translational nephrology
org
Use of vitamin D in chronic kidney disease patients
Anca Gal-Moscovici1 and Stuart M. Sprague2
1
Hebrew University of Jerusalem, Hadassah Hospital, Ein Keren, Jerusalem, Israel and 2NorthShore University HealthSystem and
University of Chicago Pritzker School of Medicine, Evanston, Illinois, USA
Chronic kidney disease (CKD) has been recognized as a
significant public health problem, with 20 million Americans,
or 11% of the adult population, currently living with CKD. Life
expectancy in patients with CKD is limited by the
development of disturbances of mineral metabolism, which
occurs in virtually all patients during the progression of their
disease, and is associated with bone loss and fractures,
cardiovascular disease, immune suppression, and increased
mortality. As kidney disease develops, there is decreased
functional renal mass and a reduction in renal 1a-hydroxylase
activity and thus in renal production of calcitriol at very
early CKD stages. Recently, a potentially important role
of vitamin D receptor activation (VDRa) in the survival of
patients undergoing dialysis has been suggested. Beyond the
effect on parathyroid hormone suppression, the pleiotropic
effect of vitamin D has been associated with improvement of
cardiovascular risk factors, including increased renin activity,
hypertension, inflammation, insulin resistance, diabetes, and
albuminuria. However, the current K/DOQI and KDIGO
recommendations limit the administration of VDRa agents for
treatment of hyperparathyroidism only. The role of vitamin D
administration in the different CKD stages will be discussed
in this review.
Kidney International (2010) 78, 146–151; doi:10.1038/ki.2010.113;
published online 26 May 2010
KEYWORDS: bone; chronic kidney disease; hyperparathyroidism; vascular
calcification; vitamin D
Correspondence: Stuart M. Sprague, Division of Nephrology and Hyperten-
sion, NorthShore University HealthSystem, University of Chicago Pritzker
School of Medicine, 2650 Ridge Avenue, Evanston, Illinois 60201, USA.
E-mail: stuartmsprague@gmail.com
Received 18 August 2009; revised 24 February 2010; accepted 2 March
2010; published online 26 May 2010
146
http://www.kidney-international.
& 2010 International Society of Nephrology
Life expectancy in patients with chronic kidney disease (CKD)
is limited, in large part, by the high rate of cardiovascular
morbidity and mortality. The development of CKD and
mineral and bone disease with its associated disorders in
calcium and phosphorus homeostasis, vitamin D metabolism,
secondary hyperparathyroidism, metabolic changes in bone,
and vascular calcification have been implicated in the patho-
genesis of this high mortality rate in patients with CKD.
The wide range of mineral and bone metabolic disorders
have become a diagnostic and therapeutic challenge in the
day-to-day management of patients with CKD.
EPIDEMIOLOGICAL FACTORS
Numerous epidemiologic studies have revealed a potentially
important role of the vitamin D receptor (VDR) in the survival
of patients undergoing dialysis.1,2 Compared with the absence
of any form of vitamin D therapy, treatment with vitamin D
compounds that activate the VDR, the so-called VDR activators
(VDRa), have been associated with decreased mortality, with
the newer VDRa analogs appearing to have a greater effect than
calcitriol.1–3 As these agents have been administered primarily to
treat secondary hyperparathyroidism, the most obvious explana-
tion for the observed benefits could be the result of lowering of
parathyroid hormone (PTH) concentrations. Elevated PTH has
been shown to be associated with a number of cardiovascular
(myocardial fibrosis, left ventricular hypertrophy, decreased
myocardial contractility, increased vascular and valvular calci-
fication, and decreased vasodilatation),4,5 metabolic (decreased
insulin sensitivity and disorders of lipid metabolism),6–8 hemato-
logical (bone marrow fibrosis and decreased erythropoiesis),9,10
and immunological11 abnormalities. Treatment of secondary
hyperparathyroidism could thus improve or reverse a number
of these abnormalities, potentially translating into a better
survival. However, the survival benefit attributed to use of
VDRa agents was apparently independent of serum calcium,
phosphate, and PTH concentrations, suggesting that treat-
ment with a VDRa in advanced CKD to treat moderate and
severe secondary hyperparathyroidism has a survival benefit
beyond its role in suppressing PTH secretion.
EXTRASKELETAL ROLE OF VITAMIN D
An increased understanding of the biologic role of vitamin D in
both bone and mineral metabolism, as well as its extraskeletal
activity, supports its association with lower mortality. Vitamin D
is a pleiotropic steroid hormone that binds to its intracellular
Kidney International (2010) 78, 146–151
A Gal-Moscovici and SM Sprague: Use of vitamin D in CKD patients
receptor to elicit a diverse genetic response.12 Part of the
difficulty in understanding the physiologic role of vitamin D
sterols is confusion with nomenclature. For the purpose of
clarity in this paper, we are using the nomenclature and
abbreviations as noted in Table 1. Experimental and epidemiologic
studies have connected lower 25-hydroxyvitamin D (25 Vit D)
and calcitriol concentrations with cardiovascular risk factors,
including increased renin activity, hypertension, inflamma-
tion, insulin resistance, diabetes, and albuminuria.13–16
The potential ameliorative effects of vitamin D on
cardiovascular risk factors include mechanisms related to
the development of vascular calcification and atherosclerosis.
In this regard, VDRa was shown to inhibit activators of
vascular mineralization such as Cbfa1 (RUNX2), bone
morphogenic protein-2, type I collagen, interleukin-1b,
interleukin-6, and transforming growth factor-a, and to
stimulate inhibitors of vascular mineralization such as matrix
Gla protein and osteopontin.17–22 Similarly, data are
emerging supporting a potential role of VDRa in preventing
or ameliorating the pathogenesis of atherosclerosis. Th1
lymphocytes, which infiltrate the subendothelial cell in
response to oxidized low-density lipoprotein, secrete inter-
feron-g that in turn suppresses the antiatherogenic Th2
lymphocytes. The favorable effect of VDRa on this process
may occur by enriching the Th2 cell population.23,24
Other potential mechanisms in which VDRa may
ameliorate or prevent cardiovascular disease include its effect
on the renin-angiotensin-aldosterone axis. Decreased VDR
activity increases circulating renin levels and blood pressure
and causes left ventricular and myocyte hypertrophy in
genetically manipulated mouse models.25 Treatment with
VDRa agents inhibits renin expression, normalizes blood
pressure, and reverses the cardiac hypertrophy.26,27
Vitamin D insufficiency and deficiency is widely prevalent
in the general population. It has been estimated that 1 billion
people worldwide have vitamin D insufficiency or defi-
ciency.12 Similar to the general population, vitamin D
insufficiency and deficiency is widely prevalent in CKD.
Regardless of the geographic location in the United States,
low 25 Vit D concentrations are present in 71% of patients
with stage 3 CKD and 83% of patients with stage 4 CKD.
Suboptimal 25 Vit D levels can be found in up to 97% of
patients on maintenance hemodialysis.28
Table 1 | Vitamin D nomenclature
Term Sterol Comment
Vitamin D Cholecalciferol D3
Ergocalciferol D2
25 Vit D Calcidiol (25(OH)D3) D3
Ercalcidiol (25(OH)D2) D2
VDRa Calcitriol (1,25(OH)2D3) D3; natural hormone
Alfacalcidol (1(OH)D3) D3; synthetic prohormonea
Doxercalciferol (1(OH)D2) D2; synthetic prohormone
Paricalcitol (19nor,1,25(OH)2D2) D2; synthetic analog
Maxacalcitol (22oxa,1,25(OH)2D3) D3; synthetic analog
Abbreviations: VDRa, vitamin D receptor agonist; 25 Vit D, 25-hydroxyvitamin D.
a
Prohormone requires 25-hydroxylation by the liver to become an active analog.
Kidney International (2010) 78, 146–151
translational nephrology
TREATMENT CONSIDERATIONS
In the light of these data, we believe that patients with CKD
should be treated similarly as the general population and
vitamin D therapy should be offered to every CKD patient
who shows vitamin D deficiency. However, administration of
VDRa agents is limited by the current K/DOQI (Kidney Disease
Outcomes Quality Initiative) recommendations. In CKD patients
undergoing renal replacement therapy, it is recommended to
use VDRa therapy only for treatment of hyperparathyroidism.
Furthermore, it is suggested that vitamin D therapy should be
stopped or not initiated when phosphate concentrations are
45.5 mg/dl, when intact PTH concentrations areo150 pg/ml,
or when the calcium–phosphate product exceeds 55 mg2/dl2.29
There is no comment on the use of vitamin D to correct the
vitamin D deficiency observed in these patients. In patients with
CKD stages 3 and 4, it is recommended to correct 25 Vit D
deficiency when hyperparathyroidism is present with the
use of nutritional replacement with either ergocalciferol or
cholecalciferol. Only if hyperparathyroidism persists, it is
recommended to use a VDRa for treatment.29
Whether any type of vitamin D therapy is beneficial in
CKD has created some controversy; in fact, a meta-analysis
by Palmer et al.30 suggested that there was no benefit of
vitamin D therapy in patients with CKD. Synthesizing 76 trials,
the researchers suggested that vitamin D compounds do not
reduce the risk of death or vascular calcification, and when
compared with placebo, calcitriol results in an increased risk
of hypercalcemia and hyperphosphatemia and did not show a
consistent reduction in PTH concentrations. Other VDRas
were associated with hypercalcemia but not with hyperpho-
sphatemia, and an effect on PTH was also not consistently
reduced. The researchers concluded that vitamin D treatment
for CKD patients remains uncertain. Unfortunately, this
analysis excluded a 220-patient 24-week placebo-controlled
randomized trial, which found that paricalcitol suppressed
PTH by an average of 42%, and 90% of patients achieved at
least a 30% suppression of PTH,31 and also a 266-patient
32-week randomized controlled trial of calcitriol versus
paricalcitol, in which 80 and 90% of patients, respectively,
achieved 450% PTH suppression.32 Instead, the researchers
included studies from the 1980s in which PTH suppression
was not the primary end point. For adverse outcomes such as
hypercalcemia, the results were driven by a single study,
which considered elevated calcium as acceptable and possibly
necessary. Numerous placebo-controlled studies show that
the newer VDRas do not result in significant hypercalcemia
or hyperphosphatemia when compared with placebo. Thus,
the conclusion that vitamin D is not useful in CKD cannot be
ascertained from this study. Prospective studies are required
to address whether VDRa therapy should be initiated in any
stage of CKD to replace the calcitriol deficiency and whether
such therapy would have physiologic benefit.
In most patients with early CKD, calcium and phosphate
disorders are not evident until advanced stage 4 (Figure 1),
and hence the high risk for cardiovascular events in this
population could not be attributed solely to disturbances in
147
translational nephrology
2000
Stage 1
50
Calcitriol (pg/ml)
FGF-23 (RU/ml)
40
Calcitriol
30
20
10
100
0
105 95
Figure 1 | Progression of changes in calcitriol, parathyroid hormone (PTH), and fibroblast growth factor-23 (FGF-23) with
chronic kidney disease (CKD). The early decrease in calcitriol with the increase of FGF-23 before the increase in PTH as CKD develops.
Adapted from references 28, 33, 38, and 39.
these minerals. However, calcitriol concentrations already
decline to the lower limit of the normal in stage 2 CKD, and
progress to low and very low levels in patients with stages 3
and 4 CKD.28,33 Vitamin D deficiency is associated with
increased mortality and cardiovascular morbidity in patients
undergoing dialysis.34 Similar association may also be present
in patients with earlier stages of CKD.35–37
The major determinant of low calcitriol levels is the
reduction in renal mass with associated decreased 1a-
hydroxylase available for converting 25 Vit D by the proximal
tubular cells. 1a-hydroxylase is further suppressed by
fibroblast growth factor-23. The secretion of fibroblast
growth factor-23 is stimulated by phosphate and its
concentrations are markedly increased in the early stages of
CKD.38,39 Recently, it was shown that fibroblast growth
factor-23 may also suppress the expression of PTH
mRNA40,41 as well as osteoblastic differentiation and bone
matrix maturation,42 in addition to its phosphaturic activity.
These findings might result in a delayed increase in PTH
concentrations and suppressed bone turnover, as an early
presentation in CKD stages 2 and 3. They could also result in
the postponement of vitamin D treatment in early CKD
stages. Although these hypotheses should be further tested by
clinical and laboratory research, several investigators have
found adynamic bone disease in pre-dialysis patients,43,44 and
also in an animal model of CKD and metabolic syndrome, in
which adynamic bone develops in early renal insufficiency
despite very mild secondary hyperparathyroidism.45
Usually the administration of VDRa in incipient CKD
with normal or slightly increased PTH concentration is
avoided because of the concern of oversuppression of the
parathyroid gland and development of adynamic bone.
However, administration of small physiologic doses of VDRa
agents in mild CKD was shown to normalize the bone
metabolism even in patients with low PTH and low-turnover
bone disease.46
148
A Gal-Moscovici and SM Sprague: Use of vitamin D in CKD patients
Stage 2 Stage 3 Stage 4
FGF
200
Intact PTH (pg/ml)
PTH
P < 0.01 150
100
50
P < 0.01
85 75 65 55 45 35 25 15
GFR (ml/min)
Low doses of VDRa agents have recently been shown to be
associated with a significantly better survival in pre-dialysis
patients.47,48 Shoben et al.47 reported a survival benefit of
therapy with calcitriol versus no therapy in patients with
stages 3 and 4 CKD. To be eligible for the study, patients had
to be calcitriol naive and have a PTH level of 70 pg/ml during
the year before starting therapy. Patients who were treated
with calcitriol had a 26% lower mortality compared with
those who were untreated. Survival benefit in patients treated
with calcitriol, despite the important limitation of the study,
was not statistically different across baseline PTH levels,
including those with lower pretreatment PTH, greater risk of
hypercalcemia, and higher phosphorus levels.47
Similar results have been reported by Kovesdy et al.48 in
520 male US veterans outpatient population with CKD stages
3–5, showing that treatment of secondary hyperparathyroid-
ism with low doses of an oral nonselective activated vitamin
D was associated with a significantly better survival. This
benefit was present in all the examined subgroups, including
patients with lower pretreatment PTH, higher calcium, and
higher phosphorus levels. There are other potential benefits
regarding the treatment of patients with CKD stages 2–4 with
VDRa agents, which include the renoprotective role in
diabetic nephropathy and the amelioration of proteinuria of
glomerular origin.49–51 An another important issue regarding
low calcitriol levels in patients with CKD is the prevalence of
25 Vit D deficiency in this population that is independent of
CKD staging.28,52,53 Interestingly, low substrate levels of 25
Vit D are associated with low calcitriol levels, except for those
with normal kidney function.54 Lower serum 25 Vit D levels
have been associated with impaired glucose tolerance and
diabetes across diverse populations, and administration of
vitamin D3 to deficient animals improves insulin secretion.55–57
The active form of vitamin D, calcitriol, is a potent
inducer of the antimicrobial protein cathelicidin. In
macrophages, this response is dependent on intracrine
Kidney International (2010) 78, 146–151
A Gal-Moscovici and SM Sprague: Use of vitamin D in CKD patients
synthesis of 1,25(OH)2D from precursor, catalyzed by the
enzyme 25-hydroxyvitamin D-1a-hydroxylase (CYP27B1).
Low cathelicidin plasma level in patients undergoing dialysis
is predictive of increases in infectious disease mortality.58
Treatment with 25 Vit D have been shown to improve the
immune response.59
Treatment with vitamin D (ergocalciferol or cholecalciferol)
to raise 25 Vit D levels was shown to increase calcitriol in
both stage 3 and 4 CKD, but lowered PTH only in CKD stage
3, but not in stage 4 patients.60,61 Similar findings were noted
with the use of cholecalciferol.62 The potential success of
ergocalciferol monotherapy might be limited, as cellular
uptake of 25 Vit D may be dependent on combined therapy
with calcitriol.63 Consistent with this notion is the finding
that VDRa treatment enhances megalin expression and that
megalin endocytosis of the 25 Vit D–vitamin D binding
protein complex from the glomerular ultrafiltrate is the
major mechanism for delivering 25 Vit D to the 1a-
hydroxylase enzyme in the proximal tubule.64,65 Thus, in
our opinion ergocalciferol or cholecalciferol should be used
to correct 25 Vit D levels in patients with CKD, either before
or during active vitamin D therapy. Clearly, appropriate
outcome studies are required to assess the role of vitamin D
therapy on outcomes in all patients with CKD.
TREATMENT IN CKD STAGES 3 AND 4
There are very little data to guide the use of VDRa agents in
CKD stages 3 and 4. Although there may be potential for
improved outcomes with the use of VDRa agents in these
patients, therapy and recommendations have focused on
treatment for hyperparathyroidism. There are four rando-
mized controlled trials that have assessed the use of
doxercalciferol, paricalcitol, alfacalcidol, or calcitriol with
placebo (Table 2). The study using calcitriol included only 30
patients and assessed laboratory values and bone histomor-
phometry.66 Unfortunately, this study was conducted in1988
and the design of the study was to increase serum calcium
and evaluate bone histology and was not specific for
reduction in PTH concentrations. Furthermore, these data
may also be hard to interpret because of changes in clinical
practice and the common use of aluminum-based phosphate
binders at that time. However, treatment with calcitriol did
result in a significant decrease in PTH (26%) compared with
Table 2 | Results of randomized controlled trials of VDRa versus placebo in non-dialysis CKD stage 3–5 patients
VDRa (final dose) Duration (months) (n)
66
Calcitriol (B0.5 mg/day) 8 (30)
Alfacalcidol46 (B0.4 mg/day) 24 (176)
Doxercalciferol67 (B1.6 mg/day) 6 (55)
Paricalcitol31 (B1.4 mg/day) 6 (220)
Abbreviations: CKD, chronic kidney disease; PTH, parathyroid hormone; VDRa, vitamin D receptor agonist.
Kidney International (2010) 78, 146–151
translational nephrology
placebo with a tendency for improved bone histology,
although adynamic bone was observed in some biopsies.
There were two studies performed using VDRa prohor-
mones, which required activation by the 25-hydroxlyase in
the liver. The study using alfacalcidol included 176 patients;
however, it was also conducted in 1995 and had some of the
same problems as the study with calcitriol, and was
conducted with reference to the clinical practice at that
time.46 The study was designed to maintain calcium levels at
the upper limit of the normal laboratory reference range.
Compared with placebo, PTH levels fell significantly (28%)
with improvement in bone turnover. The study evaluating
doxercalciferol included 55 patients, was performed with
current clinical practice, and was designed to lower PTH
concentrations.67 Compared with placebo, PTH levels fell
significantly (46%) and although no bone histology was
performed, bone-specific alkaline phosphatase levels fell
significantly in the treated subjects. However, no data for bone
alkaline phosphatase were provided for the placebo-treated
subjects. The most recently published study used paricalcitol
and included 220 patients.31 Similar to the PTH results with
doxercalciferol, PTH concentrations fell significantly (42%) and
this was associated with a significant decrease in bone-specific
alkaline phosphatase compared with placebo subjects.
Unfortunately, none of these studies provided other
outcome information. In these studies, calcium levels trended
upward for paricalcitol and doxercalciferol, whereas they
increased significantly for calcitriol- and alfacalcidol-treated
subjects. Phosphate levels and the calcium–phosphorus
product increased significantly for doxercalciferol, with an
upward trend for paricalcitol and alfacalcidol.
CONCLUSION
In conclusion, vitamin D deficiency develops very early in
the course of CKD. There is an increasing body of data
suggesting that VDRa has a central role in lowering the
morbidity and mortality observed in these patients through
mechanism involving classical skeletal and non-classical
pathways. Thus, it is imperative that future studies are
directed toward understanding the role of vitamin D and
VDRa in maintaining health. Presently, the indication for
vitamin D and VDRa treatment in CKD is predicated on the
serum or plasma PTH concentration. It is our opinion that,
Outcome Results
Bone biopsy Placebo; increase in bone formation
(many worsened)
Calcitriol; decrease in bone formation
(some better, few developed adynamic)
No difference in mineralization and volume
Change in PTH 26% reduction
Bone biopsy Alfacalcidol tended to result in improved bone turnover
Change in PTH 28% reduction
Change in PTH 46% reduction
Change in PTH 42% reduction
149
translational nephrology
consistent with K/DOQI and KDIGO (Kidney Disease:
Improving Global Outcomes) guidelines, current evidence
supports treating all patients with vitamin D (either
ergocalciferol or cholecalciferol) to correct 25 Vit D
deficiency. In the presence of hyperparathyroidism, VDRa
therapy should be strongly considered. However, until
appropriately designed outcome studies are performed, the
use of VDRa therapy to replace hormonal calcitriol deficiency
is speculative and opinion based.
DISCLOSURE
SMS serves as a consultant and has received grants from Abbott, Amgen
and Genzyme and AG-M declared no competing interests.
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