In Practice

Long-term Management of CKD–Mineral and Bone Disorder

Kevin J. Martin, MB, BCh, and Esther A. González, MD

Chronic kidney disease–mineral and bone disorder (CKD-MBD) is the term used to describe the abnormali-
ties of bone and mineral metabolism that occur in the setting of kidney disease. The spectrum of these
abnormalities is wide, ranging from severe high-turnover bone disease on one end to marked low bone
turnover bone disease on the other. Similarly, some patients have severe vascular calcifications while others
do not, and the values for biochemistry determinations, including calcium, phosphorus, and parathyroid
hormone, also may vary widely among patients. This variability may be influenced by such things as the
chronicity of the particular kidney disease, effects of therapies such as corticosteroids on modifying the course
of kidney disease, and comorbid conditions, such as diabetes, heart disease, age, and osteoporosis. The
heterogeneity of CKD-MBD makes strict protocol-driven therapeutic approaches difficult; accordingly, consid-
erable individualized therapy is required. Using a case history, we explore several of the variables and
difficulties involved in patient management.
Am J Kidney Dis. 60(2):308-315. © 2012 by the National Kidney Foundation, Inc.

INDEX WORDS: Chronic kidney disease–mineral and bone disorder (CKD-MBD); hyperparathyroidism; renal
osteodystrophy.

CASE PRESENTATION
A 56-year-old white woman with a history of lupus nephritis
class 4, which had been treated with prednisone and intravenous
cyclophosphamide with an apparent good response, returned to the
nephrology clinic after a 6-year absence. During that time, she had
remained asymptomatic, discontinued all medications, and did not
seek medical care. Evaluation showed the following values: serum
creatinine, 4.1 mg/dL (362.44 ␮mol/L; estimated glomerular filtra-
tion rate [eGFR], 12 mL/min/1.73 m2 [0.20 mL/s/1.73 m2]), which
previously was 1.2 mg/dL (106.1 ␮mol/L); calcium, 8.9 mg/dL
(2.22 mmol/L); phosphorus, 4.8 mg/dL (1.55 mmol/L); 25-
hydroxyvitamin D, 14 ng/mL (34.94 nmol/L); intact parathyroid
hormone (iPTH), 432 pg/mL (432 ng/L); and hemoglobin, 9.4
g/dL (94 g/L). Ultrasound showed kidney size to be 9.1 and 8.7 cm.
Urinary protein-creatinine ratio was 2.4 g/g. Urine sediment was
unremarkable. Anti–double-stranded DNA was negative and C3
and C4 levels were normal. Blood pressure was 152/82 mm Hg,
and there was mild peripheral edema. Therapy was initiated with
furosemide; lisinopril; ergocalciferol, 50,000 units every 2 weeks;
darbepoetin; and calcium carbonate, 500 mg, with meals. After 3
months of treatment, 25-hydroxyvitamin D level increased to 26
ng/mL (64.90 nmol/L), and iPTH level decreased to 296 pg/mL
(296 ng/L). During the next 6 months, serum creatinine level
slowly increased, and hemodialysis therapy was initiated when
serum creatinine level reached 8.7 mg/dL (769.1 ␮mol/L; eGFR, 5
mL/min/1.73 m2 [0.08 mL/s/1.73 m2]) through an arteriovenous
fistula. While receiving hemodialysis, the patient remained clini-
cally well during the next 2 years and was placed on the transplant
From the Division of Nephrology, Saint Louis University, St
Louis, MO.
Received July 7, 2011. Accepted in revised form January 4,
2012. Originally published online April 23, 2012.
Address correspondence to Kevin J. Martin, MB, BCh, Division
of Nephrology, Saint Louis University Medical Center, Division of
Nephrology (9-FDT), 3635 Vista Ave, St Louis, MO 63110. E-mail:
martinkj@slu.edu
© 2012 by the National Kidney Foundation, Inc.
0272-6386/$36.00
doi:10.1053/j.ajkd.2012.01.027
list. Cardiac stress echocardiography was negative for ischemia,
but left ventricular hypertrophy and modest calcification of the
mitral valve were noted. Calcium carbonate therapy was stopped
and sevelamer was begun as a phosphate binder to treat phospho-
rus values ranging from 5.4-6.2 mg/mL (1.74-2.0 mmol/L). iPTH
levels progressively increased, peaking at 562 pg/mL (562 ng/L);
treatment with paricalcitol, 2 ␮g per dialysis treatment, was begun.
PTH level remained at 364-486 pg/mL (364-486 ng/L) for the next
year. After approximately 3 years on dialysis therapy, the patient
began to notice vague pains in her hip and knee joints and legs and
back. Pain was aggravated by exercise, and overall, she felt that
her health was declining. These symptoms gradually became
worse during the ensuing months. Review of laboratory values for
the past year showed calcium values in the low-normal range,
phosphorus values of 5.1-6.2 mg/dL (1.6-2.0 mmol/L), and iPTH
values of 372-463 pg/mL (372-463 ng/L). Alkaline phosphatase
level was 192 U/L, having increased from 139 U/L 1 year earlier.
Dual-energy x-ray absorptiometry showed a T score of ⫺2.3 at the
hip. Bone biopsy showed severe osteitis fibrosa. Paricalcitol therapy
was intensified, and iPTH values stabilized near 200 pg/mL (200
ng/L) during the next 6 months, with a marked decrease in skeletal
symptoms occurring after 3 months of intensified paricalcitol
therapy.
INTRODUCTION
Our view of the consequences of abnormal bone
and mineral metabolism in the setting of chronic
kidney disease (CKD) has evolved from focusing
entirely on the skeleton to a broader perspective in
which not only are bone abnormalities observed and
require therapy, but these abnormalities also seem to
be related to cardiovascular disease (specifically vas-
cular calcification) and are implicated in increased
mortality risk. Accordingly, the term renal osteodystro-
phy can be considered to represent the skeletal abnor-
malities, whereas the broader term CKD–mineral and
bone disorder (CKD-MBD) spans the full spectrum of
the consequences of abnormal bone and mineral me-
tabolism in people with CKD.1 Secondary hyperpara-

308 Am J Kidney Dis. 2012;60(2):308-315

Long-term Management of CKD-MBD
thyroidism is a major part of the MBD spectrum and
has been one focus of research to understand the
factors that generate and maintain hyperparathyroid-
ism.2
To date, it is well established that phosphate reten-
tion and abnormalities in vitamin D metabolism result
from CKD and, either directly or by inducing changes
in serum calcium levels, stimulate the growth and
activity of the parathyroid glands. The resultant high
levels of PTH in blood can affect the bone, causing
osteitis fibrosa (high-turnover bone disease), manifest
with demineralization of bone, predisposition to frac-
tures, and not infrequently, bone pain. In addition, the
consequences of high PTH levels may extend to
nonskeletal tissue, contributing to abnormalities in
multiple systems throughout the body, most notably
cardiovascular disease, with manifestations including
left ventricular hypertrophy, vascular calcification,
and hypertension.
Abnormalities in vitamin D metabolism occur early
in the course of CKD, with 1,25-dihydroxyvitamin D
levels having been shown to decrease progressively,
thereby promoting increases in PTH levels. One rea-
son for the decrease in 1,25-dihydroxyvitamin D
levels is phosphate retention, which may directly
suppress the activity of 1-hydroxylase or may act
indirectly by increasing levels of fibroblast growth
factor 23 (FGF-23), which in turn will decrease 1␣-
hydroxylase activity and increase 24-hydroxylase ac-
tivity.3,4 Compensatory efforts to maintain the concen-
tration of 1,25-dihydroxyvitamin D are compromised
because 25-hydroxyvitamin D levels have been shown
to be reduced in many people with CKD, possibly
contributing to the inability of the damaged kidney to
augment 1,25-dihydroxyvitamin D production when
needed, even in the presence of hyperparathyroid-
ism.5 The accumulation of N-terminally truncated
PTH fragments also may decrease 1␣-hydroxylase
activity.6 Ultimately, when kidney disease is ad-
vanced, 1,25-dihydroxyvitamin D production may be
limited most by the marked decrease in renal parenchy-
mal mass.
PRINCIPLES OF THERAPY
As the pathophysiology of secondary hyperparathy-
roidism has been elucidated over the past, our under-
standing of this pathophysiology has provided a ratio-
nal framework for therapy in which the abnormalities
noted to contribute to hyperparathyroidism are di-
rectly targeted with therapeutic efforts. As listed in
Box 1, the principles of therapy for hyperparathyroid-
ism are to control phosphorus levels and prevent
phosphate retention, correct hypocalcemia if it is
present because this is the major driver of PTH
secretion, supply vitamin D sterols to counteract the
Am J Kidney Dis. 2012;60(2):308-315
Box 1. Principles of Therapy of Hyperparathyroidism in ESRD
Consider calcium balance
● Control hyperphosphatemia/phosphate retention
● Correct hypocalcemia (if present)
● Consider vitamin D sterols
Consider use of calcimimetic therapy or parathyroidec-
tomy in select patients
Abbreviation: ESRD, end-stage renal disease.
abnormalities in vitamin D metabolism, and, finally,
consider the use of a calcimimetic agent or parathyroid-
ectomy to directly control PTH secretion at the level
of the parathyroid gland. These measures are under-
taken in the context of minimizing the calcium burden
to the patient to prevent excessive calcium loading,
which may aggravate the progression of vascular
calcification.
Just as there is a wide spectrum of clinical and
biochemical abnormalities in patients with CKD, there
is also a wide spectrum of therapeutic approaches to
the patient with CDK-MBD, as illustrated in Fig 1.
Thus, some clinicians favor a vitamin D–based ap-
proach with calcimimetic as add-on therapy, whereas
others favor the use of a low-dose vitamin D sterol as
background for calcimimetic-based therapy. The de-
tails of individual patients likely determine the appro-
priate approach, as well as issues of treatment adher-
ence, cost, and comorbid conditions. There presently
are no definitive long-term data to compare these
approaches. These principles have been derived mostly
from observations in patients with end-stage renal
disease (ESRD), but to some degree may be applied to
the earlier stages of CKD when the abnormalities in
bone and mineral homeostasis begin. Calcimimetic
therapy is not approved for use in patients with CKD
not on dialysis therapy and therefore is not recom-
mended for such patients at this time.
In the patient under discussion, the opportunity
to begin therapy early in the course of CKD was not
possible because of loss of follow-up. However, in
general, therapy should be undertaken at this time if
possible. Because clinically measurable hyperphos-
phatemia does not occur until GFR is ⬍20 mL/min/
1.73 m2 (⬍0.33 mL/s/1.73 m2), the use of phos-
phate binders is not part of routine clinical practice.
However, phosphate binders perhaps should be
considered in light of extensive experimental obser-
vations in animals, in which dietary phosphorus
restriction in proportion to the decrease in GFR was
shown to be effective in preventing the develop-
ment of secondary hyperparathyroidism.7,8 It is
possible that in the future, measurements of FGF-23
might be useful in early CKD because these values
may increase even before elevations in PTH levels
are seen.9 However, current practice guidelines
309

Vitamin D Sterol
Calcimime
c
Non-calcium based binders
Calcium based binders
Figure 1. The spectrum of therapies for chronic kidney
disease–mineral and bone disorder (CKD-MBD). This reflects
the strategies of principally using vitamin D sterols together
with non– calcium-based phosphate binders and possibly a
low-dose calcimimetic compared with an alternate strategy of
using calcimimetic therapy together with calcium-based phos-
phate binders and low-dose vitamin D sterols.
recommend measurement of PTH in patients with
GFR ⬍60 mL/min/1.73 m2 (⬍1.0 mL/s/1.73 m2)
and, if values are elevated, suggest assessing the
level of vitamin D nutrition with measurement of
25-hydroxyvitamin D.
When the patient returned to the nephrology clinic,
25-hydroxyvitamin D levels were low and hyperpara-
thyroidism was established. Administration of ergocal-
ciferol, as currently is recommended, resulted in only
a modest increment of 25-hydroxyvitamin D levels,
although iPTH levels decreased somewhat. This result
is similar to previous findings in a larger group of
patients.10,11 Use of oral active vitamin sterols might
have been considered in this patient, but eGFR was
low and decreasing progressively and they were not
prescribed.
In applying these principles of therapy to patients
with advanced CKD, including patients with ESRD
being treated with dialysis, clinical practice guide-
lines for therapeutic biochemical targets, initially
introduced by the National Kidney Foundation’s
KDOQI (Kidney Disease Outcomes Quality Initia-
tive) guidelines and later modified and updated by
the KDIGO (Kidney Disease: Improving Global
Outcomes) guidelines, can serve as a useful re-
source. The later iteration of the CKD-MBD guide-
lines, published in 2009, was far more transparent
regarding the data limitations inherent in this
field.12,13 Both the KDOQI and KDIGO clinical
guidelines for therapy are summarized in Table 1.
Initial recommendations by KDOQI were to target
iPTH levels in dialysis patients of 150-300 pg/mL
(150-300 ng/L) because the prevailing opinion at
the time was that this range was associated with
relatively normal bone turnover. Levels of serum
calcium were recommended to be in the normal
310
Martin and González
range, with the opinion of the guideline develop-
ment team that calcium levels preferably should be
in the lower half of this range. It also was recom-
mended that phosphate values be controlled to
3.5-5.5 mg/dL (1.1-1.8 mmol/L), although the up-
per level of this range exceeded the typical labora-
tory normal range. The more recent KDIGO clinical
practice guideline sought to limit recommendations
to those with convincing data to support them.
Accordingly, these guidelines broaden the range for
iPTH to 2-9 times the upper limit of normal and
continue to suggest that serum calcium levels be
maintained within the normal range, but advocated
trying to move phosphorus values toward the nor-
mal range, if achievable. Of note, these are all level
2, or weak, clinical guidelines and cautiously worded
as suggestions rather than recommendations. The
most notable change between the KDOQI and
KDIGO guidelines is the difference in iPTH target
level. In the patient under consideration, these
laboratory values were mostly within the recom-
mended ranges, except to note that values for iPTH
exceeded the KDOQI recommendations, but were
within the KDIGO target.
One major limitation with regard to PTH target
levels is the actual measurement of PTH, reflecting a
lack of PTH standards for assays, as well as the fact
that many of the commercially available iPTH assays
show varying degrees of cross-reactivity to N-
terminally truncated PTH peptides that circulate and
may accumulate in patients with advanced kidney
disease, particularly patients treated with dialysis.14,15
The variable cross-reactivity of PTH assays to these
fragments that can accumulate in CKD renders the
recommendation as a multiple of the upper limit of
normal as conceptually problematic (in the opinion of
the authors) because of the amplification of the contri-
Table 1. Mineral Metabolism Treatment Goals: KDOQI and
KDIGO Targets in CKD Stage 5
Parameter KDOQI Goal KDIGO Goal
iPTH (pg/mL) 150-300 2-9 ⫻ upper limit
of normal
Ca (mg/dL) 8.4-10.2a 8.4-10.2
P (mg/dL) 3.5-5.5 Toward normal
Ca ⫻ P (mg2/dL2) ⬍55 Not specified
Note: Conversion factors for units: calcium in mg/dL to mmol/L,
⫻0.2495; phosphorus in mg/dL to mmol/L, ⫻0.3229. No conver-
sion necessary for iPTH in pg/mL and ng/L.
Abbreviations: Ca, calcium; Ca ⫻ P, calcium-phosphorus prod-
uct; CKD, chronic kidney disease; iPTH, intact parathyroid hor-
mone; KDIGO, Kidney Disease: Improving Global Outcomes;
KDOQI, Kidney Disease Outcomes Quality Initiative; P, phospho-
rus.
a
Lower half of range preferable.
Am J Kidney Dis. 2012;60(2):308-315
Long-term Management of CKD-MBD
bution of these PTH peptides to measured values
caused by the accumulation of these peptides in the
absence of kidney function. Thus, an assay that mea-
sures PTH fragments will result in markedly higher
values as GFR decreases compared with results of an
assay that does not recognize these fragments. Thus,
the range recommended by KDIGO includes the wid-
est range possible considering all the PTH assays that
are available. However, such a range would include
values indicative of moderate to severe hyperparathy-
roidism for many of the assays that are in use at the
present time. KDIGO guidelines also suggest evalua-
tion of changes in PTH levels over time as an additive
consideration that may be clinically useful. The issue
is complicated further because iPTH values are not a
precise index of the underlying bone histology. These
issues are reflected in the uncertainty of an appropri-
ate range for PTH measurements in patients with
ESRD.
In the patient discussed in the clinical vignette, it
was unclear whether the bone pain might represent
hyperparathyroidism or could reflect microfractures
as a result of osteoporosis from prior corticosteroid
therapy and/or postmenopausal status or be due to
another cause altogether. Although the PTH values
might be considered within the KDIGO target, the
increased alkaline phosphatase level was suggestive
of high-turnover bone. For this reason, a bone biopsy
was performed, showed severe hyperparathyroid bone
disease, and indicated that intensified therapy for
hyperparathyroidism was required. Such therapy was
successful in decreasing PTH values to the lower part
of recommended ranges and achieved marked im-
provement in symptoms. Bone biopsy is not done
often in clinical practice, but is useful in a case such as
this, for which the diagnosis may be unclear and bone
biopsy can be very useful in guiding the approach to
therapy.
It is important to emphasize that the recom-
mended values for PTH initially were focused on
the effects of PTH on bone; however, it now is
recognized that measurements of PTH alone are not
a precise predictor of the state of bone turnover,
particularly in patients receiving dialysis. More
recent studies have looked to find the relationship
between PTH values and patient outcome, with
large retrospective epidemiologic studies con-
ducted in the United States, Europe, and South
America all showing that the lowest mortality, most
of which is cardiovascular in nature, is seen with
iPTH values within the range recommended by the
initial KDOQI group, that is, iPTH values of 150-
300 pg/mL (150-300 ng/L).16-18 Such epidemio-
logic observations indicate only an association of
PTH level with outcome and should not be con-
Am J Kidney Dis. 2012;60(2):308-315
strued as indicating cause and effect. It is important
to note that such studies should be considered with
the realization that there is considerable potential
for residual confounding and limitations of the
artificial constraints induced by the statistical mod-
eling in these types of studies. Certain patient
groups may require slightly higher PTH values, so
that any recommendations with regard to the target
range for PTH should be considered “soft” and
other factors should be considered according to
clinical circumstances. Recommendations of appro-
priate PTH values in the earlier stages of CKD are
entirely opinion based at this time.
CONTROL OF HYPERPHOSPHATEMIA
Physiologically, it is intuitive that it should be
important to control hyperphosphatemia, reflecting
potential consequences for bone and mineral metabo-
lism and for the cardiovascular system, as shown in
Fig 2. Thus, hyperphosphatemia can decrease cal-
citriol production, cause resistance to the actions of
calcitriol and PTH, and lead directly to increased PTH
secretion and stimulate parathyroid growth. In addi-
tion, hyperphosphatemia is associated with an in-
creased risk of metastatic calcification, including cal-
cification in the vasculature,19-21 and has been shown
to be associated, as an independent risk factor, with
increased mortality risk.16-18,22
For these reasons, it is reasonable to try to
control hyperphosphatemia in patients on dialysis
therapy. Phosphorus control is accomplished best
by addressing both intake and clearance. Accord-
ingly, a multifaceted approach could encompass
dietary phosphorus restriction, use of phosphate
binders to complex phosphate in the intestine to
prevent its absorption, adequate hemodialysis or
peritoneal dialysis to facilitate phosphorus re-
moval, and efforts to control secondary hyperpara-
thyroidism to try to minimize phosphate efflux from
bone as a contributor to hyperphosphatemia. The
quantitative contribution of each of these ap-
proaches is not well understood at the present time,
and there are insufficient data to show that these
efforts will have a favorable influence on mortality.
Phosphate binders are an essential part of the therapy
and have evolved over many years, from the use of
aluminum compounds to the use of calcium-contain-
ing phosphate binders, such as calcium carbonate or
calcium acetate, to magnesium carbonate, sevelamer
hydrochloride, and later, to sevelamer carbonate and
lanthanum carbonate, and in the future, to other phos-
phate binders that are currently in development, as
listed in Table 2. The aluminum-based phosphate
binders largely have been abandoned in the United
States because of the risk of aluminum toxicity, but
311
 Martin and González

↑ Pi
↓ Ca++ ↓ Calcitriol
PTH Resistance Calcitriol Resistance
Figure 2. The consequences of hyper-
phosphatemia. Elevations in serum phos-
↑ PTH Secretion phate levels can affect end-organ response
to parathyroid hormone (PTH) and calcitriol,
can directly stimulate PTH secretion and
↑ Parathyroid Cell Growth parathyroid growth, and are associated with
increased fibroblast growth factor 23 (FGF-
23) levels and increased risk of vascular
Increased Risk of calcification and death. Abbreviations: Ca,
Metastatic Calcification ↑ Mortality ↑ FGF-23 calcium; Pi, inorganic phosphorus.

are still used throughout the world. If aluminum-
based phosphate binders are used, it is reasonable to
have continued surveillance of serum aluminum
levels.
Calcium-containing phosphate binders are widely
used, but in certain settings may be associated with
the development and maintenance of hypercalcemia.
Several, but not all, trials comparing calcium- versus
non–calcium-containing binders suggest that in-
creased calcium absorption may contribute to progres-
sion of vascular calcification, as suggested with the
Treat-to-Goal and other studies.23,24 This issue re-
mains somewhat controversial.25,26 Thus, the CARE
2 (Calcium Acetate Renagel Evaluation-2) Study com-
pared prevalent hemodialysis patients randomly as-
signed to calcium acetate or sevelamer hydrochloride
treatment, with both groups receiving atorvastatin to
lower cholesterol levels. Although there was a high
dropout rate, no difference in progression of vascular
calcification was observed.26 Similarly, the BRiC
(Phosphate Binder Impact on Bone Remodeling and
Coronary Calcification) study did not show a differ-
ence in rate of progression of vascular calcification in
patients treated with calcium acetate compared with
sevelamer acetate.27 Nonetheless, caution regarding
the use of high calcium intake is advised, especially in
the presence of vascular calcification. Accordingly, if
calcium-containing phosphate binders are used, ac-
cording to the KDOQI recommendations, the amount
should be limited to no more than 1.5 g of elemental
calcium per day. No specific limit was suggested by
KDIGO, but this would appear to be a reasonable
limit unless it is desirable to promote a positive
calcium balance. In the patient under discussion,
because of mitral valve calcification noted on pretrans-
plant cardiac evaluation, calcium carbonate was re-
duced and sevelamer was prescribed. Lanthanum car-
bonate also might have been considered to limit the
calcium load.
In theory, it seems intuitive that adding to the
substrate that precipitates in the vasculature (calcium
and phosphorus) would be undesirable because the
more vascular calcification that is present, the worse
the survival probability for the patient.28 To further
explore this theory, several studies have compared
survival in individuals prescribed calcium-containing

Table 2. Phosphate Binders

Type Cation Content Advantages Disadvantages

CaCO3 200 mg Ca in 500 mg CaCO3 Inexpensive; widely available 1 Ca

CaAc 169 mg Ca in 667 mg CaAc Inexpensive; widely available 1 Ca; pill burden
Ca citrate 200 mg Ca in 950 mg Ca citrate — 1 Ca; 1Al absorption
Sevelamer HCl None No Ca; 2 LDL GI side effects; cost; pill burden
Sevelamer carbonate None No Ca; 2 LDL GI side effects; cost; pill burden
Mg/CaCO3 114 mg Mg in 400 MgCO3; 80 2 Ca load Mg accumulation; not widely available
mg Ca in 200 mg CaCO3
MgCO3/CaAc 60 mg Mg in 235 MgCO3; 110 2 Ca load Mg accumulation; not widely available
mg Ca in 435 mg CaAc
La2(CO3)3 250, 500, 1,000 mg La/tablet Potent Chewable; GI side effects
Al(OH)3 100-200 mg Al/tablet Potent Al toxicity
Abbreviations: Al, aluminum; Al(OH)3, aluminum hydroxide; Ca, calcium; CaAc, calcium acetate; CaCO3, calcium carbonate; GI,
gastrointestinal; HCl, hydrochloride; La2(CO3)3, lanthanum carbonate; LDL, low-density lipoprotein cholesterol; Mg, magnesium;
MgCO3, magnesium carbonate.

312 Am J Kidney Dis. 2012;60(2):308-315

Long-term Management of CKD-MBD
or non–calcium-containing phosphate binders. The
Dialysis Clinical Outcomes Revisited (DCOR) Study,
conducted in 2,103 prevalent dialysis patients, ran-
domly assigned participants to either sevelamer or
calcium-based phosphate binders, with primary study
end points of all-cause mortality and cardiovascular
death. Overall, the study was negative and was com-
plicated by a nearly 50% dropout rate, although a
nonprespecified subgroup analysis showed a benefit
of uncertain methodologic validity in patients 65
years and older,29 the KDIGO CKD-MBD work group
states that this subgroup analysis “could be, at best,
considered hypothesis generating and should be inter-
preted with extreme caution.”13(pS55) These results are
contrasted with those in the RIND (Reversible Isch-
emic Neurological Deficit) Study, which examined
this issue in 127 incident dialysis patients. In RIND,
although the numbers of patients were considerably
smaller, use of the non–calcium-containing phosphate
binder was associated with decreased progression of
vascular calcification over time.23 Follow-up of these
patients (albeit uncontrolled) over the subsequent sev-
eral years showed an apparent survival benefit for
patients treated with sevelamer,30 raising the issue
that the DCOR results potentially may not fully reflect
the benefits of the non–calcium-containing binder
because of the use of prevalent patients, and calling to
attention that perhaps this question should be exam-
ined earlier in the course of CKD.
VITAMIN D STEROLS
Several active vitamin D sterols are available for
use in patients to control hyperparathyroidism; in the
United States, these agents include calcitriol, parical-
citol, and doxercalciferol. Use of vitamin D sterols is
an important part of the therapy for hyperparathyroid-
ism, not only because of the efficacy in controlling
PTH secretion, but also because of observations that
use of vitamin D sterols appears to be associated with
a survival advantage, first noticed in patients on
hemodialysis therapy and later in patients with
CKD.31-35 The vitamin D analogue paricalcitol was
introduced and developed to try to obtain more selec-
tive action on the parathyroid gland while minimizing
the effects of active vitamin D sterols to cause hyper-
calcemia or hyperphosphatemia (the main manifesta-
tions of vitamin D toxicity) and was supported in
detailed preclinical studies. The vitamin D2 prohor-
mone doxercalciferol, because it also was based on
the D2 structure, also appeared to have the potential
for decreased hypercalcemia and is widely used. Di-
rect head-to-head randomized studies in patients are
limited at the present time. In one observational study,
we noted that withdrawal of paricalcitol therapy does
not significantly change serum phosphate values, sug-
Am J Kidney Dis. 2012;60(2):308-315
gesting that the effects of paricalcitol on increasing
phosphate absorption are rather small.36 In contrast,
in a crossover study in which paricalcitol was com-
pared with doxercalciferol, there were more episodes
of hyperphosphatemia with doxercalciferol than with
paricalcitol, suggesting that there are potential differ-
ences between these vitamin D sterols that may be-
come relevant to their use. In patients with CKD not
on dialysis therapy, the oral forms of these active
vitamin D sterols may be used, but there are no
definitive studies of the relative efficacy or toxicity. A
substantial body of evidence in experimental animals
confirms that there are important differences between
the various vitamin D sterols, particularly dramatic in
terms of vascular calcification, as shown in the work
of Mizobuchi et al,37 in which calcitriol and doxercal-
ciferol appear to be associated with severe vascular
calcification, whereas paricalcitol was not. Compa-
rable data in patients are not available at the present
time.
Because 25-hydroxyvitamin D levels are low in
many patients with advanced kidney disease, an impor-
tant clinical question is whether this needs to be
supplemented, especially in patients who are receiv-
ing active vitamin D sterols. In this regard, one should
consider the observations of Wolf et al,38 who found
that mortality in the first 90 days of dialysis therapy
appears to stratify by 25-hydroxyvitamin D levels,
and if these patients were given an active vitamin D
sterol, this stratification was abolished. These observa-
tions suggest that administration of an active vitamin
D sterol may be sufficient to achieve the apparent
mortality benefit shown with this therapy. One also
should consider results of studies in 1␣-hydroxylase
knockout animals, in which calcitriol administration
has been shown to have beneficial effects on cardiac
hypertrophy that conceivably may be relevant to this
issue and suggesting that the circulating hormonal
form of active vitamin D may have important effects
on the cardiovascular system.39 However, cholecalcif-
erol supplementation may decrease the amount of
active vitamin D sterol required and also may de-
crease the amount of erythropoietic-stimulating agent
required.40
If hyperparathyroidism cannot be controlled with
adequate control of hyperphosphatemia, correction of
hypocalcemia, and the use of vitamin D sterols, an
additional approach in patients with ESRD is to di-
rectly target PTH secretion from the parathyroid gland
by the use of a calcimimetic agent or to consider
parathyroidectomy in selected patients. The calcimi-
metic cinacalcet was introduced for this purpose and
by targeting the calcium receptor, can decrease PTH
levels effectively, significantly decrease serum cal-
cium levels, and achieve a slight decrease in serum
313

phosphate values if taken in conjunction with the
other therapeutic measures.41,42 Recent data for 360
patients in the ADVANCE (Action in Diabetes and
Cardiovascular Disease: Preterax and Diamicron
Modified Release Controlled Evaluation) trial suggest
that this approach is associated with a trend toward
decreasing the progression of vascular and valvular
calcification and was significant for aortic valvular
calcification.43 Because this agent is administered
orally, one has to ensure patient adherence to the
regimen, which may be somewhat problematic, as
shown by the studies of Gincherman et al.44 If medi-
cal therapy cannot achieve sustained control of hyper-
parathyroidism, consideration should be given to para-
thyroidectomy. This usually is reserved for patients
with severe hyperparathyroidism for whom medical
therapy cannot be tolerated.
A recent consideration for the therapeutic approach
to this important clinical problem relates to FGF-23
levels. Thus, vitamin D therapy might be expected to
directly increase FGF-23 levels. However, because
FGF-23 comes from bone, reductions in bone cell
activity might be expected to decrease FGF-23 levels.
This issue may become important because epidemio-
logic studies indicate that high FGF-23 levels appear
to be associated with increased mortality for patients
on hemodialysis therapy.45,46 This observation also
appears to extend to patients with earlier stages of
CKD.47 Although the exact mechanism for this mortal-
ity association is not known, recent studies show
important direct effects of FGF-23 on the heart, par-
ticularly in causing left ventricular hypertrophy.48 At
the very least, FGF-23 appears to be an important
biomarker for adverse outcomes, and it may be caus-
ative for inducing left ventricular hypertrophy. It may
become useful in the future to consider what happens
to FGF-23 during our therapeutic efforts and perhaps
develop approaches to modify its production or ac-
tion. Calcimimetic therapy would be expected to
decrease FGF-23 by decreasing PTH levels, whereas
vitamin D sterols would be expected to increase
FGF-23 production by a direct effect on gene transcrip-
tion. However, in one clinical trial that compared
cinacalcet plus fixed-dose active vitamin D sterol
therapy versus active vitamin D sterol therapy alone
to control hyperparathyroidism, there appeared to be a
greater decrease in FGF-23 levels in the cinacalcet
arm.49 Further studies are required of the conse-
quences of changes in FGF-23 levels with the current
approach to treatment of abnormalities in CKD-
MBD.
Much of our approach to the treatment of mineral
and bone disorders in CKD has been in patients who
are treated with dialysis, and despite decades of clini-
cal experience, there remains a paucity of high-quality
314
Martin and González
data and many therapeutic challenges to achieving
effective and sustained control of MBD. Given the
limited overall success with addressing disease in
patients with kidney failure, at which time much of
the milieu promoting MBD has been present for years
or even decades, it becomes important to try to ad-
dress these problems earlier in the course of CKD.2,50
Possibly, if addressed early, improved and more con-
stant control of MBD during kidney failure might be
facilitated. Further ongoing research and future devel-
opments of new therapeutic agents may facilitate our
efforts on this important clinical problem.
ACKNOWLEDGEMENTS
Support: None.
Financial Disclosure: Dr Martin has served as a consultant for
Abbott, Cytochroma, Genzyme, and KAI Pharmaceuticals and as a
speaker for Abbott and Genzyme. Dr González declares that she
has no relevant financial interests.
REFERENCES
1. Moe SM, Drueke T, Lameire N, Eknoyan G. Chronic kidney
disease-mineral-bone disorder: a new paradigm. Adv Chronic
Kidney Dis. 2007;14(1):3-12.
2. Martin KJ, Gonzalez EA. Metabolic bone disease in chronic
kidney disease. J Am Soc Nephrol. 2007;18(3):875-885.
3. Perwad F, Zhang MY, Tenenhouse HS, Portale AA. Fibro-
blast growth factor 23 impairs phosphorus and vitamin D metabo-
lism in vivo and suppresses 25-hydroxyvitamin D-1alpha-hydroxy-
lase expression in vitro. Am J Physiol. 2007;293(5):F1577-F1583.
4. Shimada T, Hasegawa H, Yamazaki Y, et al. FGF-23 is a
potent regulator of vitamin D metabolism and phosphate homeosta-
sis. J Bone Miner Res. 2004;19(3):429-435.
5. Nykjaer A, Dragun D, Walther D, et al. An endocytic
pathway essential for renal uptake and activation of the steroid
25-(OH) vitamin D3. Cell. 1999;96(4):507-515.
6. Usatii M, Rousseau L, Demers C, et al. Parathyroid hormone
fragments inhibit active hormone and hypocalcemia-induced
1,25(OH)2D synthesis. Kidney Int. 2007;72(11):1330-1335.
7. Slatopolsky E, Caglar S, Gradowska L, Canterbury J, Reiss
E, Bricker NS. On the prevention of secondary hyperparathyroid-
ism in experimental chronic renal disease using “proportional
reduction” of dietary phosphorus intake. Kidney Int. 1972;
2(3):147-151.
8. Slatopolsky E, Caglar S, Pennell JP, et al. On the pathogene-
sis of hyperparathyroidism in chronic experimental renal insuffi-
ciency in the dog. J Clin Invest. 1971;50(3):492-499.
9. Isakova T, Wahl P, Vargas GS, et al. Fibroblast growth factor
23 is elevated before parathyroid hormone and phosphate in
chronic kidney disease. Kidney Int. 2011;79(12):1370-1378.
10. Al-Aly Z, Qazi RA, Gonzalez EA, Zeringue A, Martin KJ.
Changes in serum 25-hydroxyvitamin D and plasma intact PTH
levels following treatment with ergocalciferol in patients with
CKD. Am J Kidney Dis. 2007;50(1):59-68.
11. Zisman AL, Hristova M, Ho LT, Sprague SM. Impact of
ergocalciferol treatment of vitamin D deficiency on serum parathy-
roid hormone concentrations in chronic kidney disease. Am J
Nephrol. 2007;27(1):36-43.
12. National Kidney Foundation. K/DOQI Clinical Practice
Guidelines for Bone Metabolism and Disease in Chronic Kidney
Disease. Am J Kidney Dis. 2003;42(4)(suppl 3):S1-S201.
13. Kidney Disease: Improving Global Outcomes (KDIGO)
CKD-MBD Work Group. KDIGO clinical practice guideline for
Am J Kidney Dis. 2012;60(2):308-315
Long-term Management of CKD-MBD
the diagnosis, evaluation, prevention, and treatment of chronic
kidney disease-mineral and bone disorder (CKD-MBD). Kidney
Int. 2009;76(Suppl 113):S1-S130.
14. Martin KJ, Gonzalez EA. Parathyroid hormone assay: prob-
lems and opportunities. Pediatr Nephrol. 2007;22(10):1651-1654.
15. Souberbielle JC, Boutten A, Carlier MC, et al. Inter-method
variability in PTH measurement: implication for the care of CKD
patients. Kidney Int. 2006;70(2):345-350.
16. Floege J, Kim J, Ireland E, et al. Serum iPTH, calcium and
phosphate, and the risk of mortality in a European haemodialysis
population. Nephrol Dial Transplant. 2011;26(6):1948-1955.
17. Kalantar-Zadeh K, Kuwae N, Regidor DL, et al. Survival
predictability of time-varying indicators of bone disease in mainte-
nance hemodialysis patients. Kidney Int. 2006;70(4):771-780.
18. Naves-Diaz M, Passlick-Deetjen J, Guinsburg A, et al.
Calcium, phosphorus, PTH and death rates in a large sample of
dialysis patients from Latin America. The CORES Study. Nephrol
Dial Transplant. 2011;26(6):1938-1947.
19. Kendrick J, Chonchol M. The role of phosphorus in the
development and progression of vascular calcification. Am J Kid-
ney Dis. 2011;58(5):826-834.
20. Roman-Garcia P, Carrillo-Lopez N, Fernandez-Martin JL,
Naves-Diaz M, Ruiz-Torres MP, Cannata-Andia JB. High phospho-
rus diet induces vascular calcification, a related decrease in bone
mass and changes in the aortic gene expression. Bone. 2010;46(1):
121-128.
21. Srivaths PR, Goldstein SL, Silverstein DM, Krishnamurthy
R, Brewer ED. Elevated FGF 23 and phosphorus are associated
with coronary calcification in hemodialysis patients. Pediatr Neph-
rol. 2011;26(6):945-951.
22. Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Asso-
ciation of serum phosphorus and calcium x phosphate product with
mortality risk in chronic hemodialysis patients: a national study.
Am J Kidney Dis. 1998;31(4):607-617.
23. Block GA, Spiegel DM, Ehrlich J, et al. Effects of sevelamer
and calcium on coronary artery calcification in patients new to
hemodialysis. Kidney Int. 2005;68(4):1815-1824.
24. Chertow GM, Burke SK, Raggi P. Sevelamer attenuates the
progression of coronary and aortic calcification in hemodialysis
patients. Kidney Int. 2002;62(1):245-252.
25. Navaneethan SD, Palmer SC, Craig JC, Elder GJ, Strippoli
GF. Benefits and harms of phosphate binders in CKD: a systematic
review of randomized controlled trials. Am J Kidney Dis. 2009;
54(4):619-637.
26. Qunibi W, Moustafa M, Muenz LR, et al. A 1-year random-
ized trial of calcium acetate versus sevelamer on progression of
coronary artery calcification in hemodialysis patients with compa-
rable lipid control: the Calcium Acetate Renagel Evaluation-2
(CARE-2) Study. Am J Kidney Dis. 2008;51(6):952-965.
27. Barreto DV, Barreto Fde C, de Carvalho AB, et al. Phos-
phate binder impact on bone remodeling and coronary calcifica-
tion—results from the BRiC Study. Nephron Clin Pract. 2008;
110(4):c273-c283.
28. Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM.
Arterial calcifications, arterial stiffness, and cardiovascular risk in
end-stage renal disease. Hypertension. 2001;38(4):938-942.
29. Suki WN, Zabaneh R, Cangiano JL, et al. Effects of
sevelamer and calcium-based phosphate binders on mortality in
hemodialysis patients. Kidney Int. 2007;72(9):1130-1137.
30. Block GA, Raggi P, Bellasi A, Kooienga L, Spiegel DM.
Mortality effect of coronary calcification and phosphate binder
choice in incident hemodialysis patients. Kidney Int. 2007;71(5):
438-441.
Am J Kidney Dis. 2012;60(2):308-315
31. Kovesdy CP, Ahmadzadeh S, Anderson JE, Kalantar-Zadeh
K. Association of activated vitamin D treatment and mortality in
chronic kidney disease. Arch Intern Med. 2008;168(4):397-403.
32. Shoben AB, Rudser KD, de Boer IH, Young B, Kestenbaum
B. Association of oral calcitriol with improved survival in nondia-
lyzed CKD. J Am Soc Nephrol. 2008;19(8):1613-1619.
33. Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM,
Thadhani R. Survival of patients undergoing hemodialysis with
paricalcitol or calcitriol therapy. N Engl J Med. 2003;349(5):446-
456.
34. Teng M, Wolf M, Ofsthun MN, et al. Activated injectable
vitamin D and hemodialysis survival: a historical cohort study.
J Am Soc Nephrol. 2005;16(4):1115-1125.
35. Tentori F, Albert JM, Young EW, et al. The survival advan-
tage for haemodialysis patients taking vitamin D is questioned:
findings from the Dialysis Outcomes and Practice Patterns Study.
Nephrol Dial Transplant. 2009;24(3):963-972.
36. Martin KJ. When is vitamin D contraindicated in dialysis
patients? Semin Dial. 2009;22(3):247-249.
37. Mizobuchi M, Finch JL, Martin DR, Slatopolsky E. Differ-
ential effects of vitamin D receptor activators on vascular calcifica-
tion in uremic rats. Kidney Int. 2007;72(6):709-715.
38. Wolf M, Shah A, Gutierrez O, et al. Vitamin D levels and
early mortality among incident hemodialysis patients. Kidney Int.
2007;72(8):1004-1013.
39. Zhou C, Lu F, Cao K, Xu D, Goltzman D, Miao D.
Calcium-independent and 1,25(OH)2D3-dependent regulation of
the renin-angiotensin system in 1alpha-hydroxylase knockout mice.
Kidney Int. 2008;74(2):170-179.
40. Matias PJ, Jorge C, Ferreira C, et al. Cholecalciferol supple-
mentation in hemodialysis patients: effects on mineral metabolism,
inflammation, and cardiac dimension parameters. Clin J Am Soc
Nephrol. 2010;5(5):905-911.
41. Block GA, Martin KJ, de Francisco AL, et al. Cinacalcet for
secondary hyperparathyroidism in patients receiving hemodialy-
sis. N Engl J Med. 2004;350(15):1516-1525.
42. Moe SM, Chertow GM, Coburn JW, et al. Achieving
NKF-K/DOQI bone metabolism and disease treatment goals with
cinacalcet HCl. Kidney Int. 2005;67(2):760-771.
43. Raggi P, Chertow GM, Torres PU, et al. The ADVANCE
study: a randomized study to evaluate the effects of cinacalcet plus
low-dose vitamin D on vascular calcification in patients on hemo-
dialysis. Nephrol Dial Transplant. 2011;26(4):1327-1339.
44. Gincherman Y, Moloney K, McKee C, Coyne DW. Assess-
ment of adherence to cinacalcet by prescription refill rates in
hemodialysis patients. Hemodial Int. 2010;14(1):68-72.
45. Gutierrez OM, Mannstadt M, Isakova T, et al. Fibroblast
growth factor 23 and mortality among patients undergoing hemodi-
alysis. N Engl J Med. 2008;359(6):584-592.
46. Jean G, Terrat JC, Vanel T, et al. High levels of serum fibroblast
growth factor (FGF)-23 are associated with increased mortality in long
haemodialysis patients. Nephrol Dial Transplant. 2009;24(9):2792-2796.
47. Isakova T, Xie H, Yang W, et al. Fibroblast growth factor 23
and risks of mortality and end-stage renal disease in patients with
chronic kidney disease. Jama. 2011;305(23):2432-2439.
48. Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left
ventricular hypertrophy. J Clin Invest. 2011;121(11):4393-4408.
49. Wetmore JB, Liu S, Krebill R, Menard R, Quarles LD.
Effects of cinacalcet and concurrent low-dose vitamin D on
FGF-23 levels in ESRD. Clin J Am Soc Nephrol. 2010;5(1):110-
116.
50. Martin KJ, Gonzalez EA. Prevention and control of
phosphate retention/hyperphosphatemia in CKD-MBD: what is
normal, when to start, and how to treat? Clin J Am Soc Nephrol.
2011;6(2):440-446.
315