Minerals, trace elements, Vit. D and bone health

Effects of high-dose cholecalciferol on serum markers of inflammation and immunity in patients with early chronic kidney disease

  • A Corrigendum to this article was published on 06 November 2013

Abstract

Background/objectives:

Vitamin D has anti-inflammatory and immune-regulating properties. We aimed to determine if high-dose cholecalciferol supplementation for 1 year in subjects with early chronic kidney disease (CKD) improved circulating markers of inflammation and immunity.

Subjects/methods:

In this double-blind, randomized, placebo-controlled trial, 46 subjects with early CKD (stages 2 and 3) were supplemented with oral cholecalciferol (50 000 IU weekly for 12 weeks followed by 50 000 IU every other week for 40 weeks) or a matching placebo for 1 year. Serum tumor necrosis factor-α, interleukin-6, monocyte chemoattractant protein-1 (MCP-1), interferon gamma-induced protein-10 and neutrophil gelatinase-associated lipocalin were measured at baseline, 12 weeks and 1 year. Serum cathelicidin (LL-37) was measured at baseline and 12 weeks. An in vitro experiment was performed to investigate the effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment on MCP-1 secretion in THP-1 monocytes activated with lipopolysaccharide (LPS) and Pseudomonas aeruginosa.

Results:

By 12 weeks, serum MCP-1 decreased in the cholecalciferol group (66.2±2.5 to 60.8±2.6 pg/ml, group-by-time interaction P=0.02) but was not different from baseline at 1 year. Other markers of inflammation and immunity did not change. In vitro, LPS- and Pseudomonas-activated monocytes treated with 1,25(OH)2D3 had significantly less MCP-1 secretion compared with untreated cells.

Conclusions:

High-dose cholecalciferol decreased serum MCP-1 concentrations by 12 weeks in patients with early CKD, although the decrease was not maintained for the remainder of the year. In vitro results confirm an MCP-1-lowering effect of vitamin D. Future studies should determine if vitamin D-mediated reductions in MCP-1 concentrations reflect improved clinical outcomes.

Introduction

Patients with chronic kidney disease (CKD) experience progressive impairment of vitamin D metabolism, thus increasing the risk for metabolic bone disease1 and possibly cardiovascular disease.2 A chronically activated and dysregulated immune system with accompanying elevated inflammatory mediators and biomarkers is also characteristic of CKD.3, 4 This sustained state of immune dysregulation and inflammation provides a pathological connection to the increased risk for both cardiovascular morbidity/mortality5 and infection-associated morbidity/mortality6 that occur with CKD. In vitro, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the hormonally active form of vitamin D3, has both anti-inflammatory and immune-regulating properties by decreasing the production of inflammatory cytokines7, 8 and by upregulating the production of the antimicrobial peptide, LL-37 or cathelicidin,9, 10 in a variety of cell types. Furthermore, vitamin D has been implicated in all-cause and cardiovascular mortality risk,11 as well as infectious mortality risk,12, 13 in CKD. Thus, achievement and maintenance of adequate vitamin D status may have a role in managing inflammation and immunity, and ultimately, reducing morbidity and mortality in patients with CKD. Few studies have investigated systemic effects of long-term vitamin D supplementation on markers of inflammation and innate immunity in patients with CKD. The purpose of this clinical study was to investigate whether high-dose cholecalciferol (vitamin D3) supplementation for 1 year improved circulating markers of inflammation and immunity in patients with early stage CKD.

Materials and methods

Subjects and protocol

The protocol for this double-blind, randomized, placebo-controlled study has been previously described.14 Briefly, inclusion for the study were ages 18–90 years and an estimated glomerular filtration rate <90 ml/min per 1.73 m2. Participants were excluded for use of active vitamin D analogs, calcimemetics or any other medication that may influence vitamin D metabolism; intake of >1000 IU vitamin D through supplements; history of liver failure, intestinal malabsorption or chronic diarrhea; and/or an elevated serum calcium (> 10.5 mg/dl, corrected for albumin). Forty-six patients with stages 2 and 3 CKD (based on estimated glomerular filtration rate of 60–89 ml/min per 1.73 m2 for CKD stage 2 and estimated glomerular filtration rate 30–59 ml/min per 1.73 m2 for stage 3, calculated using the Modification of Diet in Renal Disease Study equation15) were randomized to 50 000 IU cholecalciferol (vitamin D3, Tischon, Salisbury, MD, USA) weekly for 12 weeks followed by 50 000 IU cholecalciferol every other week for 40 weeks (vitamin D group) or matching placebo (Tischon). Participants were seen at baseline, 12 weeks and 52 weeks. Whole blood was collected, processed for serum and stored at −80 °C at each visit. This study was approved by the Emory Institutional Review Board and the VA Research and Development Committee, and all participants provided informed consent on enrollment. This trial is registered at Clinical Trials.gov # NCT00781417.

Analytic methods

Serum 25-hydroxyvitamin D (25(OH)D) was assayed using a chemiluminescent technique with an automated machine (Immunodiagnostic Systems iSYS automated machine; Fountain Hills, AZ, USA).14 Serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1; also known as chemokine (C-C motif) ligand 2, CCL2, or small-inducible cytokine A2), interferon gamma-induced protein-10 (IP-10; also known as C-X-C motif chemokine 10, CXCL10, or small-inducible cytokine B10) and neutrophil gelatinase-associated lipocalin (NGAL; also known as lipocalin-2 or oncogene 24p3) were assayed simultaneously under the same experimental ELISA conditions (DuoSet ELISA, R&D Systems, Minneapolis, MN, USA) following the manufacturer’s instructions. Serum LL-37 was assayed with ELISA (Hycult Biotech, Uden, The Netherlands). All samples were de-identified and assayed blindly in duplicate; values with a coefficient of variation >20% were excluded from analyses.

In vitro experiment: MCP-1 release from activated monocytes on 1,25(OH)2D3 treatment

The human monocytic cell line THP-1 was grown in RPMI 1640 medium (Cellgro Mediatech, Herdon, VA, USA) supplemented with 10% fetal bovine serum and 50 IU/ml of penicillin and 50 μg/ml of streptomycin as described.16 Confluent THP-1 cells were counted and adjusted to 1 × 106 cell/ml then transferred into a six-well tissue culture plate and treated with 4 μM 1,25 (OH)2D3 (Sigma, St Louis, MO, USA) for 48 h. Control cells were treated with equal volume of phosphate-buffered saline with 5% (v/v) ethanol. After 48 h of incubation at 37 °C with 5% CO2, treated and untreated THP-1 cells were stimulated with 10 pmol/ml (20 ng/ml) of purified lipopolysaccharide (LPS) derived from Pseudomonas aeruginosa (P. aeruginosa)17 or infected with P. aeruginosa at 10 multiplicity of infection then incubated overnight at 37 °C. For the infection assay, 1 ml of THP-1 monocyte culture was transferred into a 1.5 ml Eppendorf tube and infected with live P. aeruginosa strain PAO1 at 10 multiplicity of infection for 60 min. Infected monocytes were then spun down to remove bacteria followed by washing with phosphate-buffered saline. Infected monocytes were then resuspended in 1 ml RPMI 1640 medium supplemented with 10% fetal bovine serum, 50 IU/ml of penicillin, 50 μg/ml of streptomycin and 10 μg/ml of gentamycin, transferred into 24-well tissue culture plates, and incubated overnight at 37 °C with humidity and 5% CO2. Supernatants were collected for MCP-1 determination using ELISA (DuoSet ELISA, R&D Systems) method as described.17

Statistical analyses

Descriptive statistics are reported as mean±s.d. or median (interquartile range). T-tests, χ2 tests and analysis of covariance were used to determine differences between groups. Pearson correlations or Spearman correlations were used to investigate baseline relationships of serum 25(OH)D with serum markers of inflammation and immunity as well as relationships between percent change in serum 25(OH)D from baseline and percent change in serum markers of inflammation and immunity. Multiple linear regression analysis was used to investigate relationships independent of age, sex, body mass index and race. Paired t-tests or Wilcoxon signed-rank tests were used to determine changes in outcomes from baseline to 12 weeks and from baseline to 52 weeks for each treatment group. Mixed-model repeated measures analysis of variance and analysis of covariance were also used to investigate group-by-time interaction effects. A post hoc forward stepwise linear regression analysis was performed with MCP-1 as the dependent variable. Variables explored were age, sex, body mass index, race, hypertension, diabetes mellitus, 25(OH)D, parathyroid hormone and fibroblast growth factor-23. A P-value of 0.15 was set for variables to enter and exit the model. All analyses were based on intention-to-treat. Statistical analyses were performed with JMP (version 9.0.0; SAS Institute Inc., Cary, NC, USA); all tests were two-sided and assumed a 5% significance level.

Results

Clinical study

Participant characteristics of the cohort are described in Table 1. The majority of the participants were male, had hypertension, and had type 1 or type 2 diabetes mellitus. Baseline serum 25(OH)D and markers of inflammation and immunity within each treatment group are presented in Table 2. As previously reported, serum 25(OH)D was higher in the placebo group compared with the cholecalciferol group (32±9 vs 27±7 ng/ml, P=0.03), and the prevalence of type 2 diabetes mellitus was higher in the cholecalciferol group (86 vs 54%, P=0.02).14 All other characteristics were similar between the groups. Baseline serum concentrations of the measured markers of inflammation and immunity did not differ between groups.

Table 1 Participant characteristics at baseline (N=46)a
Table 2 Baseline serum 25(OH)D and markers of inflammation and immunity by treatmenta

Pearson correlation analysis indicated that baseline serum 25(OH)D from all study participants was significantly inversely associated with baseline serum MCP-1 (Figure 1). This relationship was independent of age, sex, body mass index and race, as determined by multiple linear regression (std β=−0.46, P=0.003). There was no significant relationship between baseline serum 25(OH)D and other serum markers of inflammation and immunity. In a post hoc forward stepwise linear regression analysis with MCP-1 as the dependent variable, both 25(OH)D (std β=−0.52, P<0.001) and fibroblast growth factor-23 (std β=0.33, P=0.01) emerged as significant, independent predictors of MCP-1.

Figure 1
figure1

Relationship between baseline MCP-1 and baseline 25(OH)D. Baseline concentrations of serum MCP-1 were significantly, inversely associated with baseline serum 25(OH)D in patients with early stage CKD (n=43).

The percent changes in 25(OH)D and markers of inflammation and immunity from baseline to 12 and 52 weeks, respectively, are presented in Table 3. By 12 weeks, there was a 6.5% increase in MCP-1 in the placebo group vs a 6.2% decrease in the cholecalciferol group (two group t-test, P=0.009). The percent change in serum 25(OH)D at 12 weeks was significantly associated with the percent change in MCP-1 at 12 weeks (r=−0.43, P=0.005, Figure 2). The group-by-time interaction for MCP-1 was statistically significant (P=0.02). The group-by-time interaction for MCP-1 remained significant (P=0.02) after adjusting for baseline 25(OH)D concentrations. There were no changes or group differences in TNF-α, IL-6, NGAL, IP-10 or LL-37 at 12 weeks. There were no changes or group differences in any of the measured markers of inflammation and immunity at 1 year.

Table 3 Percent changes in serum 25(OH)D and markers of inflammation and immunity from baseline at 12 weeks and 1 year among all subjectsa
Figure 2
figure2

Relationship between percent change in 25(OH)D and percent change in MCP-1 at 12 weeks. After receiving 50 000 IU cholecalciferol weekly for 12 weeks or matching placebo, the percent change in 25(OH)D was significantly, inversely associated with percent change in MCP-1 in patients with early stage CKD (n=37).

In vitro study

To confirm our in vivo observation that high-dose cholecalciferol reduces MCP-1 concentrations, we used THP-1 human monocytic cells in an in vitro 1,25(OH)2D3 treatment and activation study. In the THP-1 monocyte cells incubated with 4 μM 1,25(OH)2D3, the basal secretion of MCP-1 was 45±2 pg/ml compared with 49±2 pg/ml in untreated cells (P=0.13). Treatment of THP-1 monocytes with 4 μM of 1,25(OH)2D3 resulted in significantly less (P=0.047) MCP-1 secretion on activation with LPS, a Toll-like receptor-4 ligand, compared with LPS-activated cells not treated with 1,25(OH)2D3 (Figure 3a). Further, 1,25(OH)2D3-treated THP-1 monocytes exposed to live bacterial infection with P. aeruginosa had significantly (P=0.006) reduced levels of MCP-1 release compared with infected cells not treated with 1,25(OH)2D3 (Figure 3b).

Figure 3
figure3

1,25(OH)2D3 reduces MCP-1 release from activated monocytes. Human THP-1 monocyte cells were treated with 4 μM of 1,25(OH)2D3 for 48 h before activation with 10 pmol/ml of purified LPS (a) or infection with P. aeruginosa at 10 multiplicity of infection (b). MCP-1 release into the supernatants of activated monocytes was measured by enzyme-linked immunosorbent assay. Error bars represent±s.d. of triplicate readings of each sample. P-value was calculated using the Student t-test.

Discussion

In a randomized, placebo-controlled, double-blind study, we have shown that high-dose cholecalciferol supplementation reduced circulating serum concentrations of MCP-1 after 12 weeks in patients with early stage CKD, although effects were not maintained by 1 year, and changes were not shown in serum concentrations of TNF-α, IL-6, NGAL, IP-10 or LL-37. We have supplemented these clinical results with an in vitro experiment demonstrating that 1,25(OH)2D3 reduces secretion of MCP-1 by cells exposed to live bacteria and/or LPS. Our data support the hypothesis that vitamin D has an important role in regulating inflammatory and immune processes, especially with regards to chemokine secretion.

MCP-1 is a chemokine secreted by various cell types, including cells of the renal system.18, 19 It is involved in the development and progression of renal injury,19 circulating concentrations may predict cardiovascular outcomes20 and it is elevated during infection.21 MCP-1 may, therefore, be a potentially useful biomarker for clinical outcomes in CKD. The active form of vitamin D (1,25(OH)2D) has been shown in vitro to downregulate the secretion MCP-1 in various cell types, including preadipocytes,22 adipocytes,23 human annulus cells,24 mesangial cells,25 monocyte-derived dendritic cells26 and human primary proximal tubular epithelial cells.27 We confirm these findings in yet another cell type. Our results indicate that 1,25(OH)2D3 treatment directly impacts MCP-1 release from THP-1 monocytes and, therefore, exerts a modulatory effect on monocyte response to infection and inflammatory signals. Vitamin D may indirectly modulate MCP-1 secretion through inhibition of nuclear factor-κB activation.25 To our knowledge, we are the first to demonstrate an in vivo reduction in circulating MCP-1 concentrations in patients with CKD who were supplemented with high-dose cholecalciferol. We did not, however, find a change in the chemokine IP-10. Bischoff-Ferrari et al.28 recently reported a decrease in circulating serum markers of innate immunity, including MCP-1 and IP-10, in generally healthy postmenopausal women treated with cholecalciferol (800 IU) or 25(OH)D3 (20 μg) for 4 months. In contrast, Kim et al.29 did not find a change in urine MCP-1 after 4 months of cholecalciferol treatment (up to 40 000 IU per week) in patients with type 2 diabetic nephropathy, and Jorde et al.30 did not find a change in serum MCP-1 or other markers of inflammation after a 1-year trial of cholecalciferol (up to 40 000 IU per week) in overweight and obese participants. The varying results may reflect differences in study population. In our study of CKD patients, serum MCP-1 was decreased from baseline at 12 weeks but not at 1 year. This could be due to the fact that the vitamin D dose was reduced by 50% after 12 weeks or that the changes in MCP-1 incurred by vitamin D are acute and may not be sustained over the long term. Further study is required to determine if a reduction in serum MCP-1 via cholecalciferol treatment corresponds with clinical improvement in patients with early CKD.

We did not find any changes in the inflammatory cytokines, IL-6 or TNF-α after cholecalciferol supplementation. To our knowledge, these cytokines have not been previously investigated in regards to vitamin D supplementation in patients with early CKD. As studies in patients on hemodialysis have shown decreases in circulating IL-6 and TNF-α after cholecalciferol treatment,31, 32, 33 it is possible that changes in serum inflammatory biomarkers would be detected in populations with more chronically elevated inflammation, such as those on hemodialysis. In vitro studies have consistently shown 1,25(OH)2D3 to downregulate the production of inflammatory cytokines in cells exposed to various conditions.7, 8, 34 It is, therefore, also possible that the anti-inflammatory effects of vitamin D occur at the cellular level and may not be readily observed at the systemic level.

Vitamin D may have a role in the regulation of the immune system. Anti-microbial peptides such as LL-37 are upregulated in various cell types by 1,25(OH)2D3.9, 10 Activation of Toll-like receptors and T cells of the innate and acquired immune system by Mycobacterium tuberculosis results in upregulation of vitamin D receptor and 1-alpha hydroxylase and subsequent increased conversion of 25(OH)D to 1,25(OH)2D3 in macrophages, followed by production of LL-37.35, 36 These anti-microbial pathways are vitamin D dependent, as knockdown of vitamin D receptor and/or 1-alpha hydroxylase inhibits induction of LL-37.35, 36 Furthermore, production of LL-37 in sera from vitamin D-deficient individuals is blunted, and supplementation with 25(OH)D restores the response, suggesting that adequate circulating 25(OH)D is necessary for local production of calcitriol and subsequent upregulation of antimicrobial defenses by the immune system. Clinical intervention trials of vitamin D supplementation on infection prevention or treatment have provided both positive37, 38, 39 and null results.38, 40, 41 In our clinical trial, we did not find a change in serum LL-37 concentrations, nor did we find changes in serum NGAL, a protein with hypothesized antimicrobial properties that may also serve as a biomarker for acute renal injury.42 However, it is possible that changes would only be seen in states of acute infection or with concurrent Toll-like receptor activation,31 and our patient population of early CKD was too ‘healthy’ and did not have any active infection to observe any noticeable changes. Monocytic cells exposed to P. aeruginosa in our in vitro experiment decreased MCP-1 secretion after treatment with 1,25(OH)2D3. Jeng et al.43 reported a positive association between plasma LL-37 and 25(OH)D concentrations in critically ill patients with sepsis. In patients on dialysis, the use of active vitamin D therapy was associated with lower risk of peritonitis44 and lower infectious mortality.13 In Toll-like receptor-activated monocytes of relatively healthy patients, treatment with ergocalciferol significantly increased monocytic LL-37 expression.45 Thus, trials of cholecalciferol in CKD patients with a concurrent infection or a longer follow-up period may be warranted to investigate effects of vitamin D on the immune system in this population.

Strengths of the study include the double-blind, randomized, placebo-controlled design and the in vitro confirmation of a vitamin D effect on MCP-1 secretion. We are the first to investigate these serum biomarkers of inflammation and immunity following long-term cholecalciferol supplementation in early stage CKD. A limitation is that the study was not originally powered for these secondary endpoints. We also did not collect specific data on incidence or prevalence of chronic inflammatory conditions or infections. Although we did not find any effects of cholecalciferol supplementation on serum IL-6, TNF-α, IP-10, NGAL or LL-37 in this population, circulating concentrations may not reflect anti-inflammatory and immune responses to vitamin D at the local cellular level. Other circulating markers of inflammation, such as C-reactive protein, which was not measured, may have responded to cholecalciferol supplementation.33 Finally, our findings may not be generalizable to a healthy population.

Conclusion

High-dose cholecalciferol supplementation reduced serum MCP-1 concentrations in patients with early CKD. Furthermore, 1,25(OH)2D3 decreased secretion of MCP-1 from LPS-stimulated monocytic cells in vitro. These data indicate a role of vitamin D and the maintenance of adequate vitamin D status in the regulation of immune-mediated processes.

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Acknowledgements

We thank Breanne Wright, Shabnan Seydafkan, Meena Kumari, Lynn Schlanger and Peggy Jenkins for their research coordinating support, and we thank Sarthak Khare for his assistance in sample preparation. Sources of support for this study include grants from the National Institutes of Health (K23AR054334 (VT), T32DK007298-32S1 (JAA), UL1 RR025008 (TRZ, VT) and K24 RR023356 (TRZ)), the Atlanta Research and Education Foundation (VT) and the Emory-Egleston Children’s Research Center (SMZ).

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Correspondence to V Tangpricha.

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Alvarez, J., Zughaier, S., Law, J. et al. Effects of high-dose cholecalciferol on serum markers of inflammation and immunity in patients with early chronic kidney disease. Eur J Clin Nutr 67, 264–269 (2013). https://doi.org/10.1038/ejcn.2012.217

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Keywords

  • vitamin D
  • cytokines
  • cathelicidin
  • monocyte chemoattractant protein-1
  • chronic kidney disease
  • inflammation

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