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Article
Effect of Vitamin D Repletion on Urinary Calcium
Excretion among Kidney Stone Formers
David E. Leaf,*
†
Ruslan Korets,
‡
Eric N. Taylor,
§
Jie Tang,
|
John R. Asplin,
¶
David S. Goldfarb,** Mantu Gupta,
‡
and
Gary C. Curhan
†
Summary
Background and objectives Despite the important role of vitamin D in maintaining bone health, many clinicians
are reluctant to treat vitamin D deficiency in kidney stone formers because of the theoretical risk of increasing
urinary calcium excretion. This study examined the effect of vitamin D repletion on urinary calcium excretion
among stone formers.
Design, setting, participants, & measurements Participants (n=29) were recruited from urology clinics affiliated
with New York Presbyterian Hospital. Enrollment criteria included a history of nephrolithiasis, urinary calcium
excretion between 150 and 400 mg/d, and a serum 25-hydroxyvitamin D level ,30 ng/ml. Participants were
given oral ergocalciferol (50,000 IU/wk) for 8 weeks. Serum and 24-hour urine tests were repeated after 8 weeks.
Results Levels of 25-hydroxyvitamin D increased significantly after vitamin D repletion (1766and35610 ng/ml,
P,0.001), but mean 24-hour urinary calcium excretion did not change (257654 and 255688 mg/d at baseline
and follow-up, respectively, P=0.91). However, 11 participants had an increase in urinary calcium excretion
$20 mg/d; these participants also had an increase in urine sodium excretion, likely reflecting dietary variability.
No participant experienced adverse effects from vitamin D, including hypercalcemia.
Conclusions Among stone formers with vitamin D deficiency, a limited course of vitamin D repletion does not
seem to increase mean urinary calcium excretion, although a subset of individuals may have an increase. These
data suggest that vitamin D therapy, if indicated, should not be withheld solely on the basis of stone disease, but
24-hour urinary calcium excretion should be monitored after repletion.
Clin J Am Soc Nephrol 7: 829–834, 2012. doi: 10.2215/CJN.11331111
Introduction
Despite the important role of vitamin D in maintain-
ing bone health, as well as a variety of other phys-
iologic functions (1), many clinicians are reluctant to
treat vitamin D deficiency or insufficiency in kidney
stone formers because of the theoretical risk of increas-
ing urinary calcium excretion. This reluctance likely de-
rives from the fact that vitamin D is often cited as a risk
factor for kidney stones (2), and epidemiologic studies
have reported associations between urinary calcium
excretion and serum levels of 25-hydroxyvitamin D
[25(OH)D] (3) and 1,25-dihydroxyvitamin D [1,25(OH)
2
D]
(4). However, although hypervitaminosis D is a well
known cause of hypercalcemia and hypercalciuria,
we are unaware of any prospective study in which
the effects of standard replacement doses of vitamin D
on urinary calcium excretion have been investigated
among stone formers (5).
However, multiple studies have examined the
effects of vitamin D supplementation among nonstone
formers and have consistently failed to show an in-
crease in urinary calcium excretion (6–8). Accordingly,
the current study was conducted to examine whether
vitamin D repletion adversely affects urinary calcium
excretion specifically among stone formers.
Materials and Methods
Study Design
We conducted an interventional study of vitamin D
repletion among outpatients followed at New York
Presbyterian Hospital (NYPH) Columbia University
Medical Center. All protocols were approved by the
Columbia University Medical Center Institutional
Review Board.
Study Participants
Participants consisted of adult outpatients followed
in the metabolic stone clinic of investigator M.G. In-
clusion criteria were (1) a history of nephrolithiasis
as per medical records, (2) urinary calcium excretion
between 150 and 400 mg/d measured within 3
months of enrollment, and (3) 25(OH)D deficiency
or insufficiency (defined as a serum level ,30 ng/ml)
measured within 3 months of enrollment. Seven ex-
clusion criteria were used. (1) Known uric acid, cys-
tine, or struvite stone disease (although participants
who had passed both uric acid and calcium oxalate
stones or stones of mixed composition that consisted
predominantly of calcium were eligible). (2) Hypercal-
cemia (defined as serum calcium .10.4 mg/dl) mea-
sured within 3 months of enrollment. (3) Acute stone
Departments of
*Medicine and
‡
Urology, Columbia
University, New York,
New York;
†
Division
of Renal Medicine,
Brigham and
Women’s Hospital,
Boston,
Massachusetts;
§
Division of
Nephrology and
Transplantation,
Maine Medical
Center, Portland,
Maine;
|
Division of
Renal Diseases and
Hypertension,
University of
Colorado, Denver,
Colorado;
¶
Litholink
Corporation, Chicago,
Illinois; and
**Nephrology
Section, New York
Harbor VA
Healthcare System,
New York, New York
Correspondence: Dr.
David E. Leaf, Renal
Division, Brigham and
Women’s Hospital, 75
Francis Street, Boston
MA 02115. Email:
DELEAF@partners.org
www.cjasn.org Vol 7 May, 2012 Copyright © 2012 by the American Society of Nephrology 829
event or gross hematuria within 2 months of enrollment. (4)
Any urologic intervention within 1 month of enrollment. (5)
Suspected or known secondary causes of hypercalciuria,
such as primary hyperparathyroidism, sarcoidosis, hyper-
thyroidism, or malignancy. (6) Addition or dose change of
medicines potentially affecting urinary calcium since the
baseline 24-hour urine collection. (7) Pregnancy.
Study Procedures
Patients with kidney stone disease followed at NYPH’s
urology clinics are encouraged to provide urine and serum
samples before their visits as part of routine care. Accord-
ingly, patients meeting the above criteria were identified
by a focused screening of electronic medical records before
their scheduled visit to an NYPH-affiliated urology clinic.
On the day of their scheduled visits, patients agreeable to
discussing the research study were screened for symptoms
suggesting active stone disease, recent urologic interven-
tions, addition or dose change of medicines affecting urinary
calcium excretion, and possible causes of secondary hyper-
calciuria. Those patients deemed eligible and wishing to en-
roll in the study provided written informed consent.
Vitamin D (ergocalciferol 50,000 IU orally once weekly
for 8 weeks) was dispensed to participants by the NYPH
research pharmacy. Participants were asked to complete
the following blood and urine tests at baseline and 8-week
follow-up visits: serum basic metabolic panel, intact para-
thyroid hormone (PTH), 25(OH)D (sum of D
2
and D
3
), and
24-hour urine collection for a comprehensive metabolic
stone panel (Litholink, Chicago, IL). On completion of
the study, participants were seen in the clinic to review
their results as well as inquire about medication adherence
and any symptoms suggestive of adverse medication
effects.
To minimize large changes in urinary calcium excretion
because of changes in diet, participants were asked to re-
cord a detailed diet log on the day of their baseline urine
collection and try to replicate, to the best of their abilities,
their baseline diet during the subsequent urine collection.
To help participants achieve this replication, a diet log
template was distributed. We have previously reported on
our experience using this approach, and we have found it
to be a reliable way of minimizing diet variability (9). We did
not collect the diet logs or attempt to analyze diet composi-
tion; their purpose was simply to help participants replicate
their diets during the urine collection periods.
Outcome Measures
The primary outcome measure was change in 24-hour
urinary calcium excretion. Secondary outcome measures
included changes in other 24-hour urine factors, including
oxalate, citrate, uric acid, phosphorus, and sodium, as well
as change in serum 25(OH)D.
Safety Monitoring
The primary safety concerns included serum calcium, 24-
hour urinary calcium excretion, and stone recurrence. For
every 10 participants who completed the study, an interim
data safety analysis was carried out by investigators D.E.L.
and M.G. Additionally, participants were educated re-
garding potential, albeit rare, adverse effects of vitamin D,
including nausea and anorexia, and were encouraged to
immediately report any such effects to the primary investi-
gator (D.E.L.). Participants were also asked to immediately
report any symptoms suggestive of stone recurrence (flank
pain or gross hematuria).
Statistical Analyses
Statistical analyses were performed with SAS version 9.2
(SAS Institute Inc., Cary, NC). Power analysis was cal-
culated with the following assumptions: mean 24-hour
urinary calcium excretion = 300 mg/d, a= 0.05, and
SD = 30. With a sample size of 30 participants, we esti-
mated that we would have the statistical power of 0.94
and 0.99 to detect a change in 24-hour urinary calcium
excretion of 20 and 25 mg/d, respectively.
Normally distributed continuous data are reported as
mean 6SD, and within-group differences were assessed
by a paired ttest. Skewed continuous data are reported as
median and interquartile range (25–75 percentiles), and
within-group differences were assessed by the Wilcoxon
signed-rank test. Correlations between changes in 24-hour
urinary calcium excretion with other urinary and serum
parameters were assessed using simple linear regression.
Finally, a multivariable linear regression model was cre-
ated to evaluate whether changes in 25(OH)D were pre-
dictive of changes in 24-hour urinary calcium excretion
after adjusting for other variables, which were significant
independent predictors of the latter. All comparisons are
two-tailed, with P,0.05 considered significant.
Results
Baseline Characteristics
Thirty participants were enrolled. Twenty-nine partic-
ipants completed the study, with one participant lost to
follow-up. Baseline characteristics for the 29 participants
who completed the study are shown in Table 1. The ma-
jority of participants were male. Among nonwhite partic-
ipants, the vast majority (16/18) were Hispanic (there is a
large community of Dominicans served by NYPH). None
of the participants had an estimated GFR ,60 ml/min per
1.73 m
2
. Similar numbers of participants had vitamin D
insufficiency (20–29 ng/ml) compared with deficiency
(,20 ng/ml), and roughly similar numbers of participants
had PTH levels above and within the normal range. Only a
single participant was taking a thiazide diuretic.
Primary and Secondary Outcomes
Baseline and follow-up 24-hour urine and serum param-
eters are shown in Table 2. 25(OH)D levels increased in all
29 participants, with a mean 6SD increase of 18610 ng/ml.
However, only 20 of 29 participants had a follow-up 25(OH)D
level .30 ng/ml. No significant change in mean urinary
calcium excretion was observed with vitamin D supplemen-
tation. Similarly, no significant changes in any of the other
24-hour urine or other serum parameters were noted.
No significant change in serum PTH was noted. Selected
subgroup analyses based on race (white versus nonwhite),
baseline vitamin D status (deficiency versus insufficiency),
and baseline PTH status (above or within the normal range)
also failed to show any significant change in serum PTH
with vitamin D repletion.
830 Clinical Journal of the American Society of Nephrology
Change in Urinary Calcium by Subgroups
Point estimates and 95% confidence intervals (CIs) for
change in 24-hour urinary calcium excretion by selected
subgroups are shown in Figure 1. The results did not seem
to differ within any subgroup. Additionally, the results
did not seem to differ by race.
Change in Urinary Calcium and Urinary Sodium by
Individual Participants
We observed a large variability in the direction and
magnitude of change in urinary calcium excretion among
participants (Figure 2A). Similarly, despite the use of a
diet log, we also observed a large variability in urinary
sodium excretion (Figure 2B). Among the 11 participants
with an increase in urinary calcium excretion of $20 mg/d
(median [interquartile range] increase of 90 [44–139]
mg/d), urine sodium and urea nitrogen excretion also
tended to increase (68 [5–80] mmol/d and 3.8 [20.5 to
4.6] g/d, respectively), although the latter did not reach
statistical significance. Among the six participants with
the greatest increase in urinary calcium excretion (139
[105–154] mg/d), urine sodium and urea nitrogen excre-
tion were not significantly increased (17 [217 to 61]
mmol/d and 2.3 [21.9 to 4.1) g/d, respectively). In both
of these subgroups, the increase in serum 25(OH)D with
vitamin D repletion was comparable with the rest of the
cohort.
Associations between Change in Urinary Calcium and
Changes in Other Variables
Change in urinary calcium excretion was positively
associated with changes in the following 24-hour urine
variables: volume (40 mg/d increase in urinary calcium per
L/d increase in volume, 95% CI=11–70, P=0.01), citrate
(17 mg/d increase in urinary calcium per 100 mg/d increase
in citrate, 95% CI=3–32, P=0.02), and sodium (8.2 mg/d in-
crease in urinary calcium per 20 mmol/d increase in so-
dium, 95% CI=2.8–13.8, P=0.005). No significant associations
were found with changes in any of the other urine or serum
parameters. A scatter plot of change in 24-hour urinary
calcium excretion versus change in 25(OH)D is shown in
Figure 3. No significant association was found [2.15 mg/d in-
crease in urinary calcium per 1 ng/ml increase in 25(OH)D,
95% CI=21.49 to 5.78, P=0.24].
Table 1. Baseline characteristics
Parameter (n=29) Value
Age in years (mean 6SD) 48612
Male (%) 76
Race n(%)
white 11 (38)
Renal function (mean 6SD)
serum creatinine (mg/dl) 0.960.2
estimated GFR (ml/min
per 1.73 m
2
)
93618
25-hydroxyvitamin D (ng/ml) n(%)
0–9 4 (14)
10–19 13 (45)
20–29 12 (41)
Parathyroid hormone (pg/ml) n(%)
#51 17 (59)
.51 12 (41)
Urine calcium (mg/d) median (IQR) 259 (216–290)
IQR, interquartile range.
Table 2. Urine and serum parameters before and after vitamin D repletion
Baseline Follow-Up PValue
24-hour urine studies
calcium (mg) 257654 255688 0.91
oxalate (mg) 42618 41615 0.84
citrate (mg) 6966383 7016320 0.92
uric acid (g) 0.7760.26 0.7760.20 0.96
pH 6.360.5 6.260.4 0.31
sodium (mmol) 228694 202665 0.23
potassium (mmol) 72633 68628 0.53
phosphorus (g) 1.060.3 1.060.3 0.91
urea nitrogen (g) 136413640.69
sulfate (mEq) 47619 44614 0.38
creatinine (mg) 18966479 18806468 0.74
volume (L) 1.7 (1.5–2.5) 2.1 (1.4–2.7) 0.50
Supersaturation
calcium oxalate 8647630.34
calcium phosphate 1.5 (1.0–2.2) 1.2 (0.8–1.6) 0.17
uric acid 0.5 (0.2–1.0) 0.6 (0.3–0.8) 0.20
Serum studies
25(OH)D (ng/ml) 176635610 ,0.001
calcium (mg/dl) 9.360.4 9.460.4 0.69
PTH (pg/ml) 43 (27–60) 39 (28–59) 0.71
Values shown are mean 6SD for normally distributed data and median (interquartile range) for skewed data. 25(OH)D,
25-hydroxyvitamin D; PTH, parathyroid hormone.
Clin J Am Soc Nephrol 7: 829–834, May, 2012 Vitamin D and Urine Calcium, Leaf et al. 831
Finally, multivariable linear regression was used to
evaluate whether change in 25(OH)D was predictive of
change in 24-hour urinary calcium excretion after inclusion
of the above three significantly associated variables. After
inclusion of these three variables in the model, the relation
between change in 25(OH)D and change in 24-hour urinary
calcium excretion remained nonsignificant [1.10 mg/d in-
crease in urinary calcium per 1 ng/ml increase in 25(OH)D,
95% CI=21.44 to 3.65, P=0.38].
Safety, Adverse Effects, and Adherence
Vitamin D supplementation was well tolerated, with no
adverse effects reported and no incidents of symptomatic
stone recurrence. No participant developed hypercalcemia.
All participants reported 100% adherence to the study drug.
All participants completed follow-up 24-hour urine and
serum testing in a timely manner (within 2 weeks of finishing
the study drug), with the exception of a single participant
who waited 4.5 weeks to complete follow-up testing.
Figure 1. |Change (95% confidence interval) in calciuria after vitamin D repletion according to subgroups.
Figure 2. |Baseline and follow-up (A) urinary calcium and (B) urinary sodium excretion for individual participants. Thick line indicates
mean change.
832 Clinical Journal of the American Society of Nephrology
Discussion
This is the first documented prospective study of the
effects of vitamin D repletion on urinary calcium excretion
among stone formers. We found that vitamin D repletion,
accomplished by administration of standard doses, does
not seem to adversely affect 24-hour urine calcium ex-
cretion among individuals with vitamin D deficiency or
insufficiency.
Patients with vitamin D deficiency and a history of
kidney stones are often deprived of the established benefits
of vitamin D repletion because of a theoretical concern of
increasing their risk of stone recurrence (10). However,
vitamin D repletion is likely to be of particular impor-
tance to stone formers, especially those patients with
hypercalciuria. Not only is hypercalciuria an important
risk factor for osteoporosis in the general population
(11), but it also seems to be associated with even higher
rates of bone loss among stone formers than nonstone
formers (12).
Given the known effects of vitamin D on intestinal
calcium reabsorption, it may seem surprising that vitamin
D repletion did not increase urinary calcium excretion.
There are at least two possible explanations for this find-
ing. First, the tightly regulated conversion of 25(OH)D to
1,25(OH)
2
D by 25-hydroxyvitamin D-1a-hydroxylase
(CYP27B1) may have limited synthesis of the active
form, thereby preventing excessive intestinal calcium reab-
sorption. Second, an increase in intestinal calcium reab-
sorption did occur but did not increase urinary calcium
excretion, because the additional calcium was deposited
in bone to restore bone mineral content (13).
Surprisingly, we did not find any evidence of PTH
suppression by vitamin D repletion. Given the known
urinary calcium-lowering effects of PTH, it is conceivable
that, if PTH had fallen, urinary calcium excretion would
have increased. Therefore, the lack of change in PTH could
partly explain the lack of change in urinary calcium
excretion. Interestingly, other studies of vitamin D reple-
tion have also not consistently shown a decline in serum
PTH (14). The lack of suppression of PTH in our study
may have been influenced by the large proportion of His-
panic participants. There is growing data that the relation
between vitamin D and PTH is different among whites
and nonwhites, with the latter group suppressing PTH at
lower levels of vitamin D (15).
Although overall urinary calcium excretion was un-
changed with vitamin D repletion, 11 participants had
increases in urinary calcium excretion $20 mg/d. Al-
though urine sodium and urine urea nitrogen also tended
to increase among these participants, reflecting dietary
changes on follow-up urine collections, it is unclear
whether the magnitude of increase in urinary calcium ex-
cretion can be fully attributable to these dietary changes
alone. Because dietary logs were not collected, differences
in dietary calcium intake could not be assessed and might
be a plausible explanation for the above findings. The
small sample size allowed for only select subgroup analy-
ses to try to identify baseline risk factors predictive of an
increase in urinary calcium excretion and found no asso-
ciations with race, baseline serum 25(OH)D, or PTH.
Limitations of this study include large intraindividual
variations in urinary sodium and urinary calcium excretion
despite the use of a diet log, a nonrepresentative population
(overrepresentation of Hispanics relative to the general US
population), a relatively short duration of follow-up (8
weeks), and a modest sample size. Our a priori sample size
calculation provided a high degree of statistical power to
detect clinically meaningful changes in urinary calcium
excretion; however, interindividual variability in urinary
calcium excretion was greater than anticipated, thus re-
ducing our power to detect differences. An additional lim-
itation is the lack of a control group, which would have
allowed for firmer conclusions to be made about intra-
individual variability in urinary calcium excretion. Finally,
nine participants did not attain a serum 25(OH)D level
greater than 30 ng/ml by completion of the study. Al-
though nearly all participants reported perfect medication
adherence, nonadherence may nonetheless have contrib-
uted to these findings. Additionally, many of the partici-
pants received vitamin D supplementation between the
winter months of December and February, during which
time they would have likely received decreased sunlight
exposure. Indeed, others have reported similar findings
when administering oral ergocalciferol during the winter
months (16).
Future studies of vitamin D repletion among stone
formers should be performed to explore the generaliz-
ability of these results, including among patients with
estimated GFR ,60 ml/min per 1.73 m
2
,agroupthatwas
not represented in the present study. Additionally, these
studies should evaluate the long-term safety of vitamin D
repletion among patients with kidney stones as well as
directly evaluate its efficacy in improving bone health.
Finally, measurement of other factors such as serum
phosphate, 1,25(OH)
2
D, and fibroblast growth factor-23
before and after vitamin D repletion could shed addi-
tional light on the pathophysiology of bone disease
among stone formers.
In conclusion, our results suggest that vitamin D can be
repleted in stone formers without causing an increase in
urinary calcium excretion. Given the known benefits of
vitamin D therapy in maintaining bone health, the potential
benefits for cardiovascular, autoimmune, and neoplastic
disease, and the findings above suggesting that it is safe, we
feel that vitamin D therapy, if otherwise indicated, should
not be withheld simply on the basis of calcium stone
disease or hypercalciuria.
Figure 3. |Change in urinary calcium versus change in serum 25-
hydroxyvitamin D.
Clin J Am Soc Nephrol 7: 829–834, May, 2012 Vitamin D and Urine Calcium, Leaf et al. 833
Acknowledgments
We thank Ignacio Granja and Susan Donahue, both from Litholink,
for their assistance with the study.
This work waspresented as an oral abstractat the American Society
of Nephrology’s Kidney Week, November 12, 2011, Philadelphia,
Pennsylvania.
Disclosures
None.
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Received: November 6, 2011 Accepted: February 18, 2012
M.G. and G.C.C. contributed equally to this work.
Published online ahead of print. Pu blication date available at www.
cjasn.org.
834 Clinical Journal of the American Society of Nephrology
