Article

25-Hydroxyvitamin D Response to Cholecalciferol Supplementation in Hemodialysis Laura A.G. Armas,* Radha Andukuri,* Janet Barger-Lux,* Robert P. Heaney,* and Richard Lund†

Summary Background and objectives Recent understanding of extrarenal production of calcitriol has led to the exploration of native vitamin D treatment in dialysis patients. This paper reports the pharmacokinetics of 25-hydroxyvitamin D response to 10,333 IU cholecalciferol given weekly in subjects on chronic dialysis. Design, setting, participants, & measurements This randomized, double-blind, placebo-controlled trial of 15 weeks of oral cholecalciferol in subjects with stage 5 CKD requiring maintenance hemodialysis was conducted from November of 2007 to March of 2010. The time course of serum 25-hydroxyvitamin D was measured over the course of treatment. Additionally, blood was drawn at baseline and last visit for calcium, phosphorus, calcitriol, and parathyroid hormone levels. Results The median (interquartile range) baseline 25-hydroxyvitamin D level was 13.3 (11.1–16.2) ng/ml for the treatment group and 15.2 (10.7–19.9) ng/ml for the placebo group. 25-hydroxyvitamin D steady state levels rose by 23.6 (19.2–29.9) ng/ml in the treatment group, and there was no change in the placebo group. Calcitriol levels also increased significantly in the treatment group. There were no significant changes in levels of calcium, albumin, phosphorus, and parathyroid hormone in either group.

*Osteoporosis Research Center and † Nephrology Division, Creighton University, Omaha, Nebraska Correspondence: Dr. Laura A.G. Armas, Osteoporosis Research Center, Creighton University, 601 North 30th Street, Suite 4820, Omaha, NE 68131. Email: [email protected]

Conclusions Cholecalciferol (10,333 IU) given weekly in patients on chronic hemodialysis produces a steady state in 25-hydroxyvitamin D of approximately 24 ng/ml. Clin J Am Soc Nephrol 7: 1428–1434, 2012. doi: 10.2215/CJN.12761211

Introduction There is a great deal of interest in vitamin D supplementation that has grown as the scientific community has discovered extrarenal production of calcitriol [1,25 (OH)2D] (1) by cells in nearly all body systems (2) and the presence of vitamin D binding receptors in nearly all tissues (3). Recent guidelines have put forth vitamin D supplementation recommendations for the healthy population (4–6), and others have addressed recommendations for patients with specific disease, such as CKD (7). In the past, 1,25(OH)2D, the active form of vitamin D, was thought to be exclusively acting in calcium homeostasis, and simply replacing it with calcitriol or one of its analogs was thought to be sufficient in CKD patients who had deficient 1,25(OH)2D levels. Understanding the ability of vitamin D to be activated by many other extrarenal cells and elucidation of its role in gene expression involved in immunity, cell differentiation, proliferation, and apoptosis (8) have led to recommendations that native vitamin D supplementation should be addressed in patients with CKD (9). The Kidney Disease Outcomes Quality Initiative guidelines (2003) recommended native vitamin D supplementation with ergocalciferol in patients with CKD stages 3 and 4 and a calcitriol analog in patients with CKD stage 5 requiring dialysis (10). 1428

Copyright © 2012 by the American Society of Nephrology

The Kidney Disease Improving Global Outcomes guidelines (2009) incorporated the extraskeletal effects of vitamin D into its recommendations, suggesting that 25-hydroxyvitamin D [25(OH)D] levels be measured in patients with CKD stages 3–5; if deficient, treatment strategies for the general population should be used (7). Although a handful of studies have reported 25 (OH)D response to cholecalciferol in dialysis patients (11–14), there was little quantification of dose response or comparison with the 25(OH)D response in healthy populations with functional kidneys. The study reported here was a randomized, double-blind, placebo-controlled study of the effects of cholecalciferol supplementation on physical performance score and quality of life (data not shown) in a group of subjects on chronic hemodialysis.

Materials and Methods Design This was a randomized, double-blind, placebocontrolled trial of oral cholecalciferol given weekly for 15 weeks from November 26, 2007 to March 31, 2010 to subjects with CKD stage 5 requiring maintenance hemodialysis. This trial was registered on clinicaltrials.gov on August 1, 2007 (NCT00511225). www.cjasn.org Vol 7 September, 2012

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Subjects Subjects (12 female and 30 male) were recruited from three hemodialysis centers located in Omaha, Nebraska (latitude 41.2° N). All subjects provided a signed written consent approved by the Creighton University Institutional Review Board. Subjects had been on maintenance dialysis for an average of 5 years. The reasons for renal failure were 14 subjects (33%) had diabetic nephropathy, 19 subjects (45%) had hypertensive kidney disease, and 9 subjects (21%) had other types of kidney disease; 29 subjects (69%) were on a calcitriol or its analog throughout the study (26 subjects were on paricalcitol, 2 subjects were on doxercalciferol, and 1 subject was on calcitriol). Patients were included if they were receiving hemodialysis at a group of three dialysis centers in Omaha, Nebraska for more than 3 months. Vitamin D status was not a criterion for participation. The patients were excluded if they were judged unlikely to be able to complete the study, were not ambulatory, were unable to complete the questionnaire with a research nurse, or had unusual difficulty with venous access. Peritoneal dialysis patients were excluded; 73 subjects were screened, of which 65 subjects met inclusion/exclusion criteria, and 18 subjects declined participation (Supplemental Materials). Randomization On study entry, subjects were randomized to oral cholecalciferol capsule or placebo by block randomization (four subjects per block). Randomization was performed by J.B.-L. All other study personnel were blinded to intervention. Intervention One time per week for 15 weeks, immediately after dialysis was completed, subjects received an oral dose of cholecalciferol or placebo. Ingestion was observed by study staff, ensuring 100% compliance. Placebo capsules were made using lactose encapsulated in an opaque capsule (Gallipot, Inc., St. Paul, MN). The cholecalciferol, an over the counter product (oil-based capsule preparation, commercially available as Maximum D3, cholecalciferol 10,000 IU, 0.25 mg; BTR Group, Inc., Pittsfield, IL), was encapsulated to match the placebo capsule. Six capsules of cholecalciferol were analyzed independently by Heartland Assays, Inc. (Ames, IA) and found to contain 10,3336344 IU per capsule (1476 IU or 36.9 mcg per day). The measured dose (10,333 IU) rather than the labeled dose was used for all calculations. Protocol At baseline, before starting a hemodialysis session, venous blood was drawn for serum calcium, phosphorus, 25(OH)D, 1,25(OH)2D, and parathyroid hormone (PTH). Oral cholecalciferol was given weekly for a total of 15 doses. Blood was drawn for 25(OH)D on days 7, 14, 21, 28, 35, 70, and 105. Additionally, blood was drawn for repeat calcium, phosphorus, 1,25(OH)2D, and PTH on day 105. All blood was drawn before the next dose of cholecalciferol was given (at the nadir) and directly before the start of a hemodialysis session. Analytical Methods Serum 25(OH)D levels were measured by radioimmunoassay using the Immuno-Diagnostics Kit (Nichols Institute,

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San Clemente, CA) in our research laboratory. Coefficient of variation of repeated measure was 1.6%–4.8%. Our research laboratory facilities are certified by the Vitamin D External Quality Assessment Scheme. Intact PTH 1–84 was measured by immunoradiometric assay using the DiaSorin N-tact PTH SP IRMA kit (DiaSorin Inc., MN) in our research laboratory. Serum 1,25(OH)2D was measured using competitive radioimmunoassay as previously described (15) at Heartland Assays, Inc. (Ames, IA). The inter- and intra-assay coefficients of variance for this assay are 12.6% and 9.8%, respectively. The laboratory normal reference range is 30–50 pg/ml. Serum calcium and phosphorus were measured by Roche Cobas Integra autoanalyzer (F Hoffmann-La Roche Ltd, Basel, Switzerland) in the medical laboratory of Creighton University. The amount and duration of skin sun exposure was assessed using the method described in the work by Barger-Lux and Heaney (16). Statistical Analyses Descriptive statistics were generated using the statistics package PASW Statistics 18.0 (SPSS Inc., Chicago, IL) and Microsoft Excel 2007 (Microsoft Corporation, Redmond, WA). The groups’ demographic data were compared using a Mann–Whitney U test for interval level data and a chi-squared test for nominal data. The groups’ laboratory values were compared with each other using a Mann–Whitney U test, and the change in laboratory values was tested with a paired t test. The groups’ change in laboratory values was compared with each other using a Mann–Whitney U test. The subjects’ baseline 25(OH)D levels, increment 25(OH)D, and reported sun exposure time and skin exposure correlations were examined using Spearman correlation. The subjects’ serum 25(OH)D increment values were fitted individually (using Sigma Plot 10.0; Systat Software, Inc., San Jose, CA) to the following equation, which was modified from an approach derived and justified in the work by Heaney et al. (17): y  ¼   að1 2 e 2 bx Þ; y is the measured increment in serum 25(OH)D above baseline, and x is the time in days. The a parameter in this equation is the equilibrium increment (i.e., the best estimate of the steady state change from baseline that would have been reached had dosing continued without change); b is the rate constant, characterizing the rapidity with which the steady state was reached. The goodness of fit to this model was excellent, with R2 averaging 0.9760.03 for the individual curves. Linear regression was used to examine the relationship of baseline 25 (OH)D levels to increment in 25(OH)D.

Results Subjects (42 total) provided data for analysis; 20 subjects were randomized to the cholecalciferol group, and 22 subjects were randomized to the placebo group. Their ages ranged from 33 to 80 years. They reported their races as African American (26; 62%), Caucasian (13; 31%), Hispanic (2; 5%), and American Indian (1; 2%). Table 1 shows subjects’ demographics. There were no significant differences between the groups in age, height, weight, body mass index, years on dialysis, diabetes occurrence, or vitamin D analog use.

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Table 1. Subject demographics

Group

Vitamin D3

Placebo

N Sex (male/female) Race (AA/C/Ot) Age (years) Height (cm) Weight (kg) Body mass index Years on dialysis On calcitriol analog Diabetic

20 14/6 10/10/0 57.6 (47.2–64.2) 1.74 (1.67–1.81) 79.6 (70.2–94.3) 26.7 (22.4–34.3) 3.2 (1.4–5.2) 13 (65%) 7 (35%)

22 16/6 15/6/1 54.3 (45.1–67.3) 1.73 (1.67–1.79) 84.2 (68.2–96.6) 26.4 (22.7–32.7) 4.3 (1.8–5.4) 16 (73%) 7 (32%)

Values are given as median (interquartile range). None of the variables were significantly different between the groups (P$0.05). AA, African American; C, Caucasian; Ot, other.

25(OH)D Results The median (interquartile range) baseline 25(OH)D level was 13.3 (11.1–16.2) ng/ml for the treatment group and 15.2 (10.7–19.9) ng/ml for the placebo group (P=0.45). The treatment group’s measured 25(OH)D level rose by 20.8 (16.6–25.5) ng/ml at the end of observation to a new steady state level of 23.6 (19.2–29.9) ng/ml (the a parameter; P,0.001). The placebo group had a nonsignificant change of 0.5 (22.3 to 2.3; P=0.60). Figure 1 shows the 25(OH)D time course for both groups. The rate constant estimate (b) for the treatment group was 2.453102261.5631022. There was a nearly significant difference in increment in 25(OH)D between African Americans (median=23.8 [18.8– 27.4] ng/ml) and Caucasians (20.1 [14.0–21.1] ng/ml) in the treatment group (P=0.05). There was no significant difference in either the final 25(OH)D level achieved (P=0.27) or the increment in 25(OH)D (P=0.19) in those subjects on calcitriol analogs compared with those subjects not on analogs. In the subjects with diabetes compared with the subjects without diabetes, there was no significant difference in either the final 25(OH)D level achieved (P=0.23) or the increment in 25(OH)D (P=0.54). There was no significant effect of baseline 25(OH)D levels on increment in 25 (OH)D (P=0.14). Other Laboratory Results Table 2 shows baseline levels and change in calcium, albumin, phosphorus, 1,25(OH)2D, or PTH levels. The 1,25 (OH)2D levels were all below the reference range at baseline, and despite a statistically significant increase in 1,25(OH)2D in the treatment group (P=0.001) and no change in the placebo group (P=0.53), all but one subject remained below the normal reference range. There were significant correlations between 25(OH)D levels and 1,25(OH)2D levels at both baseline and final time points (R2=0.49, P#0.001; R2=0.50, P#0.001, respectively). There were no significant changes in levels of calcium, albumin, phosphorus, or PTH in either the treatment or placebo group (Table 2). Sun Exposure Thirty-seven subjects completed a sun exposure assessment. Seventeen subjects reported either receiving no sun exposure or intentionally avoiding the sun. Of the 20 subjects

who reported receiving sun exposure, they reported a median of 0.9 (0.4–2.7) hours per day, with a median skin exposure of 9% (9%–27%) of skin surface exposed. This exposure level would be the equivalent to wearing a hat, long pants, and a short-sleeved shirt. There was no correlation between baseline 25(OH)D levels and reported time in sun or percent of skin exposed (R 2 =0.008, P=0.97; R2=0.366, P=0.14, respectively). There was also no correlation between the increment in 25(OH)D and reported time in sun or percent of skin exposed in either group (R2=20.004, P=0.98; R2=20.273, P=0.29, respectively).

Discussion This study quantifies the 25(OH)D response to a weekly dose of 10,3336344 IU cholecalciferol in a group of subjects with ESRD on hemodialysis. Although there are a few reports of various regimens of cholecalciferol used to improve vitamin D status in hemodialysis patients (11–14), this study is the first of which we are aware to use pharmacokinetic methods to quantify response. Increment in 25(OH)D Our main focus in this report was to quantify the rise in 25(OH)D in hemodialysis subjects. This quantification is best done using the parameter in the equation. The rate constant (b) represents how quickly the steady state is reached. It has been quantified in healthy males, both Caucasian (17) and African American (R. Heaney, M. Dowell, R. Recker, and M. Barger-Lux, personal communication, 2011), and estimates ranged from 7.931023 to 3.2831022. The rate constant from this study (2.4531022) was very similar to what has been reported elsewhere with cholecalciferol doses from 1,000 to 10,000 per day (17). Using the a parameter, the work by Heaney et al. (17) previously calculated a 25(OH)D dose response to cholecalciferol of a rise of 0.28 ng/ml in 25(OH)D per microgram (40 IU) per day of cholecalciferol input in healthy young Caucasian males (17) and 0.4 ng/ml per microgram (40 IU) per day of cholecalciferol input in healthy young African Americans (18). Other analyses of vitamin D studies have found higher 25(OH)D dose responses ranging from 0.76 to 0.88 ng/ml per microgram per day (18–20) in elderly populations without controlling for seasonal

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Figure 1. | The time course of 25-hydroxyvitamin D in the treatment group (○) and placebo group (△). The error bars are 1 SEM. The two regression lines are the least squares fits to the data (R2.0.99 for both). The upper curve is fit to y  ¼   að1 2 e 2 bx Þ, and the lower curve is fit to a straight line. Figure courtesy of R.P. Heaney.

changes. Our study found 0.56 ng/ml per microgram cholecalciferol input per day, which is between the findings in the works by Heaney et al. (17) and Chapuy et al. (19). These studies in healthy populations used daily dosing regimens, which may have an effect on the metabolism of vitamin D. A larger weekly dose may upregulate or downregulate the enzymes of vitamin D metabolism to a greater degree than smaller daily dosing (21), resulting in lower or higher 25(OH)D response. Although it would be tempting to explain the nice rise in 25(OH)D in our study as a direct result of low baseline levels, there was no correlation between increment in 25(OH)D and baseline 25 (OH)D levels in this cohort. Although sun exposure could confound the results by providing exogenous vitamin D, our subjects had minimal exposure. Much of the study was done during the winter months, when ultraviolet-B exposure is absent at this latitude (42° N). Many subjects reported no sun exposure, and those subjects who spent time outdoors typically wore clothing that covered most of their body. Although we were limited by self-reporting of sun exposure by the subject, the 25(OH)D levels in the placebo group did not change throughout the study, indicating that the seasonal effect of sun exposure on skin vitamin D production was minimal in this cohort. Vitamin D Dosing Studies in Dialysis Patients Other studies have used cholecalciferol to improve vitamin D status in hemodialysis patients. The work by Stubbs et al. (11) reported increasing 25(OH)D levels in seven hemodialysis patients from 13.9 to 53.9 ng/ml in 8 weeks; however, precise dose response quantification was impossible, because the cholecalciferol doses were adjusted two times during the study to reach predefined 25(OH)D levels. The work by Matias et al. (12) reported increasing 25(OH)D levels in 158 hemodialysis patients from 22.3 to 42.0 ng/ml with 6 months of cholecalciferol

supplementation; again, however, dose response quantification was not possible, because three different cholecalciferol regimens were used depending on baseline 25(OH)D levels. The work by Tokmak et al. (13) used a dosing regimen similar to our regimen, with 20,000 IU cholecalciferol given weekly in 64 hemodialysis patients, and 25(OH)D levels increased from 6.7 to 31.8 ng/ml at 9 months. The work by Jean et al. (14) used 100,000 IU cholecalciferol monthly (the equivalent of 3,333 IU per day) in 107 hemodialysis patients and increased 25D levels from 12.8 to 42.4 ng/ml in 15 months (reaching a plateau in 3 months). With their consistent dosing regimens, these last two studies provide enough information to permit comparison with our study. The work by Tokmak et al. (13) used two times as much cholecalciferol (labeled dose=2857 IU per day) as our current study (actual dose=1476 IU per day) and started at a much lower baseline 25(OH)D (6 versus ;16 ng/ml in our study). They produced comparable 25 (OH)D increases by the end of study (increment of 25.1 ng/ml or 0.35 ng/ml per microgram cholecalciferol). The work by Jean et al. (14) used 2.5 times the dose that we used in our study (labeled dose=3333 IU per day) and reached slightly higher 25(OH)D levels over the same period of time (3 months; increment of 29.6 ng/ml or 0.36 ng/ml per microgram cholecalciferol). Although neither study reports actual measured vitamin D content (only labeled doses), both report increments in 25(OH)D that are less than what we observed in our study. The work by Tokmak et al. (13) did not report the temporal relationship between when the blood sample was obtained and when the prior cholecalciferol dose was taken, but the work by Jean et al. (14) reported that their samples were drawn at the nadir before the monthly dose of cholecalciferol was given. Given the limitations of their study designs, neither of these studies would have captured the

full dose–response curve. Neither of these studies reported the race or ethnicity of their subjects, and therefore, it is uncertain whether race explained the difference in 25(OH) D response. Both of these studies had very low baseline 25 (OH)D levels but achieved less of a rise in 25(OH)D per microgram than our current study.

Values are given as median (interquartile range). 25(OH)D, 25-hydroxyvitamin D; PTH, parathyroid hormone; 1,25(OH)2D, calcitriol. a P value for within-group change from baseline to 15 weeks (paired t test). b P value for comparison of change between groups. c The a parameter. d n is 18 for the vitamin D3 group. n is 21 for the placebo group.

,0.001 0.87 0.72 0.38 0.42 0.001 0.60 0.24 0.89 0.19 0.98 0.53 0.5 (22.3 to 2.3)c 0.2 (20.2 to 0.6) 0.0 (20.2 to 0.2) 20.6 (21.5 to 0.2) 28.3 (256.9 to 63.4) 20.2 (21.6 to 1.7) 22 15.2 (10.7–19.9) 9.1 (8.4–9.5) 3.9 (3.7–4.1) 5.6 (4.5–6.7) 126.4 (64.9–250.8) 9.8 (7.8–12.0) 23.6 (19.2–29.9)c 0.1 (20.2 to 0.7) 0.1 (20.1 to 0.1) 0.1 (21.8 to 0.8) 225.7 (296.5 to 41.2) 6.1 (2.3–11.5) N 25(OH)D (ng/ml) Calcium (mg/dl) Albumin (g/dl) Phosphorus (mg/dl) PTH (pg/ml) 1,25(OH)2Dd (pg/ml)

20 13.3 (11.1–16.2) 8.7 (8.2–9.1) 4.0 (3.5–4.2) 5.0 (4.2–7.4) 174.1 (108.1–371.5) 9.4 (6.6–13.0)

,0.001 0.10 0.74 0.69 0.33 0.001

Pb Change Baseline Change

Vitamin D3 Group

Table 2. Subjects laboratory results

Baseline

Pa

Pa

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Baseline 25(OH)D Our hemodialysis subjects also had low 25(OH)D levels by any standard (4,22). Thirty-three (79%) subjects had 25 (OH)D levels less than 20 ng/ml. Thirty-nine (93%) subjects had levels less than 30 ng/ml. This finding is comparable with other studies reporting that 80%–100% of hemodialysis patients had low vitamin D status (9). The reasons for this low vitamin D status are many, including factors that affect vitamin D status in the general population, such as poor diet, illness, and little sun exposure because of illness (23). There are also factors that are specific to CKD patients. One such factor is the high levels of fibroblast growth factor 23 (FGF-23) that are common in dialysis patients (24). This high level directly inhibits the expression of 1-a-hydroxylase and increases 24-hydroxylase, the enzymes responsible for activating 25(OH)D and metabolizing 1,25(OH)2D, respectively (25). We did not measure FGF-23 and cannot comment on its relationship to 25(OH)D or 1,25(OH)2D in this cohort. Our cohort also had a high percentage of African Americans, and their darker skin tones can contribute to a decrease in vitamin D production and low vitamin D status (26) as well as genetic differences in hydroxylation, metabolism, or both. Effect of Vitamin D Supplementation on 1,25(OH)2D We saw a significant correlation between 25(OH)D and 1,25(OH)2D levels both at baseline and after vitamin D supplementation. Similar effects have been reported in the work by Jean et al. (27) in chronic hemodialysis patients and the work by Lambert et al. (28) in anephric patients. Although the former may still retain some renal 1-a-hydroxylase activity, the 1,25(OH)2D rise in the latter is undoubtedly a result of extrarenal 1-a-hydroxylase activity. The work by Jean et al. (27) reported a similar effect on 1,25(OH)2D levels. Although 1,25(OH)2D levels were raised, most of their subjects still remained below the normal range. Racial Effects on 25(OH)D Response We saw a greater 25(OH)D response to vitamin D supplementation in African Americans compared with Caucasians. This finding has been recently reported in the work by Heaney et al. (R. Heaney, M. Dowell, R. Recker, and M. Barger-Lux, personal communication, 2011). This finding was not apparent to us during study design, and we did not power our study to elicit racial differences; therefore, additional study and replication of these results are warranted. These racial differences are likely a result of a genetic difference in vitamin D metabolism. For example, the work by Xu et al. (29) has explained some of this variability of 25(OH)D response with differences in the DNA methylation of key enzymes controlling the metabolism of vitamin D (CYP2R1 and CYP24A1 for 25-hydroxylase and 24-hydroxylase, respectively).

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Limitations This study was limited by the use of only one dose and only one dose interval. It was also limited in its ability to differentiate between dose responses in different races. At the time of study initiation, there was little known about the effect of race on dose response.

25(OH)D Dose Response in Dialysis, Armas et al.

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7.

Clinical Implications In our study, 10,333 IU cholecalciferol weekly raised 25 (OH)D levels to a range that is considered replete by many experts. Continuing this weekly dose ad infinitum would be reasonable, because the subjects had reached a steady state that was well within a sufficient range. Checking 25 (OH)D levels 3 months after starting this regimen would give results indicative of the patient’s steady state. Rechecking 25(OH)D levels yearly, in the absence of any other health changes, would be reasonable. This study quantifies the 25(OH)D dose response to weekly oral cholecalciferol in subjects on chronic hemodialysis. Pharmacokinetic studies of vitamin D are important clinically to determine the best repletion regimen in patients on hemodialysis. The 25(OH)D response was more robust in our study than in previous reports in healthy subjects (17,18) or other reports in dialysis subjects (13,14). Differences in study design could account for some of the findings, but the effects of CKD on vitamin D metabolism and racial differences in vitamin D metabolism likely played a substantial role. Additional pharmacokinetic studies of various vitamin D regimens will be important to assess the best clinical treatment regimen. Clinical outcome measures, including the measures from this study, will be important in defining vitamin D dosing regimens in hemodialysis patients. Acknowledgments We thank Susan M. Dowell and Lisa Moffat for their hard work in recruiting and retaining subjects and Bethanie West for editorial assistance. This work was supported by a grant from Dialysis Clinics, Inc.

8. 9. 10. 11.

12.

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16. 17.

Disclosures This work was supported by a grant from Dialysis Clinics, Inc. The cholecalciferol was provided by BTR Group, Inc. BTR Group, Inc. had no involvement in study design, data analysis, or interpretation.

18.

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29. Xu X, Zhou Y, Bu F, Ye A, Zhou B, Recker R, Lappe J, Zhao L: DNA methylation levels of CYP2R1 and CYP24A1 predict vitamin D dose-response variation J Bone Miner Res 26(Suppl 1): S151, 2011 Received: December 15, 2011 Accepted: June 18, 2012 Published online ahead of print. Publication date available at www. cjasn.org. This article contains supplemental material online at http://cjasn. asnjournals.org/lookup/suppl/doi:10.2215/CJN.12761211/-/ DCSupplemental.