ORIGINAL RESEARCH
Increasing Use of Vitamin D Supplementation in the Chronic Renal Insufficiency Cohort Study Laura H. Mariani, MD, MSCE,* Matthew T. White, PhD,† Justine Shults, PhD,‡ Cheryl A. M. Anderson, PhD, MPH,§ Harold I. Feldman, MD, MSCE,‡,{ Myles Wolf, MD,** Peter P. Reese, MD, MSCE,‡,{ Michelle R. Denburg, MD, MSCE,†† Raymond R. Townsend, MD,{ Joan C. Lo, MD,‡‡ Anne R. Cappola, MD, ScM,{ Dean Carlow, MD,†† Crystal A. Gadegbeku, MD,§§ Susan Steigerwalt, MD,{{ Mary B. Leonard, MD, MSCE,‡,†† and on behalf of the CRIC Study Investigators Objective: This study examined rates and determinants of vitamin D supplementation among Chronic Renal Insufficiency Cohort (CRIC) participants and determined the association between dose and 25-hydroxyvitamin D (25(OH)D) level. The 2010 Institute of Medicine Report noted a significant increase in vitamin D supplementation in the general population, but use in chronic kidney disease (CKD) is unknown. Methods: CRIC is a multicenter prospective observational cohort study of 3,939 participants with a median baseline age of 60 and an estimated glomerular filtration rate (eGFR) of 42.1 mL/minute per 1.73 m2. Of the cohort, 54.9% was male, 42.1% were Black, and 48.4% were diabetic. Multivariable logistic generalized estimating equations were used to examine determinants of supplementation use assessed annually between 2003 and 2011. Cross-sectional linear regression models, based on a subset of 1,155 participants, assessed associations between supplement dose and 25(OH)D level, measured by high-performance liquid chromatography coupled with tandem mass spectrometry. Results: The proportion of participants reporting supplement use increased (P , .0001), from 10% at baseline to 44% at 7-year follow-up visits. This was largely due to initiation of products containing only ergocalciferol or cholecalciferol. The odds of supplementation were greater in older, female, non-Black, married participants with greater education and lower body mass index. Among participants taking supplementation, dose was positively associated with 25(OH)D level, adjusted for race, season, diabetes, dietary intake, eGFR, and proteinuria. Only 3.8% of non-Black and 16.5% of Black participants taking a supplement were deficient (,20 ng/mL), whereas 22.7% of non-Black and 62.4% of Black participants not reporting supplement use were deficient. Conclusions: Vitamin D supplementation rates rose significantly among CRIC participants over 7 years of follow-up and were associated with greater serum 25(OH)D levels. Studies of vitamin D levels on clinical outcomes in CKD and future vitamin D interventional studies should consider these changes in supplementation practices. Ó 2014 by the National Kidney Foundation, Inc. All rights reserved.
Introduction
I
N RECENT YEARS, the potential role of 25hydroxyvitamin D (25(OH)D) deficiency in a wide
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University of Michigan Medical School and Arbor Research Collaborative for Health, Ann Arbor, Michigan. † The Clinical Research Center, Boston Children’s Hospital, Boston, Massachusetts. ‡ Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. § University of California–San Diego School of Medicine, San Diego, California. { Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. ** Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida. †† Department of Pediatrics, Perelman School of Medicine, and the University of Pennsylvania Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania. ‡‡ Kaiser Permanente, Oakland, California. §§ Temple University School of Medicine, Philadelphia, Pennsylvania. {{ St. Johns Health System, Detroit, Michigan.
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range of diseases has been increasingly recognized and widely publicized. These include cardiovascular disease, malignancy, insulin resistance, diabetes, autoimmune Support: This CRIC ancillary study was supported by National Institutes of Health grants R01DK077128 and K24 DK076808 (M.B.L.); cooperative agreement project grants 5U01DK060990, 5U01DK060984, 5U01DK06102, 5U01DK061021, 5U01DK061028, 5U01DK60980, 5U01DK060963, and 5U01DK060902 from the National Institute of Diabetes and Digestive and Kidney Diseases; and grants UL1RR024134, UL1RR025005, M01RR16500, UL1RR024989, M01RR000042, UL1RR024986, UL1RR029879, RR05096, and UL1RR024131 from the National Institutes of Health. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Laura H. Mariani, MD, MSCE, University of Michigan, Division of Nephrology, Simpson Building, Room 208, 102 Observatory Street, Ann Arbor, MI 48109. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 http://dx.doi.org/10.1053/j.jrn.2014.01.015
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disease, infection, impaired physical function, fractures, and mortality.1 As a result of the increased awareness of the potential importance of vitamin D status, the number of clinical assays of 25(OH)D levels and the use of calciferol supplementation has increased dramatically in the general population, as reported in the 2010 Institute of Medicine (IOM) Report on Dietary Reference Intakes for Calcium and Vitamin D.2 A recent population-based Canadian study also reported secular increases in vitamin D supplementation use and 25(OH)D levels over 10 years.3 Trends of supplementation use among patients with chronic kidney disease (CKD) are unknown. 25(OH)D deficiency is common in CKD, especially non-Caucasian patients4 and those with advanced disease.5 Recent studies in CKD linked 25(OH)D deficiency with hyperparathyroidism, insulin resistance, anemia, inflammation, CKD progression, and mortality.5-13 CKD is associated with a heavy burden of cardiovascular, metabolic, and infectious complications, and 25(OH)D deficiency may be an important modifiable risk factor. The 2003 Kidney Disease Outcomes Quality Initiative guidelines recommended supplementation for CKD Stages 3 to 4 with hyperparathyroidism and a 25(OH)D level less than 30 ng/mL.14 The 2009 Kidney Disease Improving Global Outcomes guidelines recommended more expanded testing for all patients with CKD Stages 3 to 5 and treatment strategies as in the general population without establishing a target level.15 Studies in the general population suggest that large doses (.2,000 IU/day) are required to correct and maintain adequate 25(OH)D levels.16,17 Compared with the general population, CKD patients have additional risk factors for 25(OH)D deficiency, including urinary losses of vitamin D-binding protein and albumin, decreased 25(OH)D production by uremic skin in response to ultraviolet B ray exposure,18 and decreased dairy intake due to phosphate restriction. The objectives of this study were 2-fold. First, we examined vitamin D supplementation use at annual visits among all Chronic Renal Insufficiency Cohort (CRIC) study participants to identify determinants and trends of supplementation use. Second, we examined the cross-sectional relationship between calciferol dose and serum 25(OH)D levels in a subset of CRIC participants who completed a detailed assessment of vitamin D dose at a single visit.
Methods Study Population The CRIC study is a multicenter prospective observational study established by the National Institute of Diabetes and Digestive and Kidney Diseases to examine risk factors for CKD progression and cardiovascular disease.19 A total of 3,939 ethnically and racially diverse participants, aged 21 to 74 years, with mild to moderate CKD were recruited from 2003 to 2008 on the basis of age-specific estimated glomerular filtration rate (eGFR; 20-70 mL/minute
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per 1.73 m2) at 7 clinical sites.20 The protocol was approved by the institutional review board at each site. Participants provided informed consent.19-21
Data Collection Detailed information regarding demographics, medical history, quality of life, health behaviors, and physical activity were collected by research coordinator interview and questionnaire at the baseline visit, as previously described.19 Blood and urine specimens were collected annually, and eGFR (mL/minute per 1.73 m2) was calculated using the Modification of Diet in Renal Disease formula on the basis of serum creatinine.22 Proteinuria was assessed by 24-hour urine collection. Dietary information was collected at baseline and every other year using the National Cancer Institute’s Dietary History Questionnaire (DHQ). This validated instrument assesses food frequency and amount in the past year to compute average daily nutrient intake, including vitamin D.23 The DHQ assesses usual dietary intake of 124 food items on the basis of national dietary intake data from the 1994 to 1996 U.S. Department of Agriculture’s Continuing Survey of Food Intake in Individuals. After being manually reviewed for completeness, DHQs were analyzed using the National Cancer Institute’s DietCalc software. Approximately 10% of DHQs were excluded because unlikely values were reported for total energy intake (i.e., ,600 or .4,000 kcal for women and ,800 or .5,000 kcal for men). Medication use was assessed at each annual visit by research coordinator interview and completion of the Concomitant Medication (CMED) form. Participants were asked to bring a list of their medications and supplements taken in the prior 30 days. Name, dose, units, and frequency were recorded and matched to drug codes from the Medication Reference Tool in the data management system. A total of 72 drug codes identified a medication or supplement that contained any amount of either vitamin D2 (ergocalciferol) or D3 (cholecalciferol). If participants reported use of any of these products, then they were classified as taking a calciferol at that visit. Given the many multinutrient supplements, dose data were not available for the calciferol component. A subset of the full CRIC cohort at 4 selected clinical centers completed a single visit between 2008 and 2010 at the time of physical function testing in which augmented procedures were used to obtain detailed vitamin D intake. Research coordinators at these sites were trained to elicit a detailed vitamin D supplementation history using the Vitamin D Concomitant Medication (DCMED) form, in addition to the CMED form, at this visit. Participants were asked to bring medication and supplement bottles to record formulation, frequency, route, and calciferol content of all calciferol-containing medications used in the prior 3 months.
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In the subset that completed this DCMED form, stored serum specimens from the same visit were used to measure 25(OH)D levels by high-performance liquid chromatography coupled with tandem mass spectrometry. This assay gave a linear response from 1.3 to 135 ng/mL for 25(OH)D2 and 25(OH)D3 and the limit of quantitation (signal-to-noise ratio $ 10) was 1.3 ng/mL. The interassay coefficients of variation were 7.3% to 10.0% and 4.2% to 4.9% for 25(OH)D2 and 25(OH)D3, respectively. The specimens were collected and run at the end of the study; thus, they were not available to the participants or research team at each site.
Statistical Analysis Descriptive statistics, including mean and standard deviation for normally distributed variables, median and interquartile range (IQR) for skewed variables, and proportions for categorical variables, were used to characterize baseline participant characteristics and supplementation use at each visit. Two primary analyses were conducted. First, in the full cohort of participants, a multivariable logistic generalized estimating equation model was fit to identify determinants of supplementation use. Study visits after transplantation or initiation of dialysis were excluded. Because of concern for greater ascertainment of calciferol supplementation among participants at clinical centers using the DCMED form, we compared supplementation use before and after research coordinators from these sites were trained to use the DCMED form and to clinical centers using the CMED form. Using a piecewise logistic regression analysis, we found that neither the log odds of supplementation (P 5 .829) nor the rate of change in supplementation (P 5 .727) at DCMED centers increased more immediately after DCMED training than at CMED centers. Therefore, study visits after training were included, and sensitivity analyses excluding these visits did not alter results. Potential determinants of supplementation included age, sex, race, ethnicity, diabetes, socioeconomic status (income, education, and marital status), lifestyle variables (smoking, physical activity, and body mass index [BMI]), cause of CKD, proteinuria, eGFR, having seen a nephrologist before the baseline visit, calendar year, and study year. The second primary analysis was performed in the subset of the cohort that had both dose information and levels available. Spearman’s rank correlation coefficient (r) was used to separately assess the relationship between supplementation dose and 25(OH)D level for Black and nonBlack participants. Linear regression was used to examine the association between 25(OH)D level and calciferol supplementation dose, adjusted for determinants of 25(OH)D level, including age, sex, race, ethnicity, physical activity (a surrogate for sun exposure), BMI, diabetes, proteinuria, socioeconomic status, dietary vitamin D, and eGFR. Because 25(OH)D level was logarithmically transformed for anal-
ysis, results were presented as the percentage difference in predicted level compared with the reference category. The exponentiated regression coefficient for a particular covariate represents the ratio of 25(OH)D level for that category relative to the reference category. Analyses were performed using Stata, version 11.2 (College Station, TX), with 2-sided tests of hypotheses and a P value less than .05 as the criterion for statistical significance.
Results Trends in Vitamin D Supplementation Use Among All CRIC Participants The baseline characteristics of the 3,939 CRIC participants are summarized in Table 1. The median duration of follow-up was 5 (IQR 3-6) years with a total of 20,983 visits. Among all participants, rates of reported use of any product containing a calciferol increased dramatically according to calendar and study year (Fig. 1). Use increased with longer participation in CRIC, from 10% at the baseline visits to 44% at the 7-year visits. Similar trends were observed in analyses limited to the 708 participants with Table 1. Baseline Participant Characteristics of Full Cohort (N 5 3,939) Age (y) Male Black Diabetes Smoking Any intentional exercise Married eGFR (mL/min per 1.73 m2) .60 30-60 ,30 Proteinuria (g/24 h) ,1.5 $1.5 BMI (kg/m2) ,25 25 to ,30 30 to ,35 $35 Education Less than high school High-school graduate Some college College graduate Income #$20,000 $20,000-50,000 $50,000-100,000 .$100,000 Did not answer
60 (52, 66) 54.9% 42.1% 48.4% 13.1% 69.8% 54.8% 42.1 (32.6, 51.9) 10.3% 70.2% 19.5% 0.18 (0.07, 0.91) 81.6% 18.4% 30.9 (26.8, 36.1) 16.0% 28.6% 26.2% 29.3% 21.0% 18.8% 29.2% 31.0% 31.5% 24.4% 18.7% 10.0% 15.5%
BMI, body mass index; eGFR, estimated glomerular filtration rate. All characteristics were recorded at the participants’ baseline study visits, conducted from 2003 to 2008. Continuous variables are presented as median (interquartile range). Categorical variables are presented as percentages.
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Figure 1. Trends in calciferol supplementation use in the CRIC study over time. Patients reporting a calciferol-containing supplement on the CMED at 19,503 annual visits of the full cohort of CRIC participants from 2003 to 2011. CMED, Concomitant Medication form; CRIC, Chronic Renal Insufficiency Cohort.
7 years of follow-up. Supplementation increased with later calendar year, from 10% at visits in 2003 to 43% at visits in 2011. The increase was primarily driven by use of products containing ergocalciferol or cholecalciferol alone, whereas use of products containing calcium and calciferol increased less markedly (Fig. 2). Use of active vitamin D sterols remained stable at 2% to 3% over this same time period. The predominant formulation of calciferol switched from ergocalciferol (69.3% of supplements in 2003) to cholecalciferol (77.2% of supplements in 2010).
Predictors of Vitamin D Supplement Use Among All CRIC Participants The full cohort was used to identify predictors of supplementation use. The results of the multivariable logistic generalized estimating equation regression are shown in Table 2. Greater odds of supplementation were associated with older age, female gender, non-Black race, higher Table 2. Results of Multivariable Logistic Generalized Estimating Equation Model of Calciferol Supplementation Use Determinant
Figure 2. Trends in type of calciferol supplementation use. Patients reporting a calciferol-containing supplement on the CMED at 19,503 annual visits of the full cohort of CRIC participants from 2003 to 2011. CMED, Concomitant Medication form; CRIC, Chronic Renal Insufficiency Cohort.
Age (per 10 y) White race Female sex Married Education Less than high school High-school graduate Some college College graduate BMI (kg/m2) ,25 25 to ,30 30 to ,35 $35 Visit number Calendar year
OR (95% CI)
P
1.30 (1.23, 1.37) 1.54 (1.36, 1.74) 3.00 (2.66, 3.37) 1.15 (1.03, 1.29)
,.001 ,.001 ,.001 .016
1.0 (Reference) 1.51 (1.24, 1.84) 1.53 (1.28, 1.85) 1.77 (1.47, 2.14)
,.001 ,.001 ,.001
1.0 (Reference) 0.75 (0.64, 0.88) 0.72 (0.61, 0.85) 0.65 (0.55, 0.77) 1.12 (1.06, 1.18) 1.21 (1.15, 1.27)
,.001 ,.001 ,.001 ,.001 ,.001
BMI, body mass index; CI, confidence interval; OR, odds ratio. Data from full cohort (N 5 3,531) with a total of 19,019 annual visits and adjusted for clinical site.
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Table 3. Characteristics of Participants Enrolled in the Vitamin D Ancillary Study (n 5 1,155) Age (y) Male Black Diabetes Smoking Any intentional exercise Married eGFR (mL/min per 1.73 m2) .60 30-60 ,30 Proteinuria (g/24 h) ,1.5 $1.5 BMI (kg/m2) ,25 25 to ,30 30 to ,35 $35 Education Less than high school High-school graduate Some college College graduate Income #$20,000 $20,000-50,000 $50,000-100,000 .$100,000 Did not answer Visit calendar year 2008 2009 2010 Number of calciferolcontaining medications 0 1 2 3 4 Calciferol dose if taking $1 calciferolcontaining medications (IU/d) Dietary vitamin D intake (IU/d) 25(OH)D level (ng/mL) If taking 0 calciferolcontaining medications If taking $1 calciferolcontaining medications
64 (57, 70) 53.0% 35.5% 37.1% 7.5% 79.8% 61.6% 44.8 (33.8,54.8)
education level, married, and lower BMI. Visit number and calendar year were independent predictors. Having seen a nephrologist, stage and cause of CKD, degree of proteinuria, income level, reported exercise, and smoking status were not independent predictors.
25(OH)D Levels in a Subset of CRIC Participants Vitamin D levels and a detailed assessment of vitamin D intake were available in a subset of participants as part of a cross-sectional study of physical function and vitamin D status in CRIC. The characteristics of participants who completed this single visit are shown in Table 3. Overall, 524 (54.6%) of participants reported taking at least 1 product that contained ergocalciferol or cholecalciferol in the preceding 3 months. Many were taking more than 1 vitamin D product. Among participants who reported supplementation, the median dose was 500 (IQR 400-1000) IU/day. Figure 3 demonstrates the associations between 25(OH) D level and calciferol supplementation according to race. Dose category was positively associated with vitamin D level for Black (r 5 0.57, P ,.0001) and non-Black participants (r 5 0.45, P ,.0001). As expected, among participants taking 400 IU/day or less of calciferol, Black participants had significantly lower median 25(OH)D levels (19.3 ng/mL [IQR 13.5, 30.9]) compared with non-Black participants (31.6 ng/mL [IQR 22.8, 41.0]; P , .001). However, among participants taking more than 400 IU/ day, the race difference was not evident (P 5.17): the median 25(OH)D level was 42.0 ng/mL (IQR 35.2, 49.7) for non-Black and 40.5 ng/mL (IQR 32.3, 50.4) for Black participants. Overall, 11.2% of non-Black and 41.8% of Black
15.0% 66.5% 18.5% 0.16 (0.08, 0.63) 88.3% 11.72% 29.9 (26.1, 34.7) 18.5% 32.1% 25.6% 23.8% 7.1% 14.2% 29.2% 49.6% 12.9% 25.5% 28.1% 19.0% 14.6% 41.7% 57.1% 1.1%
45.4% 40.5% 12.3% 1.5% 0.4% 500 (400, 1000)
112 (72, 175) Black 16.9 (12.1, 26.3)
Non-Black 27.7 (20.6, 38.5)
35.4 (25.8, 45.5)
38.8 (32.2, 47.1)
BMI, body mass index; DCMED, Vitamin D Concomitant Medication form; eGFR, estimated glomerular filtration rate; 25(OH)D, 25hydroxyvitamin D. All characteristics were recorded at the participants’ vitamin D study visit (2008-2010) when augmented procedures and DCMED form were used to assess supplementation use. Continuous variables are presented as median (interquartile range). Categorical variables are presented as percentages.
Figure 3. Vitamin D level by reported daily supplement dosage for Black and non-Black participants. Data from 1,155 participants who completed a single study visit to obtain detailed vitamin D intake history at the time of physical function testing, collected using the DCMED. Dashed reference line at 20 ng/mL, below which is considered deficient. Spearman test for trend with P , .001 for Black and nonBlack participants. DCMED, Vitamin D Concomitant Medication form.
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participants had a deficient level (,20 ng/mL). However, among those taking any supplement, only 3.8% of nonBlack and 16.5% of Black participants were deficient whereas 22.7% of non-Black and 62.4% of Black participants not reporting supplement use were deficient. There was a significant dose response relationship between supplementation use and 25(OH)D level adjusted for race, season, diabetes, dietary vitamin D, proteinuria, and eGFR. The results of the linear regression model are presented in Table 4. The effect of supplementation (.400 IU/day) was greater than any other predictors in the model. There was a significant interaction between Black race and supplementation use as indicated by the relatively greater increase in level for each vitamin D dose among the Black participants. In contrast, there was no interaction between CKD stage or supplement type (calcium-containing vs. vitamin D alone) and supplementation dose in its association with 25(OH)D level. Physical activity, BMI, cause of CKD, sex, age, and smoking status were not independent predictors of 25(OH)D level. When total daily dose of calciferol was separated by formulation in this model, 1,000 IU of cholecalciferol
was associated with a 29.0% higher 25(OH)D level as compared with no supplementation (P , .001); 1,000 IU of ergocalciferol was associated with a 14.7% higher 25(OH)D level as compared with no supplementation (P 5 .008), consistent with a lower potency. When models were fit for 25(OH)D2 and 25(OH)D3 levels separately, greater daily cholecalciferol (D3) dose was associated with greater 25(OH)D3 levels (P , .001) whereas greater daily ergocalciferol (D2) dose was associated with greater 25(OH)D2 levels (P , .001).
Discussion Reported use of calciferol supplements increased markedly in the CRIC cohort over time, primarily because of increased use of single-nutrient products containing ergocalciferol or cholecalciferol. Supplementation was associated with markedly greater vitamin D levels, especially among Black participants. To our knowledge, this is the first study to examine trends in vitamin D supplementation in CKD and to relate supplement dose to vitamin D levels. These findings have important implications for future vitamin D intervention studies and for the interpretation
Table 4. Results of Linear Regression of 25(OH)D Levels (n 5 1,021) Determinant Vitamin D supplement (IU/d) 0 .0-400 .400-800 .800 Season Summer Winter Marital status Not married Married Dietary vitamin D (IU/d) ,200 $200 Diabetes No Yes Proteinuria (g/d) ,1.5 $1.5 eGFR (mL/min per 1.73 m2) .60 30-60 ,30 Serum albumin (mg/dL) ,3.5 $3.5 to ,4 $4
Relative Percent Change Compared With Reference Group (95% CI) Non-Black Reference 26.5% (16.9, 36.9)* 46.4% (32.3, 62.0)* 61.0% (47.6, 75.7)*
Black Reference 60.8% (43.8, 79.9)* 125.8% (92.2, 165.2)* 127.1% (96.9, 161.9)* Reference 211.1% (215.8, -6.1)* Reference 7.9% (2.1, 14.0)† Reference 7.7% (0.7, 15.2)† Reference 211.8% (216.5, 26.7)* Reference 217.9% (224.8, 210.3)* Reference 13.6% (5.4, 22.6)* 13.7% (3.2, 25.2)† Reference 10.6% (0.2, 22.1)† 20.8% (9.4, 33.3)*
CI, confidence interval; eGFR, estimated glomerular filtration rate; 25(OH)D, 25-hydroxyvitamin D. Data from subset cohort that completed a single vitamin D study visit, and augmented procedures were used to assess vitamin D supplement use (n 5 1,155). *P # .001. †P , .05.
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of observational studies of vitamin D levels and clinical outcomes in CKD. Specifically, the increasing prevalence of vitamin D supplementation in CKD patients may make it difficult to identify, and thus enroll, patients with deficient levels and to control the rates of supplementation use in a trial setting. Further, observational studies relying on a single vitamin D level may be affected by this increasing prevalence of supplementation use. The results of a recently published meta-analysis and accompanying editorial24,25 on vitamin D supplementation and fracture prevention in the general population highlight the importance of accounting for actual intake and baseline vitamin D status when trying to reconcile discordant results from clinical trials. There was a wide range of daily vitamin D dosage. The 2010 IOM report recommended 600 IU/day for people younger than 70 years of age and 800 IU/day for people older than 70 years of age with a maximum tolerated dose of 4,000 IU/day.2 Among CRIC participants taking a supplement, the median dose was 500 IU per day, and 1% of participants were taking 4,000 IU/day or more. Median dietary vitamin D intake was 112 IU/day and did not differ among those participants who were or were not taking a supplement. This is much lower than the median intake reported in the IOM report for the general population, which ranges from 272 to 396 IU/day depending on life stage and may be related to phosphorus restriction with consequent reductions in dairy intake. One could hypothesize that there would be minimal association between supplement dose and level in a cross-sectional analysis because patients would be a combination of those prescribed vitamin D because of severe deficiency with those who were taking a supplement regardless of level. However, our analysis reveals that supplement use was associated with significantly higher vitamin D levels, with a dose-response relationship, and had a stronger association than any other factor in the model. A recent study reported that supplementation use was an important predictor of vitamin D levels in a healthy, northern European population26; however, this had not been previously assessed in patients with CKD. Furthermore, this is the first study to examine racial differences in the relationship between vitamin D supplementation and levels. Longitudinal measures of vitamin D levels were not available to assess the response to supplementation or baseline levels. However, it was surprising to note that even modest doses of supplementation were associated with higher levels. Two large previous reports have demonstrated mixed results regarding the relationship between 25(OH)D levels and eGFR. Chonchol and colleagues analyzed data from the Third National Health and Nutrition Examination Survey and showed that 25(OH)D levels were low only among those with advanced CKD (eGFR 15-29 mL/min-
ute per 1.73 m2) after adjustment for age, sex, ethnicity, BMI, physical activity, intake of milk and vitamin D supplements, and season.5 However, in the Study to Evaluate Early Kidney Disease, Levin and colleagues reported no relationship between 25(OH)D level and eGFR after adjustment for age, gender, ethnicity, diabetes, urinary albumin, calcium, and phosphorus.27 Our study obtained detailed information regarding supplement use and dose, which we also demonstrated to be highly prevalent and an important predictor of level. Although unadjusted analysis suggested an association of lower 25(OH)D levels with lower eGFR, this association did not persist after adjusting for supplement use dosage, dietary intake, season, diabetes, and proteinuria. In fact, lower eGFR was associated with a slightly higher level in our full model. In this cross-sectional analysis, we were not able to assess changes in eGFR or changes in 25(OH)D level. A limitation of the study is reliance on self-report of supplementation use. However, review of reported calciferol supplement formulations over time revealed a switch from D2- (ergocalciferol) to D3 (cholecalciferol)-containing products, consistent with national trends among vitamin D supplement manufacturers.2 In addition, the strong association between reported supplementation and serum vitamin D levels as well as the association between reported vitamin D formulation and the respective D2and D3-specific levels provided additional evidence for the validity of the data. Self-report of ultraviolet sun exposure as a source of vitamin D was not directly collected, but season and activity level were included. Detailed information on calcium supplementation dose was also not available. Levels and dose information were only available for a subset of CRIC participants at selected clinical centers that used augmented techniques to collect information on supplementation use. All participants at these clinical centers were eligible to collect these supplemental data, and 86% did so. These high participation rates make selection bias unlikely. These study participants were somewhat healthier compared with the remainder of the CRIC cohort. This likely reflects survival to this later visit (87% of visits were performed 3-5 years after enrollment) and varying baseline participant characteristics of the participating clinical sites. Given that the primary goal was to relate supplement dose and vitamin D level, it is unlikely that these differences introduced a significant bias. Because detailed vitamin D dose information and 25(OH)D levels were available only at a single visit, our current data could not assess the longitudinal effect of vitamin D supplementation and changes in parathyroid hormone or other bone mineral metabolism laboratory values such as calcium and phosphorus. Future studies will be needed to assess this relationship as well as the association with clinical outcomes such as fracture.
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Practical Application This study revealed an increasing use of calciferol supplementation among participants in the CRIC study and that supplementation use was associated with greater 25(OH)D levels. Predictors of supplementation use included socioeconomic factors in addition to expected demographic factors. Given the recent call for interventional trials using nutritional vitamin D,2 these results demonstrate the challenges of completing these studies, especially because these participants are likely representative of other individuals who would be recruited for future clinical trials; specifically, a large and increasing proportion of CKD patients are taking vitamin D and that this supplementation use is associated with high levels.
References 1. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266-281. 2. Ross AC, Taylor CL, Yaktine AL, Del Valle HB. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: Institute of Medicine; 2010. 3. Berger C, Greene-Finestone LS, Langsetmo L, et al. Temporal trends and determinants of longitudinal change in 25-hydroxyvitamin D and parathyroid hormone levels. J Bone Miner Res. 2012;27:1381-1389. 4. Melamed ML, Astor B, Michos ED, Hostetter TH, Powe NR, Muntner P. 25-hydroxyvitamin D levels, race, and the progression of kidney disease. J Am Soc Nephrol. 2009;20:2631-2639. 5. Chonchol M, Scragg R. 25-Hydroxyvitamin D, insulin resistance, and kidney function in the Third National Health and Nutrition Examination Survey. Kidney Int. 2007;71:134-139. 6. Stefikova K, Spustova V, Krivosikova Z, et al. Insulin resistance and vitamin D deficiency in patients with chronic kidney disease stage 2-3. Physiol Res. 2011;60:149-155. 7. Lac PT, Choi K, Liu IA, Meguerditchian S, Rasgon SA, Sim JJ. The effects of changing vitamin D levels on anemia in chronic kidney disease patients: a retrospective cohort review. Clin Nephrol. 2010;74:25-32. 8. Patel NM, Gutierrez OM, Andress DL, Coyne DW, Levin A, Wolf M. Vitamin D deficiency and anemia in early chronic kidney disease. Kidney Int. 2010;77:715-720. 9. Isakova T, Gutierrez OM, Patel NM, Andress DL, Wolf M, Levin A. Vitamin D deficiency, inflammation, and albuminuria in chronic kidney disease: complex interactions. J Ren Nutr. 2011;21:295-302. 10. Stubbs JR, Idiculla A, Slusser J, Menard R, Quarles LD. Cholecalciferol supplementation alters calcitriol-responsive monocyte proteins and decreases inflammatory cytokines in ESRD. J Am Soc Nephrol. 2010;21: 353-361.
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11. Barreto DV, Barreto FC, Liabeuf S, et al. Vitamin D affects survival independently of vascular calcification in chronic kidney disease. Clin J Am Soc Nephrol. 2009;4:1128-1135. 12. Ravani P, Malberti F, Tripepi G, et al. Vitamin D levels and patient outcome in chronic kidney disease. Kidney Int. 2009;75:88-95. 13. Jean G, Lataillade D, Genet L, et al. Impact of hypovitaminosis D and alfacalcidol therapy on survival of hemodialysis patients: results from the French ARNOS study. Nephron Clin Pract. 2011;118:c204-c210. 14. 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. 15. KDIGO Clinical Practice Guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl. 2009:S1-S130. 16. Barger-Lux MJ, Heaney RP, Dowell S, Chen TC, Holick MF. Vitamin D and its major metabolites: serum levels after graded oral dosing in healthy men. Osteoporos Int. 1998;8:222-230. 17. Heaney RP. Vitamin D in health and disease. Clin J Am Soc Nephrol. 2008;3:1535-1541. 18. Jacob AI, Sallman A, Santiz Z, Hollis BW. Defective photoproduction of cholecalciferol in normal and uremic humans. J Nutr. 1984;114:1313-1319. 19. Feldman HI, Appel LJ, Chertow GM, et al. The Chronic Renal Insufficiency Cohort (CRIC) study: design and methods. J Am Soc Nephrol. 2003;14(7 Suppl 2):S148-S153. 20. Lash JP, Go AS, Appel LJ, et al. Chronic Renal Insufficiency Cohort (CRIC) study: baseline characteristics and associations with kidney function. Clin J Am Soc Nephrol. 2009;4:1302-1311. 21. Fischer MJ, Go AS, Lora CM, et al. CKD in Hispanics: baseline characteristics from the CRIC (Chronic Renal Insufficiency Cohort) and Hispanic-CRIC studies. Am J Kidney Dis. 2011;58:214-227. 22. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461-470. 23. Subar AF, Thompson FE, Kipnis V, et al. Comparative validation of the Block, Willett, and National Cancer Institute food frequency questionnaires: the Eating at America’s Table Study. Am J Epidemiol. 2001;154:1089-1099. 24. Heaney RP. Vitamin D—baseline status and effective dose. N Engl J Med. 2012;367:77-78. 25. Bischoff-Ferrari HA, Willett WC, Orav EJ, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med. 2012;367:40-49. 26. Zgaga L, Theodoratou E, Farrington SM, et al. Diet, environmental factors, and lifestyle underlie the high prevalence of vitamin D deficiency in healthy adults in Scotland, and supplementation reduces the proportion that are severely deficient. J Nutr. 2011;141:1535-1542. 27. Levin A, Bakris GL, Molitch M, et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int. 2007;71:31-38.
Increasing Use of Vitamin D Supplementation in the Chronic Renal Insufficiency Cohort Study Laura H. Mariani, MD, MSCE,* Matthew T. White, PhD,† Justine Shults, PhD,‡ Cheryl A. M. Anderson, PhD, MPH,§ Harold I. Feldman, MD, MSCE,‡,{ Myles Wolf, MD,** Peter P. Reese, MD, MSCE,‡,{ Michelle R. Denburg, MD, MSCE,†† Raymond R. Townsend, MD,{ Joan C. Lo, MD,‡‡ Anne R. Cappola, MD, ScM,{ Dean Carlow, MD,†† Crystal A. Gadegbeku, MD,§§ Susan Steigerwalt, MD,{{ Mary B. Leonard, MD, MSCE,‡,†† and on behalf of the CRIC Study Investigators Objective: This study examined rates and determinants of vitamin D supplementation among Chronic Renal Insufficiency Cohort (CRIC) participants and determined the association between dose and 25-hydroxyvitamin D (25(OH)D) level. The 2010 Institute of Medicine Report noted a significant increase in vitamin D supplementation in the general population, but use in chronic kidney disease (CKD) is unknown. Methods: CRIC is a multicenter prospective observational cohort study of 3,939 participants with a median baseline age of 60 and an estimated glomerular filtration rate (eGFR) of 42.1 mL/minute per 1.73 m2. Of the cohort, 54.9% was male, 42.1% were Black, and 48.4% were diabetic. Multivariable logistic generalized estimating equations were used to examine determinants of supplementation use assessed annually between 2003 and 2011. Cross-sectional linear regression models, based on a subset of 1,155 participants, assessed associations between supplement dose and 25(OH)D level, measured by high-performance liquid chromatography coupled with tandem mass spectrometry. Results: The proportion of participants reporting supplement use increased (P , .0001), from 10% at baseline to 44% at 7-year follow-up visits. This was largely due to initiation of products containing only ergocalciferol or cholecalciferol. The odds of supplementation were greater in older, female, non-Black, married participants with greater education and lower body mass index. Among participants taking supplementation, dose was positively associated with 25(OH)D level, adjusted for race, season, diabetes, dietary intake, eGFR, and proteinuria. Only 3.8% of non-Black and 16.5% of Black participants taking a supplement were deficient (,20 ng/mL), whereas 22.7% of non-Black and 62.4% of Black participants not reporting supplement use were deficient. Conclusions: Vitamin D supplementation rates rose significantly among CRIC participants over 7 years of follow-up and were associated with greater serum 25(OH)D levels. Studies of vitamin D levels on clinical outcomes in CKD and future vitamin D interventional studies should consider these changes in supplementation practices. Ó 2014 by the National Kidney Foundation, Inc. All rights reserved.
Introduction
I
N RECENT YEARS, the potential role of 25hydroxyvitamin D (25(OH)D) deficiency in a wide
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University of Michigan Medical School and Arbor Research Collaborative for Health, Ann Arbor, Michigan. † The Clinical Research Center, Boston Children’s Hospital, Boston, Massachusetts. ‡ Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. § University of California–San Diego School of Medicine, San Diego, California. { Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. ** Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida. †† Department of Pediatrics, Perelman School of Medicine, and the University of Pennsylvania Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania. ‡‡ Kaiser Permanente, Oakland, California. §§ Temple University School of Medicine, Philadelphia, Pennsylvania. {{ St. Johns Health System, Detroit, Michigan.
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range of diseases has been increasingly recognized and widely publicized. These include cardiovascular disease, malignancy, insulin resistance, diabetes, autoimmune Support: This CRIC ancillary study was supported by National Institutes of Health grants R01DK077128 and K24 DK076808 (M.B.L.); cooperative agreement project grants 5U01DK060990, 5U01DK060984, 5U01DK06102, 5U01DK061021, 5U01DK061028, 5U01DK60980, 5U01DK060963, and 5U01DK060902 from the National Institute of Diabetes and Digestive and Kidney Diseases; and grants UL1RR024134, UL1RR025005, M01RR16500, UL1RR024989, M01RR000042, UL1RR024986, UL1RR029879, RR05096, and UL1RR024131 from the National Institutes of Health. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Laura H. Mariani, MD, MSCE, University of Michigan, Division of Nephrology, Simpson Building, Room 208, 102 Observatory Street, Ann Arbor, MI 48109. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 http://dx.doi.org/10.1053/j.jrn.2014.01.015
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disease, infection, impaired physical function, fractures, and mortality.1 As a result of the increased awareness of the potential importance of vitamin D status, the number of clinical assays of 25(OH)D levels and the use of calciferol supplementation has increased dramatically in the general population, as reported in the 2010 Institute of Medicine (IOM) Report on Dietary Reference Intakes for Calcium and Vitamin D.2 A recent population-based Canadian study also reported secular increases in vitamin D supplementation use and 25(OH)D levels over 10 years.3 Trends of supplementation use among patients with chronic kidney disease (CKD) are unknown. 25(OH)D deficiency is common in CKD, especially non-Caucasian patients4 and those with advanced disease.5 Recent studies in CKD linked 25(OH)D deficiency with hyperparathyroidism, insulin resistance, anemia, inflammation, CKD progression, and mortality.5-13 CKD is associated with a heavy burden of cardiovascular, metabolic, and infectious complications, and 25(OH)D deficiency may be an important modifiable risk factor. The 2003 Kidney Disease Outcomes Quality Initiative guidelines recommended supplementation for CKD Stages 3 to 4 with hyperparathyroidism and a 25(OH)D level less than 30 ng/mL.14 The 2009 Kidney Disease Improving Global Outcomes guidelines recommended more expanded testing for all patients with CKD Stages 3 to 5 and treatment strategies as in the general population without establishing a target level.15 Studies in the general population suggest that large doses (.2,000 IU/day) are required to correct and maintain adequate 25(OH)D levels.16,17 Compared with the general population, CKD patients have additional risk factors for 25(OH)D deficiency, including urinary losses of vitamin D-binding protein and albumin, decreased 25(OH)D production by uremic skin in response to ultraviolet B ray exposure,18 and decreased dairy intake due to phosphate restriction. The objectives of this study were 2-fold. First, we examined vitamin D supplementation use at annual visits among all Chronic Renal Insufficiency Cohort (CRIC) study participants to identify determinants and trends of supplementation use. Second, we examined the cross-sectional relationship between calciferol dose and serum 25(OH)D levels in a subset of CRIC participants who completed a detailed assessment of vitamin D dose at a single visit.
Methods Study Population The CRIC study is a multicenter prospective observational study established by the National Institute of Diabetes and Digestive and Kidney Diseases to examine risk factors for CKD progression and cardiovascular disease.19 A total of 3,939 ethnically and racially diverse participants, aged 21 to 74 years, with mild to moderate CKD were recruited from 2003 to 2008 on the basis of age-specific estimated glomerular filtration rate (eGFR; 20-70 mL/minute
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per 1.73 m2) at 7 clinical sites.20 The protocol was approved by the institutional review board at each site. Participants provided informed consent.19-21
Data Collection Detailed information regarding demographics, medical history, quality of life, health behaviors, and physical activity were collected by research coordinator interview and questionnaire at the baseline visit, as previously described.19 Blood and urine specimens were collected annually, and eGFR (mL/minute per 1.73 m2) was calculated using the Modification of Diet in Renal Disease formula on the basis of serum creatinine.22 Proteinuria was assessed by 24-hour urine collection. Dietary information was collected at baseline and every other year using the National Cancer Institute’s Dietary History Questionnaire (DHQ). This validated instrument assesses food frequency and amount in the past year to compute average daily nutrient intake, including vitamin D.23 The DHQ assesses usual dietary intake of 124 food items on the basis of national dietary intake data from the 1994 to 1996 U.S. Department of Agriculture’s Continuing Survey of Food Intake in Individuals. After being manually reviewed for completeness, DHQs were analyzed using the National Cancer Institute’s DietCalc software. Approximately 10% of DHQs were excluded because unlikely values were reported for total energy intake (i.e., ,600 or .4,000 kcal for women and ,800 or .5,000 kcal for men). Medication use was assessed at each annual visit by research coordinator interview and completion of the Concomitant Medication (CMED) form. Participants were asked to bring a list of their medications and supplements taken in the prior 30 days. Name, dose, units, and frequency were recorded and matched to drug codes from the Medication Reference Tool in the data management system. A total of 72 drug codes identified a medication or supplement that contained any amount of either vitamin D2 (ergocalciferol) or D3 (cholecalciferol). If participants reported use of any of these products, then they were classified as taking a calciferol at that visit. Given the many multinutrient supplements, dose data were not available for the calciferol component. A subset of the full CRIC cohort at 4 selected clinical centers completed a single visit between 2008 and 2010 at the time of physical function testing in which augmented procedures were used to obtain detailed vitamin D intake. Research coordinators at these sites were trained to elicit a detailed vitamin D supplementation history using the Vitamin D Concomitant Medication (DCMED) form, in addition to the CMED form, at this visit. Participants were asked to bring medication and supplement bottles to record formulation, frequency, route, and calciferol content of all calciferol-containing medications used in the prior 3 months.
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In the subset that completed this DCMED form, stored serum specimens from the same visit were used to measure 25(OH)D levels by high-performance liquid chromatography coupled with tandem mass spectrometry. This assay gave a linear response from 1.3 to 135 ng/mL for 25(OH)D2 and 25(OH)D3 and the limit of quantitation (signal-to-noise ratio $ 10) was 1.3 ng/mL. The interassay coefficients of variation were 7.3% to 10.0% and 4.2% to 4.9% for 25(OH)D2 and 25(OH)D3, respectively. The specimens were collected and run at the end of the study; thus, they were not available to the participants or research team at each site.
Statistical Analysis Descriptive statistics, including mean and standard deviation for normally distributed variables, median and interquartile range (IQR) for skewed variables, and proportions for categorical variables, were used to characterize baseline participant characteristics and supplementation use at each visit. Two primary analyses were conducted. First, in the full cohort of participants, a multivariable logistic generalized estimating equation model was fit to identify determinants of supplementation use. Study visits after transplantation or initiation of dialysis were excluded. Because of concern for greater ascertainment of calciferol supplementation among participants at clinical centers using the DCMED form, we compared supplementation use before and after research coordinators from these sites were trained to use the DCMED form and to clinical centers using the CMED form. Using a piecewise logistic regression analysis, we found that neither the log odds of supplementation (P 5 .829) nor the rate of change in supplementation (P 5 .727) at DCMED centers increased more immediately after DCMED training than at CMED centers. Therefore, study visits after training were included, and sensitivity analyses excluding these visits did not alter results. Potential determinants of supplementation included age, sex, race, ethnicity, diabetes, socioeconomic status (income, education, and marital status), lifestyle variables (smoking, physical activity, and body mass index [BMI]), cause of CKD, proteinuria, eGFR, having seen a nephrologist before the baseline visit, calendar year, and study year. The second primary analysis was performed in the subset of the cohort that had both dose information and levels available. Spearman’s rank correlation coefficient (r) was used to separately assess the relationship between supplementation dose and 25(OH)D level for Black and nonBlack participants. Linear regression was used to examine the association between 25(OH)D level and calciferol supplementation dose, adjusted for determinants of 25(OH)D level, including age, sex, race, ethnicity, physical activity (a surrogate for sun exposure), BMI, diabetes, proteinuria, socioeconomic status, dietary vitamin D, and eGFR. Because 25(OH)D level was logarithmically transformed for anal-
ysis, results were presented as the percentage difference in predicted level compared with the reference category. The exponentiated regression coefficient for a particular covariate represents the ratio of 25(OH)D level for that category relative to the reference category. Analyses were performed using Stata, version 11.2 (College Station, TX), with 2-sided tests of hypotheses and a P value less than .05 as the criterion for statistical significance.
Results Trends in Vitamin D Supplementation Use Among All CRIC Participants The baseline characteristics of the 3,939 CRIC participants are summarized in Table 1. The median duration of follow-up was 5 (IQR 3-6) years with a total of 20,983 visits. Among all participants, rates of reported use of any product containing a calciferol increased dramatically according to calendar and study year (Fig. 1). Use increased with longer participation in CRIC, from 10% at the baseline visits to 44% at the 7-year visits. Similar trends were observed in analyses limited to the 708 participants with Table 1. Baseline Participant Characteristics of Full Cohort (N 5 3,939) Age (y) Male Black Diabetes Smoking Any intentional exercise Married eGFR (mL/min per 1.73 m2) .60 30-60 ,30 Proteinuria (g/24 h) ,1.5 $1.5 BMI (kg/m2) ,25 25 to ,30 30 to ,35 $35 Education Less than high school High-school graduate Some college College graduate Income #$20,000 $20,000-50,000 $50,000-100,000 .$100,000 Did not answer
60 (52, 66) 54.9% 42.1% 48.4% 13.1% 69.8% 54.8% 42.1 (32.6, 51.9) 10.3% 70.2% 19.5% 0.18 (0.07, 0.91) 81.6% 18.4% 30.9 (26.8, 36.1) 16.0% 28.6% 26.2% 29.3% 21.0% 18.8% 29.2% 31.0% 31.5% 24.4% 18.7% 10.0% 15.5%
BMI, body mass index; eGFR, estimated glomerular filtration rate. All characteristics were recorded at the participants’ baseline study visits, conducted from 2003 to 2008. Continuous variables are presented as median (interquartile range). Categorical variables are presented as percentages.
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Figure 1. Trends in calciferol supplementation use in the CRIC study over time. Patients reporting a calciferol-containing supplement on the CMED at 19,503 annual visits of the full cohort of CRIC participants from 2003 to 2011. CMED, Concomitant Medication form; CRIC, Chronic Renal Insufficiency Cohort.
7 years of follow-up. Supplementation increased with later calendar year, from 10% at visits in 2003 to 43% at visits in 2011. The increase was primarily driven by use of products containing ergocalciferol or cholecalciferol alone, whereas use of products containing calcium and calciferol increased less markedly (Fig. 2). Use of active vitamin D sterols remained stable at 2% to 3% over this same time period. The predominant formulation of calciferol switched from ergocalciferol (69.3% of supplements in 2003) to cholecalciferol (77.2% of supplements in 2010).
Predictors of Vitamin D Supplement Use Among All CRIC Participants The full cohort was used to identify predictors of supplementation use. The results of the multivariable logistic generalized estimating equation regression are shown in Table 2. Greater odds of supplementation were associated with older age, female gender, non-Black race, higher Table 2. Results of Multivariable Logistic Generalized Estimating Equation Model of Calciferol Supplementation Use Determinant
Figure 2. Trends in type of calciferol supplementation use. Patients reporting a calciferol-containing supplement on the CMED at 19,503 annual visits of the full cohort of CRIC participants from 2003 to 2011. CMED, Concomitant Medication form; CRIC, Chronic Renal Insufficiency Cohort.
Age (per 10 y) White race Female sex Married Education Less than high school High-school graduate Some college College graduate BMI (kg/m2) ,25 25 to ,30 30 to ,35 $35 Visit number Calendar year
OR (95% CI)
P
1.30 (1.23, 1.37) 1.54 (1.36, 1.74) 3.00 (2.66, 3.37) 1.15 (1.03, 1.29)
,.001 ,.001 ,.001 .016
1.0 (Reference) 1.51 (1.24, 1.84) 1.53 (1.28, 1.85) 1.77 (1.47, 2.14)
,.001 ,.001 ,.001
1.0 (Reference) 0.75 (0.64, 0.88) 0.72 (0.61, 0.85) 0.65 (0.55, 0.77) 1.12 (1.06, 1.18) 1.21 (1.15, 1.27)
,.001 ,.001 ,.001 ,.001 ,.001
BMI, body mass index; CI, confidence interval; OR, odds ratio. Data from full cohort (N 5 3,531) with a total of 19,019 annual visits and adjusted for clinical site.
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Table 3. Characteristics of Participants Enrolled in the Vitamin D Ancillary Study (n 5 1,155) Age (y) Male Black Diabetes Smoking Any intentional exercise Married eGFR (mL/min per 1.73 m2) .60 30-60 ,30 Proteinuria (g/24 h) ,1.5 $1.5 BMI (kg/m2) ,25 25 to ,30 30 to ,35 $35 Education Less than high school High-school graduate Some college College graduate Income #$20,000 $20,000-50,000 $50,000-100,000 .$100,000 Did not answer Visit calendar year 2008 2009 2010 Number of calciferolcontaining medications 0 1 2 3 4 Calciferol dose if taking $1 calciferolcontaining medications (IU/d) Dietary vitamin D intake (IU/d) 25(OH)D level (ng/mL) If taking 0 calciferolcontaining medications If taking $1 calciferolcontaining medications
64 (57, 70) 53.0% 35.5% 37.1% 7.5% 79.8% 61.6% 44.8 (33.8,54.8)
education level, married, and lower BMI. Visit number and calendar year were independent predictors. Having seen a nephrologist, stage and cause of CKD, degree of proteinuria, income level, reported exercise, and smoking status were not independent predictors.
25(OH)D Levels in a Subset of CRIC Participants Vitamin D levels and a detailed assessment of vitamin D intake were available in a subset of participants as part of a cross-sectional study of physical function and vitamin D status in CRIC. The characteristics of participants who completed this single visit are shown in Table 3. Overall, 524 (54.6%) of participants reported taking at least 1 product that contained ergocalciferol or cholecalciferol in the preceding 3 months. Many were taking more than 1 vitamin D product. Among participants who reported supplementation, the median dose was 500 (IQR 400-1000) IU/day. Figure 3 demonstrates the associations between 25(OH) D level and calciferol supplementation according to race. Dose category was positively associated with vitamin D level for Black (r 5 0.57, P ,.0001) and non-Black participants (r 5 0.45, P ,.0001). As expected, among participants taking 400 IU/day or less of calciferol, Black participants had significantly lower median 25(OH)D levels (19.3 ng/mL [IQR 13.5, 30.9]) compared with non-Black participants (31.6 ng/mL [IQR 22.8, 41.0]; P , .001). However, among participants taking more than 400 IU/ day, the race difference was not evident (P 5.17): the median 25(OH)D level was 42.0 ng/mL (IQR 35.2, 49.7) for non-Black and 40.5 ng/mL (IQR 32.3, 50.4) for Black participants. Overall, 11.2% of non-Black and 41.8% of Black
15.0% 66.5% 18.5% 0.16 (0.08, 0.63) 88.3% 11.72% 29.9 (26.1, 34.7) 18.5% 32.1% 25.6% 23.8% 7.1% 14.2% 29.2% 49.6% 12.9% 25.5% 28.1% 19.0% 14.6% 41.7% 57.1% 1.1%
45.4% 40.5% 12.3% 1.5% 0.4% 500 (400, 1000)
112 (72, 175) Black 16.9 (12.1, 26.3)
Non-Black 27.7 (20.6, 38.5)
35.4 (25.8, 45.5)
38.8 (32.2, 47.1)
BMI, body mass index; DCMED, Vitamin D Concomitant Medication form; eGFR, estimated glomerular filtration rate; 25(OH)D, 25hydroxyvitamin D. All characteristics were recorded at the participants’ vitamin D study visit (2008-2010) when augmented procedures and DCMED form were used to assess supplementation use. Continuous variables are presented as median (interquartile range). Categorical variables are presented as percentages.
Figure 3. Vitamin D level by reported daily supplement dosage for Black and non-Black participants. Data from 1,155 participants who completed a single study visit to obtain detailed vitamin D intake history at the time of physical function testing, collected using the DCMED. Dashed reference line at 20 ng/mL, below which is considered deficient. Spearman test for trend with P , .001 for Black and nonBlack participants. DCMED, Vitamin D Concomitant Medication form.
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participants had a deficient level (,20 ng/mL). However, among those taking any supplement, only 3.8% of nonBlack and 16.5% of Black participants were deficient whereas 22.7% of non-Black and 62.4% of Black participants not reporting supplement use were deficient. There was a significant dose response relationship between supplementation use and 25(OH)D level adjusted for race, season, diabetes, dietary vitamin D, proteinuria, and eGFR. The results of the linear regression model are presented in Table 4. The effect of supplementation (.400 IU/day) was greater than any other predictors in the model. There was a significant interaction between Black race and supplementation use as indicated by the relatively greater increase in level for each vitamin D dose among the Black participants. In contrast, there was no interaction between CKD stage or supplement type (calcium-containing vs. vitamin D alone) and supplementation dose in its association with 25(OH)D level. Physical activity, BMI, cause of CKD, sex, age, and smoking status were not independent predictors of 25(OH)D level. When total daily dose of calciferol was separated by formulation in this model, 1,000 IU of cholecalciferol
was associated with a 29.0% higher 25(OH)D level as compared with no supplementation (P , .001); 1,000 IU of ergocalciferol was associated with a 14.7% higher 25(OH)D level as compared with no supplementation (P 5 .008), consistent with a lower potency. When models were fit for 25(OH)D2 and 25(OH)D3 levels separately, greater daily cholecalciferol (D3) dose was associated with greater 25(OH)D3 levels (P , .001) whereas greater daily ergocalciferol (D2) dose was associated with greater 25(OH)D2 levels (P , .001).
Discussion Reported use of calciferol supplements increased markedly in the CRIC cohort over time, primarily because of increased use of single-nutrient products containing ergocalciferol or cholecalciferol. Supplementation was associated with markedly greater vitamin D levels, especially among Black participants. To our knowledge, this is the first study to examine trends in vitamin D supplementation in CKD and to relate supplement dose to vitamin D levels. These findings have important implications for future vitamin D intervention studies and for the interpretation
Table 4. Results of Linear Regression of 25(OH)D Levels (n 5 1,021) Determinant Vitamin D supplement (IU/d) 0 .0-400 .400-800 .800 Season Summer Winter Marital status Not married Married Dietary vitamin D (IU/d) ,200 $200 Diabetes No Yes Proteinuria (g/d) ,1.5 $1.5 eGFR (mL/min per 1.73 m2) .60 30-60 ,30 Serum albumin (mg/dL) ,3.5 $3.5 to ,4 $4
Relative Percent Change Compared With Reference Group (95% CI) Non-Black Reference 26.5% (16.9, 36.9)* 46.4% (32.3, 62.0)* 61.0% (47.6, 75.7)*
Black Reference 60.8% (43.8, 79.9)* 125.8% (92.2, 165.2)* 127.1% (96.9, 161.9)* Reference 211.1% (215.8, -6.1)* Reference 7.9% (2.1, 14.0)† Reference 7.7% (0.7, 15.2)† Reference 211.8% (216.5, 26.7)* Reference 217.9% (224.8, 210.3)* Reference 13.6% (5.4, 22.6)* 13.7% (3.2, 25.2)† Reference 10.6% (0.2, 22.1)† 20.8% (9.4, 33.3)*
CI, confidence interval; eGFR, estimated glomerular filtration rate; 25(OH)D, 25-hydroxyvitamin D. Data from subset cohort that completed a single vitamin D study visit, and augmented procedures were used to assess vitamin D supplement use (n 5 1,155). *P # .001. †P , .05.
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of observational studies of vitamin D levels and clinical outcomes in CKD. Specifically, the increasing prevalence of vitamin D supplementation in CKD patients may make it difficult to identify, and thus enroll, patients with deficient levels and to control the rates of supplementation use in a trial setting. Further, observational studies relying on a single vitamin D level may be affected by this increasing prevalence of supplementation use. The results of a recently published meta-analysis and accompanying editorial24,25 on vitamin D supplementation and fracture prevention in the general population highlight the importance of accounting for actual intake and baseline vitamin D status when trying to reconcile discordant results from clinical trials. There was a wide range of daily vitamin D dosage. The 2010 IOM report recommended 600 IU/day for people younger than 70 years of age and 800 IU/day for people older than 70 years of age with a maximum tolerated dose of 4,000 IU/day.2 Among CRIC participants taking a supplement, the median dose was 500 IU per day, and 1% of participants were taking 4,000 IU/day or more. Median dietary vitamin D intake was 112 IU/day and did not differ among those participants who were or were not taking a supplement. This is much lower than the median intake reported in the IOM report for the general population, which ranges from 272 to 396 IU/day depending on life stage and may be related to phosphorus restriction with consequent reductions in dairy intake. One could hypothesize that there would be minimal association between supplement dose and level in a cross-sectional analysis because patients would be a combination of those prescribed vitamin D because of severe deficiency with those who were taking a supplement regardless of level. However, our analysis reveals that supplement use was associated with significantly higher vitamin D levels, with a dose-response relationship, and had a stronger association than any other factor in the model. A recent study reported that supplementation use was an important predictor of vitamin D levels in a healthy, northern European population26; however, this had not been previously assessed in patients with CKD. Furthermore, this is the first study to examine racial differences in the relationship between vitamin D supplementation and levels. Longitudinal measures of vitamin D levels were not available to assess the response to supplementation or baseline levels. However, it was surprising to note that even modest doses of supplementation were associated with higher levels. Two large previous reports have demonstrated mixed results regarding the relationship between 25(OH)D levels and eGFR. Chonchol and colleagues analyzed data from the Third National Health and Nutrition Examination Survey and showed that 25(OH)D levels were low only among those with advanced CKD (eGFR 15-29 mL/min-
ute per 1.73 m2) after adjustment for age, sex, ethnicity, BMI, physical activity, intake of milk and vitamin D supplements, and season.5 However, in the Study to Evaluate Early Kidney Disease, Levin and colleagues reported no relationship between 25(OH)D level and eGFR after adjustment for age, gender, ethnicity, diabetes, urinary albumin, calcium, and phosphorus.27 Our study obtained detailed information regarding supplement use and dose, which we also demonstrated to be highly prevalent and an important predictor of level. Although unadjusted analysis suggested an association of lower 25(OH)D levels with lower eGFR, this association did not persist after adjusting for supplement use dosage, dietary intake, season, diabetes, and proteinuria. In fact, lower eGFR was associated with a slightly higher level in our full model. In this cross-sectional analysis, we were not able to assess changes in eGFR or changes in 25(OH)D level. A limitation of the study is reliance on self-report of supplementation use. However, review of reported calciferol supplement formulations over time revealed a switch from D2- (ergocalciferol) to D3 (cholecalciferol)-containing products, consistent with national trends among vitamin D supplement manufacturers.2 In addition, the strong association between reported supplementation and serum vitamin D levels as well as the association between reported vitamin D formulation and the respective D2and D3-specific levels provided additional evidence for the validity of the data. Self-report of ultraviolet sun exposure as a source of vitamin D was not directly collected, but season and activity level were included. Detailed information on calcium supplementation dose was also not available. Levels and dose information were only available for a subset of CRIC participants at selected clinical centers that used augmented techniques to collect information on supplementation use. All participants at these clinical centers were eligible to collect these supplemental data, and 86% did so. These high participation rates make selection bias unlikely. These study participants were somewhat healthier compared with the remainder of the CRIC cohort. This likely reflects survival to this later visit (87% of visits were performed 3-5 years after enrollment) and varying baseline participant characteristics of the participating clinical sites. Given that the primary goal was to relate supplement dose and vitamin D level, it is unlikely that these differences introduced a significant bias. Because detailed vitamin D dose information and 25(OH)D levels were available only at a single visit, our current data could not assess the longitudinal effect of vitamin D supplementation and changes in parathyroid hormone or other bone mineral metabolism laboratory values such as calcium and phosphorus. Future studies will be needed to assess this relationship as well as the association with clinical outcomes such as fracture.
VITAMIN D SUPPLEMENTATION IN CRIC
Practical Application This study revealed an increasing use of calciferol supplementation among participants in the CRIC study and that supplementation use was associated with greater 25(OH)D levels. Predictors of supplementation use included socioeconomic factors in addition to expected demographic factors. Given the recent call for interventional trials using nutritional vitamin D,2 these results demonstrate the challenges of completing these studies, especially because these participants are likely representative of other individuals who would be recruited for future clinical trials; specifically, a large and increasing proportion of CKD patients are taking vitamin D and that this supplementation use is associated with high levels.
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