ORIGINAL RESEARCH

Prevalence of Vitamin D Deficiency and Effects of Supplementation With Cholecalciferol in Patients With Chronic Kidney Disease Sun Moon Kim, MD, PhD,* Hyung Jin Choi, MD, PhD,* Jung Pyo Lee, MD, PhD,†,‡ Dong Ki Kim, MD, PhD,† Yun Kyu Oh, MD, PhD,†,‡ Yon Su Kim, MD, PhD,† and Chun Soo Lim, MD, PhD†,‡ Objective: We aimed to evaluate the vitamin D status, the effect of cholecalciferol supplementation, and the factors associated with vitamin D restoration in nondialytic patients with chronic kidney disease (CKD). Design: The present study was a prospective open-label trial. Setting: This study took place at the Seoul National University Boramae Medical Center. Subjects: Patients with nondialytic CKD (estimated glomerular filtration rate [eGFR] 10-59 mL/min per 1.73 m2) participated in this study. Intervention: Vitamin D status in 210 CKD patients was assessed and the patients with vitamin D deficiency (,30 ng/mL) were administered cholecalciferol (1,000 IU/day) for 6 months. Main Outcome Measure: The restoration rate of vitamin D deficiency at 3 and 6 months and the response-related factors were analyzed. Results: The prevalence of vitamin D deficiency was 40.7% in CKD Stage 3, 61.5% in Stage 4, and 85.7% in Stage 5. The subgroup with vitamin D deficiency had a greater proportion of patients with diabetes, lower eGFR, and higher proteinuria. With the supplementation, 52 patients (76.5%) reached levels of 25-hydroxy vitamin D (25(OH)D) of 30 ng/mL or greater at 3 months, and the restoration of vitamin D was observed in 61 patients (89.7%) at 6 months. Lower levels of 25(OH)D and a higher amount of proteinuria at baseline were the factors associated with lower response to vitamin D supplementation. Conclusion: Vitamin D deficiency rate was high in nondialytic CKD patients, and the proportion increased as renal function decreased. A higher amount of proteinuria was the independent risk factor of nonresponse with supplementation. Vitamin D was replenished in most patients with cholecalciferol supplementation without any significant adverse effects. Ó 2014 by the National Kidney Foundation, Inc. All rights reserved.

Introduction

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ITAMIN D DEFICIENCYand other disorders in calcium and phosphorus homeostasis are common at all stages of chronic kidney disease (CKD). A recent crosssectional study has shown that up to 80% of nondialytic patients with CKD are vitamin D insufficient.1 The prevalence of vitamin D deficiency increased significantly from one CKD stage to the next.1,2 The reasons for the high prevalence of vitamin D deficiency in the CKD *

Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea. † Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea. ‡ Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Chun Soo Lim, MD, PhD, Department of Internal Medicine, Seoul National University Boramae Medical Center, 20 Boramae-ro 5-gil, Dongjak-gu, Seoul 156-707, Korea. 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.2013.07.003

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population are not clear. Multifactorial mechanisms may be involved: increased proteinuria causing loss of urinary vitamin D binding protein (VDBP), uremic epidermis impairing the photoproduction of vitamin D, inadequate sun exposure, and a poor diet intake.3-6 The accumulated evidence from epidemiological and experimental research suggests that vitamin D is integral not only for its classical effects on the skeletal system, but also for its extraskeletal benefits such as those on cardiovascular health, muscle, and immune function.7,8 Moreover, lower circulating 25-hydroxy vitamin D (25(OH)D) concentrations were associated with higher all-cause mortality risk in all stages of CKD.9 In this regard, guidelines on the management of CKD-related bone and mineral disorders point out the importance of treating hypovitaminosis D,3,10 and the National Kidney Foundation guidelines state that optimal 25(OH)D levels should be greater than 30 ng/mL.3 Although an increasing number of studies on vitamin D supplementation in CKD have been conducted in recent years, evidence is still lacking in several aspects— namely, a protocol of treatment to restore vitamin D status with the greatest benefit for the patients. Moreover, the

Journal of Renal Nutrition, Vol 24, No 1 (January), 2014: pp 20-25

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CHOLECALCIFEROL SUPPLEMENTATION IN CKD

potential factors that may influence the response to vitamin D supplementation in CKD patients and the effect of replenishing vitamin D on outcomes have been poorly investigated. In the present study, we aimed (1) to evaluate the prevalence of vitamin D deficiency in nondialytic patients with CKD, (2) to examine the effectiveness of cholecalciferol supplementation in the restoration of vitamin D status, and (3) to investigate the factors that affect the response to treatment.

Methods Subjects Between July 2011 and September 2011, 521 patients with nondialytic CKD visited outpatient clinics of Seoul National University Boramae Medical Center (Seoul, Republic of Korea), and 210 patients among them underwent an assessment of vitamin D status. These patients were mainly from an urban population of Seoul. Inclusion criteria were being 18 years of age or older and having an estimated glomerular filtration rate (eGFR) between 10 and 59 mL/min per 1.73 m2 as calculated by the 4-variable Modification of Diet in Renal Disease study equation. Patients were excluded if the serum-corrected calcium level was greater than 10.0 mg/dL, if intact parathyroid hormone (iPTH) was greater than 600 pg/mL, if they had used any type of vitamin D compounds in the previous 3 months, or if their renal function was not in a steady state at baseline. In addition, patients with a kidney transplant, active systemic inflammation, active liver disease, or malignancy within the previous 5 years were excluded. Study Design and Variables This study was a 6-month prospective interventional study. The patients with vitamin D deficiency (25(OH)D , 30 ng/mL) received oral supplementation of cholecalciferol (1,000 IU/day) for 6 months. Mandatory clinical evaluation and laboratory tests of the following were performed at 0, 3, and 6 months: 25(OH)D, iPTH, serum calcium, phosphorus, albumin, creatinine, hemoglobin (Hb), and urinary protein-to-creatinine ratio. The patients were discontinued from the study if their serum-corrected calcium concentration was greater than 10.5 mg/dL, if 25(OH)D was greater than 150 ng/mL, or if they started renal replacement therapy. This study was approved by the Institutional Review Board of Boramae Medical Center, and informed consent was obtained from each patient. Statistical Analysis Data are presented as mean 6 standard deviation. The levels of proteinuria were log-transformed given the large range of values; thus, they are presented as median (interquartile range). The final analysis included the patients who completed the 6-month follow-up. The c2 test for comparison of categorical variables and independent t test for continuous variables were used to assess statistical

significance in serum 25(OH)D subgroups ($30 vs. , 30 ng/mL). Changes in continuous variables from the baseline within a group were evaluated using the paired t test. Pearson’s linear correlation coefficients were calculated to evaluate the associations among changes of variables. The c2 test and independent t test were performed to compare the baseline characteristics between nonresponder patients, defined as those who had not achieved serum 25(OH) D 30 ng/mL or greater after 6 months of 1,000-IU/day cholecalciferol supplementation, and the responders (25(OH)D $ 30 ng/mL). Using the variables that were significantly different between the groups (nonresponders vs. responders) and adjusting for known factors that interfere with the response (age, sex, and eGFR), a multiple logistic regression analysis was performed using the groups as the dependent variable. All analyses were conducted using SPSS for Windows version 17.0 (SPSS Inc., Chicago, IL), and P values less than .05 were considered statistically significant. Additional statistical analyses using Bonferroni correction were applied to adjust for multiple testing.

Results Of a total of 210 patients assessed for vitamin D status, 13 patients were excluded because their renal function was not at a steady state (5 patients) or because they refused informed consent (8 patients, Fig. 1). Clinical and laboratory characteristics are listed in Table 1. The mean patient age was 65.1 years, and 114 (57.9%) were men. Diabetic nephropathy, hypertensive nephrosclerosis, and primary glomerulonephritis were the main causes of CKD (39.6%, 31.5%, and 17.8%, respectively). Vitamin D deficiency, defined as serum 25(OH)D less than 30 ng/mL, was found in 100 patients (50.8%). The prevalence of vitamin D deficiency was 40.7% in CKD Stage 3, 61.5% in Stage 4, and 85.7% in Stage 5. The subgroup with vitamin D deficiency had a greater proportion of patients with

Figure 1. Flow diagram of patients enrolled in the study.

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KIM ET AL

Table 1. Baseline Characteristics in Serum 25(OH)D Subgroups

Age (y) Gender (% male) Diabetes (%) Hypertension (%) Heart failure (%) Stroke (%) RAAS inhibitor (%) Hb (g/dL) Creatinine (mg/dL) eGFR (mL/min per 1.73 m2) Proteinuria (g/g) cCalcium (mg/dL) Phosphorus (mg/dL) Alkaline phosphatase (IU/L) 25(OH)D (ng/mL) iPTH (pg/mL)

Total (n 5 197)

,30 ng/mL (n 5 100)

$30 ng/mL (n 5 97)

P , 30 vs. $ 30

65.1 6 11.8 57.9 44.2 85.3 8.6 15.2 82.2 11.38 6 1.76 2.19 6 0.93 33.65 6 12.43 0.62 (0.12, 1.45) 8.73 6 0.49 3.64 6 0.70 88.3 6 32.3 35.76 6 23.99 81.3 6 70.8

65.0 6 12.2 55.0 57.0 87.0 8.0 17.0 85.0 10.74 6 1.51 2.43 6 1.03 29.87 6 11.67 1.00 (0.21, 1.85) 8.64 6 0.54 3.80 6 0.75 92.6 6 30.6 18.79 6 6.28 97.0 6 84.6

65.1 6 11.4 60.8 30.9 83.5 9.3 13.4 79.4 12.04 6 1.75 1.94 6 0.74 37.54 6 12.05 0.31 (0.33, 1.04) 8.82 6 0.43 3.47 6 0.62 83.9 6 33.6 53.25 6 22.92 65.2 6 48.3

.985 .408 ,.001 .489 .749 .482 .302 ,.001 ,.001 ,.001 .002 .011 .001 .059 ,.001 .001

cCalcium, corrected calcium; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; 25(OH)D, 25-hydroxy vitamin D; iPTH, intact parathyroid hormone; RAAS, renin-angiotensin-aldosterone system. Values are mean 6 standard deviation or median (interquartile range). Results are of c2 test or independent t test.

diabetes, lower eGFR, and higher proteinuria compared with the subgroup without vitamin D deficiency (Table 1). Eighty-three patients started cholecalciferol supplementation (1,000 IU/day), and 15 patients were dropped out during the study period: 2 patients began renal replacement therapy, 1 patient died, 6 patients discontinued cholecalciferol supplementation, and 6 patients were lost to follow-up during the study period. The remaining 68 patients completed a 6-month follow-up. The laboratory parameters during the follow-up are summarized in Table 2. There was a significant increase in 25(OH)D levels at 3 and 6 months when compared with those values at baseline. At 3 months, 52 patients (76.5%) reached levels of 25(OH)D of 30 ng/mL or greater, and at 6 months restoration of vitamin D was observed in 61 patients (89.7%). Corrected calcium significantly increased whereas iPTH showed a decreasing tendency at 6 months. We performed additional analysis with Bonferroni correction. The

changes in corrected calcium, alkaline phosphatase, and 25(OH)D were significant even after stringent Bonferroni correction (0.003 5 0.05/18). The changes in other parameters were not significant after Bonferroni correction. To investigate the factors associated with poor response to cholecalciferol therapy, baseline characteristics of the patients who restored 25(OH)D to normal levels (responders) were compared with those who did not normalize vitamin D status (nonresponders) after 3 and 6 months. At 3 months, the nonresponder group had a lower Hb (nonresponders vs. responders: 10.16 6 1.31 g/dL vs. 11.07 6 1.51 g/dL; P 5 .033) and lower vitamin D (nonresponders vs. responders: 15.08 6 5.62 ng/mL vs. 20.51 ng/mL 6 5.43 ng/mL; P 5.001) at baseline. The multivariate logistic regression analysis showed initial lower levels of 25(OH)D as the independent factor associated with lower response to vitamin D supplementation for 3 months. At 6 months, the nonresponder group had lower Hb, higher levels of

Table 2. Laboratory Findings During the Follow-Up (n 5 68)

Hb (g/dL) Creatinine (mg/dL) eGFR (mL/min per 1.73 m2) Proteinuria (g/g) cCalcium (mg/dL) Phosphorus (mg/dL) Alkaline phosphatase (IU/L) 25(OH)D (ng/mL) iPTH (pg/mL)

Baseline

Month 3

Month 6

P 0 mo vs. 3 mo

P 0 mo vs. 6 mo

10.85 6 1.50 2.43 6 0.85 29.07 6 10.43 1.15 (0.59, 2.02) 8.61 6 0.51 3.84 6 0.78 92.0 6 28.2 19.23 6 5.91 94.2 6 91.5

10.98 6 1.42 2.45 6 0.85 29.11 6 11.23 1.15 (0.51, 2.28) 9.05 6 0.50 3.66 6 0.72 85.2 6 25.8 42.57 6 18.84 85.2 6 108.8

11.06 6 1.40 2.66 6 0.18 27.28 6 11.01 1.02 (0.53, 2.72) 9.13 6 0.61 3.78 6 0.81 80.5 6 23.0 52.28 6 22.67 75.7 6 90.1

.258 .739 .963 .561 ,.001 .048 .005 ,.001 .167

.145 .011 .030 .387 ,.001 .448 ,.001 ,.001 .022

cCalcium, corrected calcium; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; 25(OH)D, 25-hydroxy vitamin D; iPTH, intact parathyroid hormone. Values are mean 6 standard deviation or median (interquartile range). Results are of paired t test.

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CHOLECALCIFEROL SUPPLEMENTATION IN CKD Table 3. Baseline Characteristics of the Patients According to Restoration of Vitamin D Status at 6 mo

Age (y) Gender (% male) Diabetes (%) Hypertension (%) Hb (g/dL) eGFR (mL/min per 1.73 m2) Proteinuria (g/g) cCalcium (mg/dL) Phosphorus (mg/dL) Alkaline phosphatase (IU/L) 25(OH)D (ng/mL) iPTH (pg/mL)

Nonresponders (n 5 7)

Responders (n 5 61)

P

60.0 6 12.8 71.4 85.7 71.4 9.60 6 0.86 27.42 6 10.27 3.01 (1.64, 10.88) 8.37 6 0.72 4.33 6 0.69 93.6 6 25.8 14.04 6 5.25 142.9 6 81.8

62.8 6 12.5 55.7 57.4 90.2 11.00 6 1.50 29.26 6 10.51 1.06 (0.46, 1.95) 8.64 6 0.48 3.79 6 0.77 91.8 6 28.7 19.83 6 5.72 88.6 6 91.4

.582 .355 .148 .188 .019 .661 .008 .188 .081 .874 .013 .138

cCalcium, corrected calcium; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; 25(OH)D, 25-hydroxy vitamin D; iPTH, intact parathyroid hormone. Values are mean 6 standard deviation or median (interquartile range). Results are of c2 test or independent t test.

urinary protein excretion, and lower vitamin D at baseline (Table 3). There was no difference in baseline eGFR between the nonresponder group and the responder group. The multivariate logistic regression analysis pointed out the higher amount of proteinuria as the main factor associated with lower response to vitamin D supplementation for 6 months (Table 4). The correlations among changes of 25(OH)D, iPTH, and other parameters are shown in Table 5. Changes in 25(OH)D were correlated with changes in eGFR at 3 months; however, this correlation was not maintained at 6 months. Changes of corrected calcium, phosphorus, and iPTH were not related to 25(OH)D changes. Changes of iPTH were significantly correlated with changes of phosphorus and negatively correlated with those of corrected calcium. In addition, there were significant correlations among changes of eGFR, corrected calcium, and phosphorus. Except for 1 patient who was withdrawn from the study because of hypercalcemia in the fourth month of supplementation (serum-corrected calcium of 11.6 mg/dL and Table 4. Multivariate Analysis of Risk of Nonresponse to Cholecalciferol Supplementation at 6 mo

Model 1 Age Gender (male) Hb eGFR Proteinuria* 25(OH)D Model 2 Hb Proteinuria* 25(OH)D

Odds Ratio

P

95% CI

0.996 1.934 0.591 0.962 13.134 0.894

.941 .562 .351 .549 .047 .283

0.904-1.098 0.209-17.857 0.196-1.785 0.848-1.092 1.032-167.204 0.729-1.097

0.641 15.040 0.894

.345 .026 .283

0.255-1.611 1.376-164.370 0.729-1.097

CI, confidence interval; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; 25(OH)D, 25-hydroxy vitamin D. Data are done by using logistic regression analysis. *Proteinuria values were log-transformed.

25(OH)D of 41.6 ng/mL), no other adverse effects were observed during the study period.

Discussion In the present study, we found that cholecalciferol supplementation (1,000 IU/day) was safe and effective in restoring vitamin D to nondialytic CKD patients. At 3 months, 76.5% of patients reached levels of 25(OH)D of 30 ng/mL or greater, and 89.7% reached this level at 6 months. In addition, cholecalciferol supplementation resulted in a decrease of iPTH levels and an increase of corrected calcium levels. Three months of cholecalciferol treatment could not increase blood 25(OH)D levels up to a normal range in some patients with low baseline 25(OH)D. However, 6 months of cholecalciferol treatment successfully normalized blood 25(OH)D levels in most patients. Heavy proteinuria was the main factor associated with nonresponsiveness after 6 months of therapy. Although much has been studied about the risk factors of hypovitaminosis D in CKD patients,11 there have been few studies about the factors influencing the effect of vitamin D supplementation. Garcia-Lopes and colleagues12 investigated the effect of ergocalciferol therapy on the response of vitamin D and iPTH in 45 patients with nondialytic CKD. The study pointed out increased adiposity (high body mass index [BMI] or high truncal fat index) as the main factor associated with lower response to vitamin D supplementation. Serum creatinine, urinary protein excretion, or vitamin D level at baseline did not influence the effect of vitamin D supplementation in the study.12 Obesity has been established as a risk factor of vitamin D deficiency in the general population and in CKD patients.6,13 Because vitamin D, either produced in skin or provided in the diet, may be sequestered by the adipose tissue, it is expected that oral cholecalciferol is also captured by the adipose tissue cells.14 In the study of Garcia-Lopes and colleagues,12 75% of participants showed a BMI greater than 27 kg/m2. Considering Asians have a relatively low BMI, the results

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Table 5. Correlation Among Change of 25(OH)D, iPTH, and Other Parameters After Cholecalciferol Treatment Change of 25(OH)D (ng/mL)

Change of eGFR (mL/min per 1.73 m2) Change of cCalcium (mg/dL) Change of phosphorus (mg/dL) Change of 25(OH)D (ng/mL) Change of iPTH (pg/mL)

Change of iPTH (pg/mL)

Month 3

Month 6

Month 3

Month 6

0.385 (.001) 0.066 (.592) 0.009 (.944) – 20.082 (.505)

20.090 (.464) 0.097 (.432) 0.101 (.412) – 0.188 (.124)

20.140 (.255) 0.093 (.453) 0.330 (.006) 20.082 (.505) –

20.201 (.101) 20.353 (.003) 0.387 (.001) 0.188 (.124) –

cCalcium, corrected calcium; eGFR, estimated glomerular filtration rate; 25(OH)D, 25-hydroxy vitamin D; iPTH, intact parathyroid hormone. Data are correlation coefficients with P value in parentheses. Results are of Pearson’s linear correlation test.

might be different among various ethnic groups. We did not check BMI in this study. In the present study, baseline vitamin D level was the principal factor to determine nonresponsiveness at 3 months whereas most of patients replenished vitamin D regardless of baseline level at 6 months. Thus, patients whose vitamin D level is low (,15-20 ng/mL) must be treated with vitamin D supplementation more than 6 months. In addition, proteinuria was the main risk factor of vitamin D nonresponsiveness at 6 months. Patients with heavy proteinuria had a risk of vitamin D deficiency (25(OH)D , 30 ng/mL) although cholecalciferol was supplemented. Taking into consideration that patients with heavy proteinuria had vitamin D deficiency partly because of urinary loss of VDBP,3,4 those patients with heavy proteinuria might have poor vitamin D restoration with cholecalciferol supplementation. Although a recent study showed that nutritional vitamin D as well as active vitamin D had an antiproteinuric effect,15 this study could not confirm the findings, which might be due to the diverse underlying diseases of the study population and various amount of proteinuria. In our study, a decrease in iPTH was observed after 6 months of cholecalciferol therapy. The improvement in secondary hyperparathyroidism by increasing 25(OH)D levels has been demonstrated in some16,17 but not in all studies18 of CKD patients. There are several reasons speculated for these conflicting results: the difference of iPTH levels in the study population, the difference of vitamin D supplementation protocol, and the degree of restoration of vitamin D status. The mechanism involved in the decrease in PTH at 3 months is difficult to clearly identify because of multiple interactions among markers of mineral metabolism. In our study, changes of iPTH were not related to 25(OH)D changes, but serum calcium appeared to influence the decrease in iPTH. Therefore, we could assume that the effect of cholecalciferol supplementation on iPTH was caused indirectly by increasing intestinal calcium absorption. Indeed, it is well known that calcium, as well as vitamin D, is a potent regulator of iPTH. However, in the previous studies,17,18 the level of calcium was not increased with the vitamin D supplementation. These contrary findings should be elucidated by a large-scale controlled trial.

The regimen of cholecalciferol (1,000 IU/day) was quite safe. A corrected serum calcium increase above 10.5 mg/dL only occurred in 1 of 197 patients. A previous study19 reported low prevalence of hypercalcemia or hyperphosphatemia when administering cholecalciferol or ergocalciferol in contrast to active vitamin D analogs. It is interesting to note that active vitamin D has been shown to be associated with the risk of cardiovascular disease in patients with childhood-onset end-stage renal disease, but nutritional vitamin D has not.20,21 In conclusion, approximately half of nondialytic CKD patients had vitamin D deficiency, and the proportion increased as renal function decreased. We demonstrated that the cholecalciferol regimen of daily 1,000 IU for 6 months was safe and effective in restoring vitamin D status in most patients. Although low vitamin D level at baseline was a risk factor for nonresponse at 3 months, vitamin D levels reached a target level in most of the patients after a 6-month supplementation. Considering the high burden of risk factors associated with bone and mineral disturbances among CKD patients, these results can contribute to assisting clinicians in the management of vitamin D deficiency in CKD patients.

Practical Application Hypovitaminosis D is highly prevalent among patients with nondialytic CKD. A dose of 1,000 IU of cholecalciferol is safe and sufficient to correct 25(OH)D deficiencies in most CKD patients.

Acknowledgments This work was supported by clinical collaborative research grants from the Seoul National University Boramae Medical Center (06-2009-35).

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CHOLECALCIFEROL SUPPLEMENTATION IN CKD 4. National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42(suppl 3):S1-S201. 5. Cheriet S, Royer M, Rajzbaum G, Tremollieres F. Vitamin D supplementation in patients with chronic kidney disease. Joint Bone Spine. 2012;79(suppl 2):S110-S113. 6. Figuiredo-Dias V, Cuppari L, Garcia-Lopes MG, de Carvalho AB, Draibe SA, Kamimura MA. Risk factors for hypovitaminosis D in nondialyzed chronic kidney disease patients. J Ren Nutr. 2012;22:4-11. 7. Judd SE, Tangpricha V. Vitamin D therapy and cardiovascular health. Curr Hypertens Rep. 2011;13:187-191. 8. Kamen DL, Tangpricha V. Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity. J Mol Med (Berl). 2010;88:441-450. 9. Pilz S, Iodice S, Zittermann A, Grant WB, Gandini S. Vitamin D status and mortality risk in CKD: a meta-analysis of prospective studies. Am J Kidney Dis. 2011;58:374-382. 10. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. 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;76:S1-S130. 11. Cuppari L, Garcia-Lopes MG. Hypovitaminosis D in chronic kidney disease patients: prevalence and treatment. J Ren Nutr. 2009;19:38-43. 12. Garcia-Lopes MG, Pillar R, Kamimura MA, et al. Cholecalciferol supplementation in chronic kidney disease: restoration of vitamin D status and impact on parathyroid hormone. Ann Nutr Metab. 2012;61:74-82. 13. Vilarrasa N, Maravall J, Estepa A, et al. Low 25-hydroxyvitamin D concentrations in obese women: their clinical significance and relationship

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with anthropometric and body composition variables. J Endocrinol Invest. 2007;30:653-658. 14. Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr. 2000;72:690-693. 15. Kim MJ, Frankel AH, Donaldson M, et al. Oral cholecalciferol decreases albuminuria and urinary TGF-b1 in patients with type 2 diabetic nephropathy on established renin-angiotensin-aldosterone system inhibition. Kidney Int. 2011;80:851-860. 16. Al-Aly Z, Qazi RA, Gonzalez EA, Zeringue A, Martin KJ. Changes in serum 25-hydroxyvitamin D and plasma intact PTH levels following treatment with ergocalciferol in patients with CKD. Am J Kidney Dis. 2007;50:59-68. 17. Zisman AL, Hristova M, Ho LT, Sprague SM. Impact of ergocalciferol treatment of vitamin D deficiency on serum parathyroid hormone concentrations in chronic kidney disease. Am J Nephrol. 2007;27:36-43. 18. Chandra P, Binongo JN, Ziegler TR, et al. Cholecalciferol (vitamin D3) therapy and vitamin D insufficiency in patients with chronic kidney disease: a randomized controlled pilot study. Endocr Pract. 2008;14:10-17. 19. Kandula P, Dobre M, Schold JD, Schreiber MJ Jr, Mehrotra R, Navaneethan SD. Vitamin D supplementation in chronic kidney disease: a systematic review and meta-analysis of observational studies and randomized controlled trials. Clin J Am Soc Nephrol. 2011;6:50-62. 20. Oh J, Wunsch R, Turzer M, et al. Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure. Circulation. 2002;106:100-105. 21. Briese S, Wiesner S, Will JC, et al. Arterial and cardiac disease in young adults with childhood-onset end-stage renal disease-impact of calcium and vitamin D therapy. Nephrol Dial Transplant. 2006;21:1906-1914.

Prevalence of vitamin D deficiency and effects of supplementation with cholecalciferol in patients with chronic kidney disease.

We aimed to evaluate the vitamin D status, the effect of cholecalciferol supplementation, and the factors associated with vitamin D restoration in non...
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