in VSMC and by Beck et al in osteoblastic cells (41)(42).
These authors have demonstrated that the effect of media phosphorus was through activation
of ERK1/2, and it was blocked by an inhibitor of sodium dependent phosphate transport
proteins, phosphonoformic acid (PFA). However the effects of PFA are relatively specific to
the type 2 Na/Pi cotransporters (43). A sodium dependent phosphate transport protein of the
VSMC is Pit-1, and an RNAi to Pit-1 also inhibited the actions of high phosphorus media
(40,43). The effects of PFA in VSMC mineralization may have been due to the role of
phosphonates to inhibit phosphate crystal formation, although NaPi2a has recently been found
in osteoblast-like cells (43,44). Other recent studies of Pi transport in VSMC indicate that Pit-1
and Pit-2 account for Na-dependent transport, which is only modestly inhibited by high
concentrations of PFA(45). In subsequent studies reported in abstract form at this writing, the
authors demonstrate that these concentrations of PFA induce cytotoxicity (46). Despite the
recent clarification regarding effects of PFA on VSMC, the studies with RNAi to Pit-1 (45)
(40) indicate that blocking the actions of high phosphorus culture media in vitro are similar to
the effects of lowering the serum phosphorus in vivo, that of inhibiting osteoblastic stimulation
of matrix mineralization.
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Thus, phosphorus is more than a stimulator of vascular calcification acting through an elevated
calcium-phosphorus product in CKD and ESKD. It is a signaling molecule serving to complete
osteoblastic differentiation in the aorta, and an important component of the action of CKD to
stimulate atherosclerotic calcification. The results of the translational animal studies and the
studies in vitro just discussed are in agreement with a new clinical consensus that has lead to
renaming of renal osteodystrophy by the KDIGO Foundation as the chronic kidney disease
mineral bone disorder (CKD-MBD) in recognition of the roles of the skeleton in
hyperphosphatemia and vascular calcification (47).
Other Hyperphosphatemic Syndromes
Hyperphosphatemic syndromes occur due to a variety of causes (Table 1). Hyperphosphatemia
due to intravenous hyperalimentation (TPN) in an immobilized patient is the most common
cause of hyperphosphatemia in clinical medicine. Here the phosphate content of the TPN
prescription equivalent to normal dietary intake is associated with hyperphosphatemia leading
to removal of phosphate from the parenteral alimentation. Sometimes removal of phosphate
intake does not correct the hyperphosphatemia and patients require inhibition of bone
resorption to correct the hyperphosphatemia. The immobilization syndrome has at least two
key features in common with the hyperphosphatemia of CKD. The first is the severe inhibition
of bone formation associated with immobilization that resembles the inhibition of bone
formation in the adynamic bone disorder of CKD/ESKD. The second is the excess bone
resorption contributing to the hyperphosphatemia. The major difference from the
hyperphosphatemia of CKD may be duration of the syndrome which in the case of
immobilization is insufficient to calcify the vasculature and produce cardiac events due to the
hyperphosphatemia.
Transcellular shifts of phosphate associated with catabolism, tumor lysis or rhabdomyolysis
are also relatively common causes of hyperphosphatemia (Table 1). Hyperphosphatemic
syndromes due to decreased renal excretion besides chronic kidney disease are uncommon in
clinical medicine. Of these, FGF23 deficiency genetically produced in the mouse is especially
instructive. FGF23 null mice exhibit hyperphosphatemia, elevated calcitriol levels and
increased skeletal mineralization including chondrosseous junctions, the primary spongiosa,
and heterotopic sites such as various organs and the vasculature (48). The mice die at about
thirteen weeks due to cardiovascular complications. The phenotype of the FGF23 null mice is
rescued by the production of a double genetic deficiency for FGF23 and 25
hydroxycholecalciferol 1 alpha hydroxylase (49). This demonstrates the role of excess
calcitriol in the FGF23 null phenotype. Interestingly, the vascular calcification of the FGF23
null phenotype is also rescued by low phosphate diets (50).
FGF23 is a recently discovered phosphaturic hormone, responsible for autosomal dominant
hypophosphatemic rickets through an activating mutation (51). The recent discovery that
inactivating mutations cause the rare human disease of familial tumoral calcinosis completes
the story told by the FGF23 null mice due to similarities in the phenotypes. The premature
cardiac death in FGF23 deficient mice is reminiscent of the early coronary artery disease in
Klotho mice (52,53). Klotho has recently been discovered to function as a co-receptor for
FGF23 in the proximal tubule (54), and Klotho inactivation has also been found to cause
familial tumoral calcinosis (55). Thus, the role of hyperphosphatemia in stimulating heterotopic
mineralization has clearly been demonstrated in mice and men. The unique aspect of
hyperphosphatemia in CKD is that the skeletal response to hyperphosphatemia, increased
deposition of phosphate, is blocked.
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Renal Osteodystrophy
There are several disorders of bone remodeling that complicate CKD and ESKD. These have
been characterized histomorphometrically and correlated to PTH levels to estimate bone
turnover rates. This process has to be replaced in order to monitor the skeleton more closely
as is necessary to optimize cardiovascular therapy in CKD. Our current practice of using PTH
levels to correlate with bone turnover is insufficient in terms of sensitivity and fails to detect
excess bone resorption. Presently, high PTH levels (>500 pg/ml with an intact hormone assay)
are thought to indicate increased skeletal remodeling due to secondary hyperparathyroidism.
While this is generally correct, it does not measure the impact of elevated remodeling in CKD
on bone mass or strength. The elevated remodeling associated with secondary
hyperparathyroidism, produces an osteoblast phenotype that has reduced secretion of type 1
collagen and increased production of RANK ligand (RANKL), the critical osteoclast
differentiation factor. This results in bone resorption outpacing bone formation. In addition,
the high remodeling rates are characterized by insufficient replacement of newly formed
atypical “woven” bone with bone formed on collagen lamellae. Thus, even with normal bone
mass, skeletal frailty may be problematic in high turnover osteodystrophy in CKD/ESKD.
A secondary effect of hyperphosphatemia in CKD is stimulation of nodular hyperplasia of the
parathyroid glands (56–59). Hyperplastic chief cells from the nodular areas are of clonal origin
demonstrating less of cell cycle control (60). Clinically, this phenomenon accounts for the loss
of control of the adaptive function of secondary hyperparathyroidism in CKD, and results in
very elevated PTH levels that are difficult to treat and clinical manifestations of severe
secondary hyperparathyroidism. This often leads to parathyroidectomy in order to treat the
clinical complications of the uncontrolled PTH levels.
With prevalent administration of high doses of vitamin D analogs in CKD/ESKD, a newer
(discovered in the 1980’s) low turnover form of renal osteodystrophy has become increasingly
common, termed the adynamic bone disorder (ABD) (61–63). The ABD was originally thought
to be due to suppression of osteoblast function with high doses of vitamin D analogs (61,63).
The finding that vitamin D analogs stimulate, not inhibit, bone formation and osteoblast
function has put this contention to rest (64–66). What is likely the case is that the negative
effects of CKD on skeletal anabolism are uncovered by suppression of PTH. This demonstrates
that higher than normal PTH levels are required to maintain bone remodeling in CKD (67).
Many different mechanisms of resistance to the actions of PTH in CKD have been proposed
including desensitization of the PTH receptor by persistent high PTH levels (68). While this
is likely, another mechanism is probably central and critical. The endosteal osteoblast forms
the niche of the hematopoietic stem cell (HSC) (69–71), and loss of osteoblast surface and
number as a result of loss of skeletal anabolism due to kidney injury threatens hematopoiesis.
There are three principles that regulate the HSC niche, the bone morphogenetic proteins
(BMPs), the Wnts, and PTH (69,71). Loss of BMP or Wnt influence as a result of kidney injury
would lead to a need for higher levels of PTH to protect niche function and skeletal remodeling.
The point that is well established is that in ESKD, higher than normal PTH levels are required
to maintain normal rates of skeletal remodeling, i.e. PTH levels recommended in the KDOQI
guidelines.
The loss of skeletal remodeling after renal injury produces a mechanism of increasing PTH
secretion due to the decrease in the exchangeable phosphorus pool size (Figure 2). Now boluses
of phosphorus, as with meals, distribute in a smaller pool and produce intermittent short-lived
stimuli to increased PTH secretion either through secondary effects on serum Ca or due to
direct effects of transient increased in serum phosphorus that may be within the normal range.
This all occurs in the face of normal fasting levels of Ca and PO4. Renal osteodystrophy begins
early in CKD. It is often first detected by elevated PTH levels in the face of normal Ca, PO4
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and calcitriol levels (14). In this setting, the cause of the increase in PTH levels is a decrease
in the exchangeable PO4 pool size due to a loss of the skeletal mineralization front that occurs
when the normal stimulus to bone formation is lost due to kidney injury. The role of FGF23
which is increased before changes in Ca, Pi or calcitriol on PTH secretion are unclear despite
recent studies (72). The underpinning of renal osteodystrophy by a loss of skeletal anabolic
potential due to kidney injury is poorly appreciated, but it is often uncovered when PTH levels
are suppressed to near normal levels, producing the adynamic bone disorder (62,63,73).
Osteoporosis in chronic kidney disease
The balance between bone formation and resorption may be either negative or positive in CKD.
When positive, osteosclerosis results, but this is rare in modern medicine. In the case of negative
bone balance, bone loss occurs in cortical and cancellous bone and is more rapid when bone
turnover is high. In those cases, bone densitometry will detect osteopenia or osteoporosis. The
prevalence of osteoporosis in the population with CKD exceeds the prevalence in the general
population (74–76). Osteoporosis is observed in CKD before dialysis is required for end stage
kidney failure (77). When bone turnover is high, as in secondary hyperparathyroidism with
osteitis fibrosa, bone resorption rates are in excess of bone formation and osteopenia
progressing to osteoporosis may result. When bone turnover is low, although both bone
formation rates and bone resorption may be reduced, resorption is in excess and loss of bone
mass occurs. Thus, osteoporosis may be observed with either high turnover (77–80) or low
turnover (81) forms of osteodystrophy. When bone resorption exceeds bone formation rates in
CKD, phosphorus and calcium release contribute to hyperphosphatemia and hypercalcemia.
The increase in skeletal mineral deposition that should result from hyperphosphatemia or
hypercalcemia is blocked, and heterotopic mineralization is stimulated, especially in the
vasculature. The failure of the skeleton to absorb positive phosphate balance in CKD is an
important stimulus to heterotopic mineralization, and links the skeleton and osteoporosis in
CKD to cardiovascular events and mortality. This link between osteoporosis and vascular
calcification, now partly defined in CKD, is not specific to CKD. Type 2 osteoporosis is
strongly associated with vascular calcification, and perhaps, the mechanisms defined in CKD
related to the serum phosphorus as a signal and positive phosphate balance also apply.
The discussion of osteoporosis in CKD above is focused on osteoporosis caused by CKD itself.
However, many patients with CKD have osteoporosis independent of CKD. These patients
may be elderly or may have post-menopausal osteoporosis. In addition, it is clear that gonadal
hormone deficiency, as in post-menopausal osteoporosis, is also caused by CKD and is another
factor in the pathogenesis of osteoporosis in CKD. Thus, osteoporosis in CKD presents a
difficult differential diagnosis between the type 2 osteoporosis of aging, gonadal hormone
deficiency, and excess bone resorption associated with the CDK-BMD.
Conclusion
In conclusion, hyperphosphatemia in CKD is a distinct syndrome. It represents one component
of the increased risk of cardiovascular disease in CKD that has been successfully analyzed.
Hyperphosphatemia in CKD represents a signal that heterotopic sites of mineralization are
being used to compensate for the failure of reservoir function of the skeleton in positive
phosphate balance. In fact, hyperphosphatemia itself is one of the signals activating heterotopic
deposition sites, and functions as a signaling molecule in stimulating atherosclerotic neointimal
mineralization that is markedly increased in CKD. Unique features of hyperphosphatemia in
CKD, especially the failure of the skeletal reservoir function, qualify it as a distinct syndrome
characterized by phosphate excretion failure, contribution of the skeleton to
hyperphosphatemia, heterotopic mineralization including the vasculature, and severe
cardiovascular disease leading to morbid cardiac events and often to demise.
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Acknowledgments
We would like to thank Helen Odle and Frank Strebeck for administrative and technical support, Celina Mount of
CDRAC for artistic support, and Jose Menoyo (Genzyme) for valuable discussion.
Disclosure:
The manuscript and the studies reported here were supported by NIH grants DK070790 and AR41677, and by grants-
in-aid from Genzyme and Shire. KAH received consultation fees from Genzyme and Shire Pharmaceutical. PQ and
RP are employees of Shire Pharmaceuticals. SM received consultation fees from Genzyme, and RL received
consultation fees from Abbott.
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Fig. 1.
Phosphorus balance in normal physiology. The kidney is the main regulator of human
phosphate homeostasis. In adulthood, exit from the exchangeable phosphorus pool into the
skeleton (bone formation) is roughly equal to entry into the exchangeable pool due to bone
resorption. The skeleton is a storage depot for Pi and contains 85% of the total body phosphorus.
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Fig. 2.
Phosphorus homeostasis is lost in chronic kidney disease due to failure of excretion. Despite
reductions in the fraction of filtered phosphorus that is reabsorbed, eventually the filtered load
becomes insufficient to maintain homeostasis, and positive phosphorus balance ensues. Kidney
disease decreases the exchangeable phosphorus pool size by inhibiting bone formation. The
skeletal mineralization fronts at the sites of new bone formation are significant components of
the exchangeable phosphorus pool. Positive phosphate balance is associated with establishment
of heterotopic mineralization sites in soft tissue organs and the vasculature. Exit from the
exchangeable phosphorus pool into the vasculature is portrayed as a bidirectional process
because we have been able to demonstrate that stopping the exit into the vasculature results in
diminishment of established vascular calcification levels.
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Fig. 3.
Regulation of phosphorus balance in chronic kidney disease. Regulation of phosphorus
homeostasis is complex. In chronic kidney disease, a decrease in calcitriol production leads to
a decrease in calcium absorption, hypocalcemia, and hyperparathyroidism.
Hyperparathyroidism is one factor contributing to the decrease in the fraction of filtered
phosphorus reabsorbed (decrease in the TRP). Additionally, high levels of FGF23 and
hyperphosphatemia itself, contribute to reducing the TRP. However, when kidney failure
becomes too severe, hyperphosphatemia ensues.
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Fig. 4.
Vascular calcification causes cardiac morbidity and mortality in chronic kidney disease.
Vascular calcification increases arterial stiffness leading to an increase in pulse wave velocity
and pulse pressure both of which contribute to development of cardiac ischemia, and left
ventricular hypertrophy and cardiac failure.
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Fig. 5.
Control of hyperphosphatemia in translational studies results in reduction of established
vascular calcium levels. LDLR−/− mice on high-fat diets with chronic kidney disease have
established vascular calcification at 22 wks (baseline) which increases in vehicle treated
animals sacrificed at 28 wks (veh). However, in animals treated with sevelamer carbonate (1%
sev and 3% sev), aortic calcium levels were significantly reduced compared to baseline, as the
hyperphosphatemia was controlled (28).
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Fig. 6.
Schematic of the experimental plan for in vitro studies demonstrating that high phosphorus
causes vascular calcification and osteoblastic gene expression. Human vascular smooth muscle
cells (hVSMC) derived from atherosclerotic aortas expressed increased levels of morphogens,
specific transcription factors and biomarkers of the osteoblast and decreased levels of those
corresponding to contractile hVSMC. Yet the cells did not mineralize until media Pi was
increased from 1 to 2mM. High media Pi stimulated osterix expression, and when osterix
expression was diminished in the presence of high media Pi there was no mineralization (38).
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Fig. 7.
Expression of osterix in the aortas of LDLR−/− high-fat fed mice. High fat feeding had a small
effect to increase aortic osterix expression in sham operated animals (sham fat) compared to
wild type mice. Induction of chronic kidney disease (CKD high fat) produced a several-fold
increase in osterix expression which was eliminated by treatment with phosphate binders, in
this case lanthanum carbonate 1% or 3% added to the diet (38).
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Hruska et al. Page 19
Table 1
Hyperphosphatemic Syndromes
Increased intake
Transcellular shifts from intracellular to extracellular spaces
Excess bone resorption
Decreased renal excretion
Idiopathic hyperparathyroidism
Pseudohypoparathyroidism
FGF23 deficiency
Tumoral calcinosis
Chronic kidney disease
Acromegaly
Artifactual
Kidney Int. Author manuscript; available in PMC 2009 August 31.
