PTH, PHOSPHATE AND VITAMIN D: CURRENT ISSUES AND CONCERNS
Pathophysiology of Calcium, Phosphorus, and Magnesium
Dysregulation in Chronic Kidney Disease
Arnold J. Felsenfeld,* Barton S. Levine,* and Mariano Rodriguez†
*Department of Medicine, VA Greater Los Angeles Healthcare System and the David Geffen School of
Medicine at UCLA, Los Angeles, California, and †Nephrology Service, IMIBIC, Hospital Universitario Reina
Sofia, University of Cordoba, Cordoba, Spain
ABSTRACT
Calcium, phosphorus, and magnesium homeostasis is
altered in chronic kidney disease (CKD). Hypocalcemia,
hyperphosphatemia, and hypermagnesemia are not seen
until advanced CKD because adaptations develop.
Increased parathyroid hormone (PTH) secretion main-
tains serum calcium normal by increasing calcium efflux
from bone, renal calcium reabsorption, and phosphate
excretion. Similarly, renal phosphate excretion in CKD
is maintained by increased secretion of fibroblast growth
factor 23 (FGF23) and PTH. However, the phospha-
turic effect of FGF23 is reduced by downregulation of
its cofactor Klotho necessary for binding FGF23 to
FGF receptors. Intestinal phosphate absorption is
Calcium
Calcium Homeostasis in the Normal State
To comprehend changes in calcium metabolism in
chronic kidney disease (CKD), an appreciation of
calcium homeostasis in the normal state is needed
(Fig. 1). Three forms of calcium circulate in the
blood. These are albumin-bound (40%), ionized
(50%) and complexed (10%, primarily with citrate,
phosphate, and bicarbonate). The latter two forms
of calcium are filterable at the glomerulus. The
primary regulator of serum calcium is parathyroid
hormone (PTH) with PTH secretion modulated by
the interaction between calcium and the calcium-
sensing receptor (CaSR) located on the cell surface
of the parathyroid gland. Hypocalcemia stimulates
PTH secretion and hypercalcemia suppresses PTH
secretion.
The relationship between serum calcium and PTH
is best represented as a sigmoidal curve. In the basal
state the PTH value is approximately 25% of
Address corresspondence to: Mariano Rodriguez, MD, Ser-
vicio de Nefrologia, Hospital Universitario, Reina Sofia, Avd
Menendez Pidal s/n, Cordoba 14004, Spain, Tel.: +34
667401150, or e-mail: marianorodriguezportillo@gmail.com.
Seminars in Dialysis—Vol 28, No 6 (November–December)
2015 pp. 564–577
DOI: 10.1111/sdi.12411
© 2015 Wiley Periodicals, Inc.
564
diminished in CKD due in part to reduced levels of
1,25 dihydroxyvitamin D. Unlike calcium and phospho-
rus, magnesium is not regulated by a hormone, but
fractional excretion of magnesium increases as CKD
progresses. As 60–70% of magnesium is reabsorbed in
the thick ascending limb of Henle, activation of the cal-
cium-sensing receptor by magnesium may facilitate mag-
nesium excretion in CKD. Modification of the TRPM6
channel in the distal tubule may also have a role.
Besides abnormal bone morphology and vascular calcifi-
cation, abnormalities in mineral homeostasis are associ-
ated with increased cardiovascular risk, increased
mortality and progression of CKD.
maximal PTH levels achieved under stimulation
induced by hypocalcemia. Because of the sigmoidal
relationship, a small decrease in serum calcium pro-
duces a large increase in PTH. The increased PTH
secretion restores serum calcium to normal by (i)
increasing calcium efflux from bone; (ii) enhancing
the calcemic response to PTH at bone by reducing
serum phosphorus through the phosphaturic action
of PTH; (iii) increasing calcium reabsorption in the
distal convoluted tubule (DCT); and (iv) stimulating
1,25 vitamin D (1,25D) production which indepen-
dently increases gut absorption of calcium, calcium
efflux from bone, and calcium reabsorption in the
DCT. Conversely, the effect of hypercalcemia is to
suppress PTH secretion and stimulate CaSR activity
in the thick ascending limb of Henle (TALH).
Approximately 10,000 mg of calcium is filtered
daily at the glomerulus in normal humans but
only approximately 200 mg is excreted in the
urine. Filtered calcium of 60–70% is passively
reabsorbed in the proximal tubule (PT), 20–30% is
reabsorbed in the TALH and 10% in the DCT
(Fig. 1). In the TALH, calcium reabsorption is
regulated by the basolaterally located CaSR and
in the DCT by the apical calcium channel,
TRPV5. The interplay between the TALH and
DCT fine tunes calcium excretion. Recent studies
have shown that CaSR activation protects against
the development of hypercalcemia by (i) increasing
 CALCIUM, PHOSPHORUS, AND MAGNESIUM IN CKD
Fig. 1. Schematic of calcium balance is shown for the young
adult who ingests 1000 mg/day of dietary calcium. In the sche-
matic, the calcium balance is neutral (zero). The skin calcium
loss, which rarely is measured, is not included in the calculation.
Also shown is an inset showing that calcium balance in bone is
positive in the young child and adolescent, neutral in the young
adult and negative in the elderly adult. The values (in mg) in the
figure represents per day; Ca, calcium. Adapted from reference
(155). (Published with permission from the Clinical Journal of
the American Society of Nephrology).
calcium excretion in the TALH and (ii) stimulating
calcitonin secretion which decreases bone efflux of
calcium (1–3).
As intestinal calcium absorption exceeds renal
calcium excretion during the first 30 years of life, a
positive calcium balance results in bone growth.
After the third or fourth decade, a negative calcium
balance results in bone loss. Also, other factors can
accelerate bone loss during aging such as low-grade
metabolic acidosis generated from high dietary pro-
tein ingestion and reduced renal function (4–8).
One of the hallmarks of calcium metabolism in
CKD is secondary hyperparathyroidism (2HPT),
which is also seen in aging and vitamin D defi-
ciency. In aging, the efficiency of intestinal calcium
absorption decreases (9), and PTH levels increase
(10,11). Changes in serum phosphorus (sP) also
occur, which interestingly are different between men
and women (12,13).
In men, sP values decrease in aging while in
women sP values increase after menopause (12,13).
In comparison with healthy young men, PTH values
were approximately two-fold greater in healthy
elderly men for the same ionized calcium concentra-
tion (10). The higher PTH in elderly men also
resulted in lower sP, showing that PTH is both a
calcemic and phosphaturic hormone. The need in
elderly men for a two-fold greater increase in PTH
to maintain the same sCa concentration even with
lower sP, which potentiates the bone response to
PTH, suggests that skeletal resistance to the cal-
cemic action of PTH is present. Furthermore, serum
1,25D was similar in the two groups despite the
supposed stimulatory effect of a greater PTH and
lower sP, suggesting a reduced capacity to produce
1,25D in elderly men. FGF23 enhances phospha-
turia and reduces renal production of 1,25D; in
elderly patients with very moderate reduction in
565
GFR, FGF23 levels are already significantly
increased, therefore the 1,25D deficiency could be
attributed in part to the increase in FGF23 (14,15).
In postmenopausal women, the failure of an
increase in PTH to decrease sP has been attributed
to a decrease in estrogen, which has an independent
phosphaturic action (16). Estrogens may also regu-
late PTH indirectly, possibly through FGF23; estro-
gens significantly increase FGF23, which is known
to inhibit PTH production (17).
Moreover, in postmenopausal women, the inci-
dence of primary HPT is four to six times greater
than in similarly aged men, which may be because
the increase in sP increases the demand for PTH,
which in turn, stimulates parathyroid gland growth.
In contrast to the 2HPT of CKD, renal function
is normal when 2HPT develops in vitamin D defi-
ciency. In dogs given a vitamin D and calcium defi-
cient diet, a four-fold increase in PTH values was
seen (18). Interestingly, 1,25 D values were
increased at 24 weeks despite a marked decrease in
25D. The increase in PTH was associated with an
almost 50% decrease in sP because of the phospha-
turic effect of PTH in animals with normal renal
function. Ionized calcium remained normal for the
first 24 weeks probably because of high PTH and
1,25D values and hypophosphatemia. Thus, in the
first stages of vitamin D deficiency, increases in
1,25D and marked decreases in sP probably
enhance the calcemic action of PTH. Conversely in
CKD, the failure of PTH to lower sP and to
increase 1,25D, decreases the calcemic action of
PTH resulting in a continuously increasing demand
for PTH to maintain sCa normal as CKD evolves
(19).
Calcium Homeostasis in CKD
In CKD, dietary phosphate and low values of
25D and 1,25D can affect mineral metabolism. For
example, in parathyroidectomized rats given a
replacement dose of PTH sufficient to maintain nor-
mal sCa, sP and 1,25D values, the same PTH
replacement dose failed to maintain normal sCa, sP
and 1,25D values after renal failure was surgically
induced although dietary phosphate was not chan-
ged (20). But in rats with intact parathyroid glands
placed in renal failure, a two-fold increase in PTH
secretion did maintain normal sCa, sP and 1,25D
values. Thus, for the same dietary phosphate, more
PTH is required to maintain a normal sCa concen-
tration in renal failure. Conversely, when azotemic
animals were placed on a phosphate restricted diet,
PTH decreases while the sCa value is maintained
(21,22). Finally, several clinical studies have shown
that low 25D values often seen in CKD patients
contribute to the development of 2HPT (23,24).
Hyperparathyroidism in CKD
In CKD, 2HPT develops to prevent hypocal-
cemia. In cross-sectional studies, PTH levels
566
increase when the GFR fell below 60 ml/minute
(25) and perhaps even in stage 2 CKD (24). The
progression from stage 2 to stage 5 CKD was
accompanied by a four-fold increase in PTH (25,26)
(Fig. 2). Hypocalcemia and hyperphosphatemia
were uncommon until the GFR decreased below
30 ml/minute. Decreases in 1,25D were seen in
fewer than 20% of patients in stage 2 CKD, but the
percent of patients with decreased 1,25D values
increased greatly from stage 3 to stage 5 CKD. As
CKD progressed, an increasing PTH was needed to
maintain a normal sCa and sP value. The failure of
an increased PTH to lower sP and increase 1,25D
exacerbated resistance to the calcemic action of
PTH. An interesting finding in mineral metabolism
in CKD is the greater PTH value in African
Felsenfeld et al.
Americans as compared with Hispanic, Asian, and
white patients for the same degree of decreased
renal function (27,28). However, the increase in
PTH may not have clinical consequences because of
greater bone mass and decreased bone sensitivity to
PTH in African Americans (29,30). Finally, as has
been shown previously, sP has a major effect on the
capacity to maintain serum calcium. Besides PTH
other factors including FGF23, Klotho, and 1,25D
affect phosphate and these will be discussed in the
section of phosphorus.
Besides detecting 1–84 PTH (intact PTH), the
standard second generation assay for intact PTH
detects varying amounts of non 1–84 PTH amino-
terminal truncated fragments of which 7–84 PTH is
the prototype (31). This is because among the

A B C

D E F

G H I

Fig. 2. Shown is a cross-sectional representation of values for (A) serum calcium; (B) serum phosphate; (C) calcium-phosphate
product; (D) PTH (E) 25 hydroxyvitamin D; (F) 1,25 dihydroxyvitamin D; (G) urine calcium (H) urine phosphate and (I) fractional
excretion of phosphate in a large number of patients in stages 1 through 5 CKD (26) (Published with permission from Nephrology,
Dialysis, and Transplantation).
 CALCIUM, PHOSPHORUS, AND MAGNESIUM IN CKD
different second generation intact PTH assays the
antibodies are directed against epitopes that vary
from 4–84 to 15–84 PTH (31). Also for the second
generation intact PTH assay, PTH values may vary
considerably among assays, but results are consis-
tent within single assays (31). With the original sec-
ond generation assay for PTH (Allegro-intact PTH
by Nichols), non 1-84 PTH fragments accounted for
approximately 20% of measured intact PTH in nor-
mal humans, but in CKD, these fragments
accounted for approximately 50% (32).
Interest in the 7–84 PTH fragment increased
when 7–84 PTH was shown to inhibit the calcemic
action of PTH (33,34). The effect of 7–84 PTH may
be mediated by its binding to the carboxy-PTH
receptor present in osteocytes and other cells of
osteoblast lineage including lining cells on the bone
surface (35,36). Finally, 7–84 PTH may also reduce
calcitriol production in CKD (37). Thus, in CKD,
increased 7–84 PTH could contribute to the devel-
opment of hypocalcemia resulting in an increased
demand for PTH with progressive parathyroid
gland hyperplasia.
Besides PTH, 1,25D is the other primary calcemic
hormone. In CKD, decreased 1,25D values result
in: (i) reduced intestinal calcium absorption; (ii) fail-
ure to inhibit PTH synthesis as 1,25D acts through
the vitamin D receptor (VDR) in the parathyroid
gland to decrease PTH mRNA; and (iii) decreased
calcemic effect of PTH on bone. Together the
decreased calcemic action of 1,25D and PTH in
CKD increase the demand for PTH resulting in
parathyroid gland hyperplasia. As parathyroid
gland hyperplasia develops, the number of secretory
cells in the parathyroid glands increase (38,39).
With continued demand for PTH, diffuse hyper-
plasia of the parathyroid glands develops with cells
characterized by loss of the VDR and CaSR, which
reduces inhibitory capacity of 1,25D and calcium
on parathyroid function. In the next stage, nodules
characterized by a single clone of parathyroid cells
selected for enhanced proliferative capacity form in
the parathyroid gland. Severe nodular hyperplasia is
generally only seen in patients on prolonged dialy-
sis. Pathology of parathyroid glands obtained at
parathyroidectomy have shown that once parathy-
roid gland weight exceeds 500 mg (normal <40 mg),
nodularity in some form is present in greater than
90% of glands (40).
Often overlooked in CKD is the early decrease in
renal calcium excretion. In one study, 24 hour urine
calcium excretion decreased from approximately
150 mg in stages 1 and 2 CKD to 80 mg in stage 3
CKD and further decreased to approximately
50 mg in stages 4 and 5 CKD (26) (Fig. 2). In
CKD, the prevailing response of PTH is to prevent
hypocalcemia. While the decreased amount of cal-
cium filtered at the glomerulus in CKD contributes
to the decreased renal calcium excretion, the
reduced filtered calcium also potentiates the possi-
bility of hypercalcemia with calcium loading
and may also result in vascular and soft tissue
567
calcification. Whether diminished CaSR activity in
CKD is an important factor in the decreased cal-
cium excretion remains to be determined. In the
DCT, known factors that enhance calcium reab-
sorption via TRPV5 activation include 1,25D,
Klotho and alkalosis, which are reduced or absent
in CKD. PTH, which enhances TRPV5 activity, is
increased in CKD and could play an important
role. Estrogen and tissue kallikrein have also been
reported to enhance calcium reabsorption via
TRPV5.
In dialysis patients, the relationship between
serum calcium and PTH is important to understand
because of its implication for treatment. Similarly,
elevated PTH values are often seen across a wide
spectrum of serum calcium values. In one study of
hemodialysis patients with similarly elevated pre-
dialysis PTH values, patients were divided into
three groups based on their predialysis (basal)
serum calcium concentration (<8.5 mg/dl, 8.5–
9.5 mg/dl and >9.5 mg/dl) (41). Also, maximally
stimulated and suppressed PTH values were
obtained during separate dialyses with low and
high calcium dialysates. Despite similar predialysis
PTH values, the maximal PTH response to
hypocalcemia was quite different (Fig. 3A). Patients
with predialysis serum calcium <8.5 mg/dl had a
lower maximal PTH than the other two groups,
while the group with predialysis serum calcium
>9.5 mg/dl had the greatest maximal PTH. The
ratio of basal/maximal PTH progressively increased
from >9.5 mg/dl group to <8.5 mg/dl group, sug-
gesting that hypocalcemia was stimulating PTH
secretion in the latter group while hypercalcemia
was actually suppressing PTH secretion in the for-
mer group (Fig. 3B). These results support the con-
cept that hypocalcemic patients with elevated
predialysis PTH values benefit from treatment with
VDR activators (42).
Important differences in the sensitivity of PTH
secretion to serum calcium were also revealed by
studying the dynamics of PTH secretion in
hemodialysis patients with severe, moderate, and
mild HPT. Respective predialysis (basal) PTH val-
ues were 959  80 pg/ml (severe), 586  51 pg/ml
(moderate) and 117  13 pg/ml (mild) in the three
groups. In both the severe and moderate HPT
groups, a modest, but significant increase in maxi-
mal PTH was seen as the predialysis serum calcium
increased (Fig. 4). However, only in the severe HPT
group did the predialysis (basal) PTH increase as
serum calcium increased (Fig. 4, middle panel, A
and B) (43).
The basal/maximal PTH ratio reflects how the
basal PTH is changing with respect to the maxi-
mal secretory capacity (maximal PTH) and a
decreasing basal/maximal PTH ratio reflects a sen-
sitivity to an increasing serum calcium. In severe
HPT, the basal/maximal PTH ratio did not
change as predialysis serum calcium increased
indicating a lack of sensitivity to serum calcium.
In moderate HPT, the basal/maximal PTH ratio
568 Felsenfeld et al.

A The parathyroids possess specific receptor for

PTH (pg/ml) (Thousands) FGF23, the FGFR1-Klotho receptor. In normal
4 parathyroid glands FGF23 reduces PTH secretion
* P<0.05 vs <8.5 mg/dl Basal Calcium
and synthesis and upregulates the expression of
* <8.5 mg/dl
CaSR and VDR (44,45). In parathyroid glands
3 8.5-9.5 mg/dl
Maximal PTH
from rats with uremic 2HPT and from hemodialysis
>9.5 mg/dl patients that underwent parathyroidectomy, the
2 * expression of FGFR1-Klotho is markedly reduced
and the very high circulating levels of FGF23
Basal PTH
1
observed in advanced CKD are not able to inhibit
* parathyroid function (45–47). Thus, in advanced
* Minimal
PTH 2HPT, there is a reduction in the expression of
0 parathyroid receptors that could transduce inhibi-
7 8 9 10 11
Serum Calcium (mg/dl) tory signals (CaSR, VDR, and FGFR1/klotho com-
plex).
B As advanced CKD is treated by kidney transplan-
PTH (%) tation, a brief discussion of calcium metabolism after
100 Basal Calcium kidney transplantation is provided. Even in a well-
<8.5 mg/dl
functioning kidney transplant, stage 2 or 3 CKD is
8.5-9.5 mg/dl
present (48). Because of pre-existing parathyroid
75 >9.5 mg/dl
hyperplasia often with nodularity (38,40), the high
* pretransplant PTH values only gradually decrease. In
50 * approximately 20% of kidney transplant recipients,
PTH values remain elevated at 1 year. The elevated
posttransplant PTH values together with high
25
* P<0.05 vs <8.5 mg/dl FGF23 values, which gradually return to CKD stage
appropriate levels at 1 year, increase phosphaturia
0 often resulting in hypophosphatemia. Because of per-
7 8 9 10 11
sistent hyperparathyroidism and PTH- and FGF23-
Serum Calcium (mg/dl)
induced hypophosphatemia, hypercalcemia may
Fig. 3. Hemodialysis patients with similarly elevated predialysis develop between 1 and 3 months post transplanta-
PTH values were divided according to their predialysis (basal) tion before usually resolving by 1 year, but can per-
serum calcium concentration (<8.5 mg/dl, 8.5–9.5 mg/dl, and sist longer. Finally, bone loss during the first year
>9.5 mg/dl) (41). (A) Despite similar predialysis PTH values, the
after transplantation is often a major problem.
maximal PTH response to hypocalcemia was quite different.
Patients with predialysis serum calcium <8.5 mg/dl had a lower
maximal PTH than the other two groups. (B) The ratio of basal/
maximal PTH progressively increased from >9.5 mg/dl group to Phosphorus
<8.5 mg/dl group, suggesting that hypocalcemia was stimulating Phosphate Homeostasis in the Normal State
PTH secretion in the latter group while hypercalcemia was actu-
ally suppressing PTH secretion in the former group. Maintenance of phosphate balance is critical for
survival. Phosphate plays a vital role in physiologi-
cal processes, such as cell metabolism, intracellular
decreased as the predialysis serum calcium signaling, bone structure, and protein synthesis.
increased, indicating that predialysis serum cal- Approximately 85% of phosphate is in bone, with
cium was inhibiting PTH secretion. In mild HPT, the remainder primarily in the intracellular pool
the sensitivity to serum calcium is the most appar- and less than 1% is in the extracellular pool. Sev-
ent because both the basal PTH and the basal/ eral organs regulate phosphate homeostasis main-
maximal PTH ratio decrease as the predialysis taining sP in the normal range. These include the
serum calcium increases. gut, bone, parathyroid glands, and kidney (Fig. 5).
In the severe HPT group, a multiple regression Normal intake of phosphate in the American diet
analysis was performed with basal PTH as the is 1000–1500 mg/day. Intestinal absorption of diet-
dependent variable and predialysis serum calcium ary phosphate is approximately 60–80% and
and maximal PTH as independent variables. The remains relatively constant over a wide range of
predialysis serum calcium was significant (p = 0.01), phosphate intake. The small intestine is the primary
but it was a positive value indicating that basal site of phosphate absorption in which absorption
PTH was not sensitive to serum calcium and even occurs by both active transcellular and passive para-
that PTH was driving the serum calcium. Con- cellular processes (49–51). The precise contribution
versely, in the moderate and mild HPT groups, the of transcellular versus paracellular absorption varies
predialysis serum calcium was a negative value with with dietary phosphate intake (49,51). Transcellular
p values of 0.008 and <0.001, respectively, indicating absorption of phosphate is greatest in the jejunum,
that in both groups an increasing predialysis serum followed by the duodenum with minimal activity in
calcium was suppressing PTH secretion. the ileum (50). Phosphate uptake across the entero-
 CALCIUM, PHOSPHORUS, AND MAGNESIUM IN CKD 569

A Severe Hyperparathyroidism B Moderate Hyperparathyroidism C Mild Hyperparathyroidism

Basal PTH 959±80 pg/ml Basal PTH 586±51 pg/ml Basal PTH 117±13 pg/ml
Maximal PTH (pg/ml) (Thousands) Maximal PTH (pg/ml) (Thousands) Maximal PTH (pg/ml)
4 4 800
r=0.40, P=0.05 r=0.46, P=0.02 r=-0.28, P=NS
600

2 2 400

200

0 0
0.9 1 1.1 1.2 1.3 0.9 1 1.1 1.2 1.3 0
Ionized Calcium (mM) Ionized Calcium (mM) 7 8 9 10 11 12
Serum Calcium (mg/dl)
Basal PTH (pg/ml) (Thousands) Basal PTH (pg/ml) (Thousands) Basal PTH (pg/ml)
2 2 300
r=0.59, P=0.002 r=0.06, P=NS r=-0.58, P<0.001

200

1 1
100

0
0 0
0.9 1 1.1 1.2 1.3 0.9 1 1.1 1.2 1.3 7 8 9 10 11 12
Ionized Calcium (mM) Ionized Calcium (mM) Serum Calcium (mg/dl)
Basal/Maximal PTH (%) Basal/Maximal PTH (%) Basal/Maximal PTH (%)
100 100 100
r=0.34, P=0.09 r=-0.55, P=0.004
r=-0.52, P<0.001
80 80 75

60 60 50

40 40 25

20 20 0
0.9 1 1.1 1.2 1.3 0.9 1 1.1 1.2 1.3 7 8 9 10 11 12
Ionized Calcium (mM) Ionized Calcium (mM) Serum Calcium (mg/dl)

Fig. 4. Dynamics of PTH secretion in hemodialysis patients with different degrees of hyperparathyroidism: A. Severe (959  80 pg/
ml); B. Moderate (586  51 pg/ml) and C. Mild HPT (117  13 pg/ml). Only in the severe HPT group did the predialysis (basal) PTH
increase as serum calcium increased. The basal/maximal PTH ratio reflects sensitivity to an increasing serum calcium. In severe HPT,
the basal/maximal PTH ratio did not change as predialysis serum calcium increased. In mild HPT, the sensitivity to serum calcium is
the most apparent because both the basal PTH and the basal/maximal PTH ratio decrease as the predialysis serum calcium increases
(43).

cyte brush border membrane (BBM), the rate-limit-
ing step for phosphate absorption, is mediated by
the luminal Na-dependent phosphate transporter,
NaPi2b (52,53). PIT-1, a type III Na-dependent
phosphate transporter is present in the small
intestine, but under normal circumstances does not
play a significant role in phosphate absorption
(49,52,54).
Intestinal absorption of phosphate is mediated by
NaPi2b, which is regulated primarily by dietary
phosphate and 1,25D (52–54). Fibroblast growth
factor 23 (FGF23), a phosphatonin produced by
osteocytes and osteoblasts, downregulates NaPi2b
by enhancing degradation and indirectly by sup-
pressing production and enhancing degradation of
1,25D (55). sP only changes minimally in humans
with inactivating mutations in the NaPi2b trans-
porter likely due to upregulation of the renal phos-
phate transporter NaPi2a (56). The gut also has an
important role in maintaining phosphate homeosta-
sis by producing an unidentified phosphatonin in
response to dietary phosphate loading (57).
Bone is an important regulator of internal phos-
phate balance (58). Bone is a reservoir for phosphate
and can either absorb or release phosphate based on
need. PTH, 1,25D and acidosis enhance the release
of phosphate from bone, while PTH and 1,25D,
under certain circumstances, may increase bone
deposition of phosphate. PIT-1 is present in osteo-
blasts and chondrocytes and may play an important
role in bone phosphate homeostasis (53,59). Bone
also plays an important role in phosphate homeosta-
sis through production of FGF23.
The primary regulator of phosphate homeostasis
is the kidney, which adjusts the excretory load of
phosphate to the dietary load. The PT reabsorbs 60–
70% of filtered phosphate and another 10–20% is
reabsorbed in the DCT. Uptake across the PT BBM
is the rate-limiting step for phosphate reabsorption.
Several phosphate transporters are located in the PT
BBM, including NaPi2a, NaPi2c, and PIT-2 (53,59).
NaPi2a and NaPi2c are primarily responsible for
transepithelial transport. The relative importance of
these transporters varies among species (53,59,60).
570 Felsenfeld et al.

Fig. 5. Normal phosphate balance. Normal dietary phosphate intake is 1000–1500 mg/day of which 60–80% is absorbed. Calcitriol
(1,25D) stimulates intestinal phosphate absorption while fibroblast growth factor 23 (FGF23) indirectly decreases intestinal phosphate
absorption by lowering 1,25D values. The gut may also regulate phosphate homeostasis by producing an unknown phosphatonin in
response to dietary phosphate loading. Bone regulates internal phosphate balance by serving as a reservoir for phosphate. PTH and
1,25D regulate bone deposition and release of phosphate. Bone also is the site of FGF23 production. The primary regulator of phos-
phate homeostasis is the kidney which adjusts the excretory to the dietary load of phosphate. The proximal tubule (PT) is the primary
site for phosphate reabsorption. Phosphate transporters, NaPi-2a, and 2c responsible for transepithelial transport, are primarily regu-
lated by phosphate load, PTH, and FGF23/Klotho. Both PTH and FGF23 inhibit PT phosphate reabsorption. FGF23 acts through the
FGF receptor (FGFR) system using the protein Klotho as a cofactor. The majority of renal Klotho expression is in the distal convo-
luted tubule (DCT), but the mechanism of transmission of the FGF23 signal to the PT remains unidentified. One possibility is that
secreted Klotho may be the messenger between the DCT and PT and another is that small amounts of Klotho expressed in the PT may
be sufficient for FGF23 to act directly on the PT. The production and action of FGF23 is modified by several factors including 1,25D,
phosphate load, calcium intake, and PTH. FGF23 in turn inhibits PTH production, parathyroid gland expression of the CaSR and
VDR, and 1,25D production forming a closed loop. Solid lines indicate a positive effect and broken/dotted lines an inhibitory effect.

These transporters are primarily regulated by phos-
phate load, PTH, and FGF23/Klotho (53).
Both PTH and FGF23 inhibit PT phosphate
reabsorption and decrease NaPi2a and NaPi2c
BBM expression. PTH responds acutely to a phos-
phate load, while the FGF23 response is delayed
and may be more important long term (61). FGF23
acts through the FGF receptor (FGFR) system
using the antisenescence protein Klotho as a cofac-
tor (Fig. 5). It is unclear which FGFRs are respon-
sible for the renal actions of FGF23, but FGFR1
likely plays a predominant role (62). Specific knock-
out of Klotho in the DCT, the primary site of kid-
ney Klotho expression, suggests that FGF23
initially acts on the DCT, but the mechanism of
transmission of the FGF23 generated signal to the
PT has not been fully explained (58,63,64).
Klotho, a single transmembrane protein, mark-
edly enhances the affinity of FGF23 for FGFRs
and provides tissue specificity for FGF23 actions.
The extracellular domain of Klotho can be cleaved
generating soluble or cleaved Klotho (cKlotho)
which is present in the circulation, urine and cere-
brospinal fluid. Circulating and urine levels of
cKlotho correlate with kidney Klotho expression
(58). cKlotho directly inhibits the NaPi2a and
NaPi2c transporters in the PT (58). One study has
shown that in mice transfected with cKlotho the
production of FGF23 is increased, with profound
phosphate wasting, marked hyperparathyroidism,
hypocalcemia, and rickets (58,66).
The production and action of FGF23 is increased
by several factors, including 1,25D, phosphate load,
calcium intake, and PTH (58,65). FGF23 in turn
acts on the parathyroids and kidneys; in parathy-
roids, FGF23 inhibits PTH production and
increases expression of the CaSR and VDR as well
as its own receptor FGFR1 (45). The renal effects
of FGF23 include phosphaturia and the reduction
of 1,25D production (Fig. 5) (58).
Intestinal Phosphate Absorption in CKD
Intestinal absorption of phosphate is decreased in
CKD patients over a wide range of phosphate intake
(Table 1) and increases with calcitriol administration
(67–69). In stage 3 and 4 CKD patients, the percent
absorption of phosphate (50%) was substantially
lower than in normals (80%), with phosphate balance
neutral at a phosphate intake of approximately
1500 mg/day (48,65). In ESRD patients, the active
component of jejunal phosphate absorption was
 CALCIUM, PHOSPHORUS, AND MAGNESIUM IN CKD
TABLE 1. Intestinal and renal phosphate handling in CKD
Change Factors
Decreased intestinal Increased FGF 23
absorption of phosphate Decreased 1,25D
Decreased 24,25 dihydroxyvitamin D
Decreased NaPi2b transportersa
Increased fractional Intrinsic tubular adaptation
excretion of phosphate Increased PTH
Increased FGF 23
Decreased NaPi2a transporters
Decreased NaPi2c transporters
a
Information is not uniform.
decreased and improved with calcitriol administra-
tion without altering paracellular absorption (66).
Studies evaluating intestinal phosphate absorption in
5/6 nephrectomized rats have either shown a decrease
or no change in active phosphate transport or NaPi2b
expression with nephrectomy (50,52,70,71). NaPi2b
deletion in mice with adenine-induced CKD improved
hyperphosphatemia and attenuated the rise in
FGF23, suggesting that active intestinal absorption of
phosphate contributes to the hyperphosphatemia seen
in CKD (72).
Normally, the active component of intestinal phos-
phate absorption is enhanced with dietary phosphate
deprivation (70), but in CKD the data are conflicting
(52,70,73). If intestinal and renal adaptation to
changes in dietary phosphate occur in CKD, these
adaptations may thwart attempts at normalizing sP
through dietary manipulation (50). In CKD, it is not
clear to what extent GI phosphate absorption is mod-
ulated by dietary phosphate. Therefore, it is not
known how much this mechanism could be interfer-
ing with the objective of reducing phosphate load by
dietary phosphate restriction.
Another factor that may play a role in intestinal
phosphate absorption is 24,25-vitamin D3, which
inhibits the 1,25D rapid response system in the
intestine, blunting 1,25D stimulation of intestinal
phosphate absorption. Conversely, the low levels of
24,25-vitamin D3 in CKD could increase intestinal
sensitivity to 1,25D and contribute to hyperphos-
phatemia (74).
Renal Handling of Phosphate in CKD
In early CKD, adaptive processes increase the
fractional excretion of phosphate (FEpo4) and
decrease the phosphate threshold clearance (TmP/
GFR) to maintain normal sP values (75,76). PT
Na-dependent phosphate uptake decreases in CKD
as do NaPi2a mRNA and protein expression
(70,71,77,78). The increase in PTH in CKD plays a
central role in the adaptive process (79) (Table 1).
Factors contributing to the rise in PTH in CKD
include hypocalcemia, hyperphosphatemia, PTH
resistance, low levels of 1,25D, and resistance to the
FGF23/Klotho axis (56,76,80–82). The importance
of PTH in maintaining renal phosphate excretion in
CKD is shown by the rise in sP that occurs in
predialysis CKD patients treated with the CaSR
571
agonist, cinacalcet (83), although cinacalcet will also
lower FGF23 and this could further decrease phos-
phaturia (84).
Another factor that maintains phosphate home-
ostasis in CKD is the FGF23/Klotho axis. As CKD
progresses FGF23 levels rise and stimulate renal
phosphate excretion (58,80) (Table 1). Normally,
phosphaturia would be counterbalanced by the
PTH suppressive effect of FGF23. But parathyroid
gland Klotho and FGFR1 expression decrease as
GFR deteriorates conferring parathyroid gland
resistance to FGF23 (58,85).
In a cross-sectional study of 87 patients with
stages 1–5 CKD, cKlotho, and 1,25D values
declined linearly with eGFR (86). The early decline
in cKlotho and 1,25D was subsequently followed by
an increase in FGF23 suggesting that the early
decrease in 1,25D in CKD may not be from an
observable increase in FGF23. Moreover, resistance
to FGF23 may occur early in CKD due to
decreased renal Klotho expression and urinary
Klotho values, which progressively decline as the
GFR falls (58,87). The decline in 1,25D values in
CKD may also modify the phosphaturic action of
FGF23, because 1,25D stimulates Klotho which is
important for FGF23 action (88). Resistance to
FGF23 may also be related to the accumulation of
uremic toxins such as indoxyl sulfate (89). The resis-
tance to FGF23 may account for the extremely high
FGF23 values (>1000 fold) that are seen in late
stage CKD (80).
When the eGFR is below 30 ml/minute/1.73 m2,
adaptive mechanisms can no longer maintain the sP
in the normal range due to an imbalance in phos-
phate intake and renal excretory capacity. The
phosphaturic effect of PTH and FGF23 diminish
and markedly elevated PTH values along with acid-
emia directly enhance bone resorption releasing
more phosphate. Because the CaSR is pH sensitive,
acidemia may also stimulate PTH secretion (90,91).
Consequences of Disruption of Phosphate
Homeostasis in CKD
Abnormal phosphate homeostasis in CKD results
in adverse effects both from consequences of hyper-
phosphatemia and adaptations designed to maintain
phosphate balance (79,80). Phosphate retention
plays a pivotal role in the development of CKD-
Mineral Bone Disorder (CKD-MBD) (92). Phos-
phate retention contributes to the development of
renal osteodystrophy via stimulation of PTH and
FGF 23 secretion, impairment of the calcemic
response to PTH and suppression of 1,25D produc-
tion (92). Phosphate retention also contributes to
CKD-MBD by contributing to the development of
vascular calcification. Epidemiogical studies have
shown that higher sP, even in the normal range and
in the absence of CKD, is an independent risk fac-
tor for cardiovascular disease (CVD) (93) (Table 2)
(Fig. 6). Both intimal and medial vascular calcifica-
tions are common in CKD and contribute to
572 Felsenfeld et al.
TABLE 2. Cardiovascular consequences of abnormal phosphate porters and initiates the transformation to
homeostasis in CKD osteoblast-like phenotype (95). VSMC knockout of
Cardiovascular Potential Causative PIT-1, however, does not inhibit phosphate uptake
Abnormality Factors References presumably due to upregulation of PIT-2 (85). High
extracellular calcium or phosphate suppresses
Vascular/valvular Increased serum phosphorus (94,95,143) Klotho expression in human aortic smooth muscle
calcification Decreased Klotho (58,96,109)
Decreased 1,25D (144) cells (HA-SMC), which may further increase suscep-
Endothelial Increased serum phosphorus (97,98,145) tibility to vascular calcification (96). In addition,
dysfunction Decreased Klotho (58,146) hyperphosphatemia contributes to endothelial dys-
Left ventricular Increased PTH (147–149) function (97,98) by increasing apoptosis, increasing
hypertrophy Increased FGF 23 (106)
Decreased Klotho (58,108)
the generation of reactive oxygen species, impairing
1,25D (150,151) nitric oxide production and decreasing annexin II
Cardiovascular Increased serum phosphorus (103,151,152) expression (97,98).
Disease/Mortality Increased FGF 23 (80) Hyperphosphatemia is a risk factor for more
Decreased Klotho (58) rapid progression of CKD (99). Dietary phosphate
Increased PTH (153)
Decreased 1,25D (154) restriction reduces the rate of progression of CKD
in a variety of animal models (100). Phosphate may
also attenuate the renoprotective effects of angioten-
atherosclerotic disease and vascular stiffness (94). sin converting enzyme inhibitors or low protein diet
Studies evaluating the role of phosphate in vascular (58,99,101).
calcification have provided biological plausibility Perturbation of the FGF23/Klotho axis in CKD is
that abnormal phosphate homeostasis is an impor- perhaps an even greater risk factor for CVD and mor-
tant CVD risk factor. tality than is sP (102) (Table 2). High FGF23 concen-
Vascular calcification, which produces vascular trations are associated with increased mortality,
stiffness, shares similarities to bone ossification atherosclerosis, left ventricular hypertrophy (LVH),
(94,95). The calcification process is complex and vascular stiffness, CVD and accelerated progression
results from an imbalance of factors which promote of CKD (80,101,103). In the Heart and Soul study,
or inhibit ossification (85,94,95). Phosphate is a pri- subjects with resistance to the phosphaturic effects of
mary stimulus for transformation of vascular FGF23 had the highest risk for a cardiovascular event
smooth muscle cells (VSMC) to an osteoblast-like with or without CKD (103).
phenotype capable of ossification. Exposure of FGF23 normally may have vascular protective
VSMC to high extracellular phosphate concentra- effects (96). FGF23 stimulates VSMC proliferation
tions stimulates phosphate uptake via PIT-1 trans- in the presence of Klotho and inhibits extracellular

Fig. 6. Trade-off hypothesis revisited. With a decrease in GFR and increase in the phosphate load relative to GFR, various factors
involved in mineral homeostasis are perturbed. Some changes, such as the rise in parathyroid hormone (PTH) and fibroblast growth fac-
tor 23 (FGF23), are adaptive changes that increase the fractional excretion of phosphate and maintain sP in the normal range. Other
factors, such as a decline in 1,25D and Klotho, do not appear to be adaptations, per se, but contribute to the rise in PTH and FGF23,
respectively. With a more severe decline in GFR (late) the efficacy of PTH and FGF23 to enhance renal excretion of phosphate dimin-
ishes due to the extensive loss of renal mass as well as resistance to their action. The bone resorptive effect of PTH also contributes to
abnormal sP levels. Hyperphosphatemia, elevated PTH and FGF23 values, and low 1,25D and Klotho values all appear to indepen-
dently increase the cardiovascular risk profile in CKD leading to vascular/valvular calcification, left ventricular hypertrophy (LVH),
endothelial dysfunction and increased risk for cardiovascular events and mortality.
 CALCIUM, PHOSPHORUS, AND MAGNESIUM IN CKD
calcium deposition (96). Klotho, expressed in the
medial layer of human vasculature, colocalizes with
FGFRs (96). Vascular Klotho and FGFR expres-
sion are low in CKD and exposure of HA-SMC to
“uremic” serum suppresses Klotho and FGFR
expression (96). Inflammatory cytokines, angioten-
sin II and TGF-b1 which are elevated early in CKD
have been shown to suppress Klotho expression
(104). Low vascular Klotho expression appears to
confer resistance to FGF23 (96). Vitamin D recep-
tor activators normalize Klotho and FGFR expres-
sion in HA-SMC, reverse the resistance to FGF23
and prevent calcification (58,96). Very high FGF23
levels, in the absence of Klotho, induce LVH, a
known risk factor for CVD (105). Therefore, low
Klotho levels in CKD may obviate the beneficial
effects of FGF23 on the vasculature and may con-
tribute to the excessive rise in FGF23 levels seen
particularly in late stage CKD, which in turn
induces LVH through a non-Klotho dependent
mechanism. Data from other authors do not sup-
port Klotho-mediated FGF23 effects in the vascula-
ture, nevertheless confirmative studies in humans
are warranted (106).
Circulating and vascular Klotho, independent of
FGF23, protect against vascular calcification
through a variety of mechanisms (58,107). Circulat-
ing Klotho can inhibit vascular calcification
through the inhibition of Na-dependent phosphate
uptake (108). The low levels of circulating Klotho
in CKD may further increase the susceptibility to
vascular calcification and its consequences.
Although Klotho is not expressed in the heart,
Klotho knockout mice develop LVH. It is
unknown if the induction of LVH is a direct effect
of lack of Klotho or results from the disruption of
other factors such as elevations in FGF23 seen in
this model (58). More recent work suggests that
low klotho may induce LVH directly through
upregulation of TRP6, a calcium channel involved
in cardiomyocyte remodeling (109).
Magnesium
In the normal adult, total body magnesium is
approximately 24 g as compared to 1000 g for cal-
cium (109,110). Magnesium is the second most com-
mon intracellular cation. Unlike calcium regulation
by PTH, there is no known hormone regulating
magnesium. Extracellular magnesium accounts for
only 1% of total body magnesium and does not
reflect total body stores. Extracellular magnesium is
approximately 60% ionized, 30% protein bound
and 10% complexed. Normal serum magnesium
(sMg) concentration ranges from 1.8 to 2.6 mg/dl
and 70% of circulating magnesium is filtered at the
glomerulus. Of the other 99% of total body magne-
sium, 60–65% is in bone and the remainder is intra-
cellular with approximately 25–30% in muscle and
10–15% in other soft tissues (111). Only 1–5% of
intracellular magnesium is ionized and the remain-
573
der is bound to proteins, negatively charged mole-
cules and adenosine triphosphate (ATP).
Magnesium is a cofactor for more than 300 enzy-
matic reactions (110). The radius of hydrated mag-
nesium is 16 times larger than that of hydrated
calcium perhaps explaining the difficulty of magne-
sium to pass through narrow biological channels
readily traversed by calcium (110). Finally, magne-
sium is a known inhibitor of calcification in bone
and soft tissue, including the vasculature.
Magnesium balance is determined by dietary
ingestion and absorption, bone and soft tissue depo-
sition and efflux, and renal excretion. Most of
ingested magnesium is absorbed in the small intes-
tine through a passive, paracellular pathway. Active,
transcellular absorption does occur in the colon via
the magnesium channel TRPM6. Intestinal magne-
sium absorption varies from 30% to 60% (110) and
paracellular absorption is enhanced by 1,25D, possi-
bly through regulation of claudins 2 and 12 (112).
Little is known about magnesium influx to, and
efflux from, bone and soft tissue, but bone accumu-
lation of magnesium occurs during growth. As sMg
measurements often do not adequately reflect mag-
nesium stores, a magnesium loading/retention test
was devised in which magnesium retention is used to
diagnose magnesium deficiency (109).
During the past decade, major advances have
been made in our understanding of renal handling
of magnesium. Approximately, 2400 mg of magne-
sium is filtered daily, of which 90–95% is reab-
sorbed. At only 10–25%, proximal tubular
reabsorption of magnesium is much less than that
of 60–70% for calcium (112). Whether the large
radius of hydrated magnesium is an explanation for
the difference is a possibility. The TALH accounts
for up to 70% of magnesium absorption, with the
transepithelial gradient as the driving force for
paracellular reabsorption. Claudins 16 and 19,
which form a cation-selective tight junction, are
important gatekeepers (112). CaSR activation by
hypercalcemia and perhaps hypermagnesemia
enhances calcium and magnesium excretion by mod-
ifying the transepithelial gradient (2). Ten percent
of magnesium reabsorption occurs via an active
transcellular process in the DCT through the apical
epithelial channel, TRPM6. The mechanism for
basolateral extrusion and whether a transcellular
chaperone is present remain unknown. Epidermal
growth factor regulates TRPM6 activity, while
TRPM6 expression is modified by estrogen and
sMg. Acidosis, alkalosis, and tacrolimus/cy-
closporine also modify TRPM6 expression and/or
activity (113).
Many questions remain unanswered regarding
magnesium in CKD. Low 1,25D levels may
decrease intestinal magnesium absorption in CKD
patients (114,115). In a classic study in CKD
patients, hypermagnesemia developed when the
GFR decreased to less than 30 ml/minute because
magnesium excretion decreased even though frac-
tional excretion of magnesium increased (116). In
574 Felsenfeld et al.
patients with stage 3 CKD, hypermagnesemia is
uncommon, but fractional excretion of magnesium
is increased (116). In dialysis patients, sMg can be
controlled by modifying the dialysate magnesium
concentration (113,119).
In CKD patients, mild-to-moderate hypermagne-
semia may have both potential beneficial and harm-
ful effects. Benefits include improved vascular
endothelial function, retardation of vascular calcifi-
cation and a decrease in PTH from activation of
the CaSR (2,113,117–123). The reduction in vascu-
lar calcification could be from activation of the
TRPM7 channel, stimulation of the CaSR, or direct
inhibition of calcification in vascular smooth muscle
(2,121). An important potentially harmful effect of
hypermagnesemia is impaired bone mineralization,
possibly resulting in osteomalacia, although infor-
mation from clinical studies has not always been
uniform (121,124,125).
The protective role of magnesium on vascular calci-
fication has been evaluated in several studies. Magne-
sium supplementation reduced calcification in rats
subjected to aortic transplantation and in mice with a
genetic predisposition to calcification (119,124,125).
Essentially all studies evaluating magnesium have
been performed in dialysis patients and most have
been observational. In dialysis patients, higher sMg
levels have been associated with decreased progression
of vascular calcification (119,126,127). A similar bene-
ficial effect of magnesium was reported for mitral
valve calcification (128). High sMg levels have also
been associated with decreased intimal–medial carotid
artery thickness both in dialysis patients and the gen-
eral population (119,129,130). In an interventional
study in which hemodialysis patients were divided into
two groups, magnesium supplementation for only
2 months reduced intimal–medial carotid artery
thickness (131).
Hypermagnesemia activates the CaSR in the
parathyroid gland and suppresses PTH secretion,
but its suppressive effect is two to three times less
potent than calcium (121,132). sMg reduces PTH
secretion mainly when a moderately low calcium
concentration is present; sMg also modulates
parathyroid gland function through upregulation of
the key cellular receptors CaSR, VDR and FGF23/
Klotho system (133). A study in pregnant women
showed that intravenous magnesium infusion sup-
pressed PTH secretion (134). In CKD, studies on
the effect of magnesium on PTH secretion have
been done entirely in dialysis patients. Several such
studies have shown an inverse relationship between
sMg and PTH (111,135–137), but prospective stud-
ies are lacking as are studies in developing CKD.
The only studies of bone magnesium in CKD are
those in dialysis patients. In a remote study, bone
magnesium was reported increased, but patients had
been dialyzed for a mean of 2 years with a higher
magnesium concentration than recommended today
(115,138). Lowering dialysate magnesium was
reported to improve osteomalacia (123). In another
study, total bone magnesium was not increased in
any form of renal osteodystrophy, but the ratio of
magnesium to calcium was increased although nei-
ther bone magnesium nor calcium in dialysis
patients was different from controls (139). Finally,
several studies have shown magnesium carbonate to
be an effective and low cost phosphate binder in
dialysis patients (140,141). After many years of
studies in CKD, much still remains to be learned
about magnesium, which may have a role as an
inhibitor of vascular calcification in evolving and
established CKD (142).
In summary, hypocalcemia, hyperphosphatemia,
and hypermagnesemia are not seen until advanced
CKD because compensating adaptations maintain
normal levels of sCa, sP, and sMg through stages 2
and 3 CKD. sCa is maintained normal by increases
in PTH which increase calcium efflux from bone and
renal calcium reabsorption while at the same time
increased phosphate excretion lowers sP which results
in enhanced calcemic action of PTH. Increases in
PTH and FGF23 during evolving CKD increase
renal phosphate excretion which maintains sP normal
until advanced CKD. However, as CKD progresses
the phosphaturic action of FGF23 is reduced by
downregulation of its coreceptor Klotho. Moreover,
a reciprocal relationship is present between FGF23
and 1,25D in which 1,25D stimulates FGF23 produc-
tion and FGF23 suppresses 1,25D. The early increase
in FGF23 in CKD may account for the greater than
expected decrease in 1,25D seen in early CKD.
Unlike sCa and sP, sMg is not regulated by a
known hormone. However, fractional excretion of
magnesium increases as CKD evolves, maintaining
sMg normal until advanced CKD. As 60–70% of
magnesium reabsorption occurs in the TALH, it is
possible that magnesium activation of the CaSR in
that segment could play a role in increasing the
fractional excretion of magnesium. Besides abnor-
mal bone morphology and vascular calcification,
abnormalities in mineral metabolism are associated
with increased cardiovascular risk, increased mor-
bidity and progression of CKD.
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