The immunoregulatory function of vitamin D: Implications in chronic kidney disease

Nature Reviews Nephrology

Volumn 8, Issue 7, 2012, Pages 403-412

  Sterling, Kevin A ^a   Eftekhari, Parham ^a   Girndt, Matthias ^b   Kimmel, Paul L ^a   Raj, Dominic S ^a  

^a GEORGE WASHINGTON UNIVERSITY SCHOOL OF MEDICINE AND HEALTH SCIENCES   (United States)

^b MARTIN LUTHER UNIVERSITY HALLE WITTENBERG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

25 HYDROXYVITAMIN D; CALCITRIOL; COLECALCIFEROL; ERGOCALCIFEROL; VITAMIN D;

ADAPTIVE IMMUNITY; CHRONIC KIDNEY DISEASE; HUMAN; IMMUNOREGULATION; INFECTION; INNATE IMMUNITY; KIDNEY FAILURE; MORTALITY; PRIORITY JOURNAL; REVIEW; VITAMIN D DEFICIENCY; ZINC DEFICIENCY;

HUMANS; RENAL INSUFFICIENCY, CHRONIC; RISK FACTORS; SIGNAL TRANSDUCTION; VITAMIN D; VITAMIN D DEFICIENCY;

EID: 84862888280     PISSN: 17595061     EISSN: 1759507X     Source Type: Journal    
DOI: 10.1038/nrneph.2012.93     Document Type: Review

References (135)

1. US Renal Data System. USRDS 2010 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States [online], http://www.usrds.org/atlas10.aspx (2010).
2. Crews, D. C. et al. Prevalence of chronic kidney disease in persons with undiagnosed or prehypertension in the United States. Hypertension 55, 1102-1109 (2010).
3. de Boer, I. H. et al. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA 305, 2532-2539 (2011).
4. Tonelli, M. et al. Chronic kidney disease and mortality risk: a systematic review. J. Am. Soc. Nephrol. 17, 2034-2047 (2006). (Pubitemid 44036188)
5. Kimmel, P. L. et al. Immunologic function and survival in hemodialysis patients. Kidney Int. 54, 236-244 (1998). (Pubitemid 28288040)
6. Kato, S. et al. Aspects of immune dysfunction in end-stage renal disease. Clin. J. Am. Soc. Nephrol. 3, 1526-1533 (2008).
7. Jaber, B. L. Bacterial infections in hemodialysis patients: pathogenesis and prevention. Kidney Int. 67, 2508-2519 (2005). (Pubitemid 41623423)
8. Vanholder, R. & Ringoir, S. Infectious morbidity and defects of phagocytic function in end-stage renal disease: a review. J. Am. Soc. Nephrol. 3, 1541-1554 (1993).
9. Stinghen, A. E., Bucharles, S., Riella, M. C. & Pecoits-Filho, R. Immune mechanisms involved in cardiovascular complications of chronic kidney disease. Blood Purif. 29, 114-120 (2010).
10. Amore, A. & Coppo, R. Immunological basis of inflammation in dialysis. Nephrol. Dial. Transplant. 17 (Suppl. 8), 16-24 (2002). (Pubitemid 34918874)
11. Wolf, M. et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int. 72, 1004-1013 (2007). (Pubitemid 47530570)
12. Teng, M. et al. Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J. Am. Soc. Nephrol. 16, 1115-1125 (2005). (Pubitemid 41710323)
13. Kalantar-Zadeh, K. et al. Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients. Kidney Int. 70, 771-780 (2006). (Pubitemid 44215354)
14. Melamed, M. L. et al. Changes in serum calcium, phosphate, and PTH and the risk of death in incident dialysis patients: a longitudinal study. Kidney Int. 70, 351-357 (2006). (Pubitemid 44086585)
15. Maalouf, N. M. The noncalciotropic actions of vitamin D: recent clinical developments. Curr. Opin. Nephrol. Hypertens. 17, 408-415 (2008).
16. Rice, J. C. & Haverty, T. P. Vitamin D and immune function in uremia. Semin. Dial. 3, 237-239 (1990).
17. Bikle, D. D. Vitamin D and the immune system: role in protection against bacterial infection. Curr. Opin. Nephrol. Hypertens. 17, 348-352 (2008).
18. Andress, D. Nonclassical aspects of differential vitamin D receptor activation: implications for survival in patients with chronic kidney disease. Drugs 67, 1999-2012 (2007). (Pubitemid 47524562)
19. Hewison, M. Vitamin D and the immune system: new perspectives on an old theme. Endocrinol. Metab. Clin. North Am. 39, 365-379 (2010).
20. Bikle, D. D. Vitamin D and immune function: understanding common pathways. Curr. Osteoporos. Rep. 7, 58-63 (2009).
21. Mathieu, C. & Jafari, M. Immunomodulation by 1,25-dihydroxyvitamin D3: therapeutic implications in hemodialysis and renal transplantation. Clin. Nephrol. 66, 275-283 (2006). (Pubitemid 44541215)
22. Casteels, K., Bouillon, R., Waer, M. & Mathieu, C. Immunomodulatory effects of 1,25-dihydroxyvitamin D3. Curr. Opin. Nephrol. Hypertens. 4, 313-318 (1995).
23. Cantorna, M. T., Zhu, Y., Froicu, M. & Wittke, A. Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. Am. J. Clin. Nutr. 80, 1717S-1720S (2004).
24. Baeke, F., van Etten, E., Gysemans, C., Overbergh, L. & Mathieu, C. Vitamin D signaling in immune-mediated disorders: evolving insights and therapeutic opportunities. Mol. Aspects Med. 29, 376-387 (2008).
25. Dusso, A. S., Brown, A. J. & Slatopolsky, E. Vitamin D. Am. J. Physiol. Renal Physiol. 289, F8-F28 (2005). (Pubitemid 40863568)
26. Christakos, S., Ajibade, D. V., Dhawan, P., Fechner, A. J. & Mady, L. J. Vitamin D: metabolism. Endocrinol. Metab. Clin. North Am. 39, 243-253 (2010).
27. Midgett, R. J., Spielvogel, A. M., Coburn, J. W. & Norman, A. W. Studies on calciferol metabolism. VII. The renal production of the biologically active form of vitamin D, 1,25-dihydroxycholecalciferol; species, tissue and subcellular distribution. J. Clin. Endocrinol. Metab. 36, 1153-1161 (1973).
28. Henry, H. L. Regulation of vitamin D metabolism. Best Pract. Res. Clin. Endocrinol. Metab. 25, 531-541 (2011).
29. Krajisnik, T. et al. Fibroblast growth factor-23 regulates parathyroid hormone and 1?-hydroxylase expression in cultured bovine parathyroid cells. J. Endocrinol. 195, 125-131 (2007). (Pubitemid 350056006)
30. Bajwa, A., Forster, M. N., Maiti, A., Woolbright, B. L. & Beckman, M. J. Specific regulation of CYP27B1 and VDR in proximal versus distal renal cells. Arch. Biochem. Biophys. 477, 33-42 (2008).
31. Bikle, D. D., Pillai, S., Gee, E. & Hincenbergs, M. Tumor necrosis factor-alpha regulation of 1,25-dihydroxyvitamin D production by human keratinocytes. Endocrinology 129, 33-38 (1991).
32. Insogna, K. L., Dreyer, B. E., Mitnick, M., Ellison, A. F. & Broadus, A. E. Enhanced production rate of 1,25-dihydroxyvitamin D in sarcoidosis. J. Clin. Endocrinol. Metab. 66, 72-75 (1988). (Pubitemid 18027732)
33. Holick, M. F. Vitamin D deficiency. N. Engl. J. Med. 357, 266-281 (2007).
34. Institute of Medicine. Dietary reference intakes for calcium and vitamin D (The National Academies Press, Washington DC, 2011).
35. Verstuyf, A., Carmeliet, G., Bouillon, R. & Mathieu, C. Vitamin D: a pleiotropic hormone. Kidney Int. 78, 140-145 (2010).
36. Manson, J. E. Vitamin D and the heart: why we need large-scale clinical trials. Cleve. Clin. J. Med. 77, 903-910 (2010).
37. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01169259?term=NCT01169259&rank=1 (2011).
38. Li, Y. C. Renoprotective effects of vitamin D analogs. Kidney Int. 78, 134-139 (2010).
39. Dusso, A. S. & Tokumoto, M. Defective renal maintenance of the vitamin D endocrine system impairs vitamin D renoprotection: a downward spiral in kidney disease. Kidney Int. 79, 715-729 (2011).
40. Gal-Moscovici, A. & Sprague, S. M. Use of vitamin D in chronic kidney disease patients. Kidney Int. 78, 146-151 (2010).
41. Cunningham, J. & Zehnder, D. New vitamin D analogs and changing therapeutic paradigms. Kidney Int. 79, 702-707 (2011).
42. Tentori, F. et al. Mortality risk among hemodialysis patients receiving different vitamin D analogs. Kidney Int. 70, 1858-1865 (2006). (Pubitemid 44684819)
43. Shoben, A. B., Rudser, K. D., de Boer, I. H., Young, B. & Kestenbaum, B. Association of oral calcitriol with improved survival in nondialyzed CKD. J. Am. Soc. Nephrol. 19, 1613-1619 (2008).
44. Teng, M. et al. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N. Engl. J. Med. 349, 446-456 (2003). (Pubitemid 36910023)
45. Girndt, M., Sester, M., Sester, U., Kaul, H. & Köhler, H. Defective expression of B7-2 (CD86) on monocytes of dialysis patients correlates to the uremia-associated immune defect. Kidney Int. 59, 1382-1389 (2001). (Pubitemid 32281226)
46. de la Barrera, S., Alemán, M. & Sasiain Mdel, C. Toll-like receptors in human infectious diseases. Curr. Pharm. Des. 12, 4173-4184 (2006). (Pubitemid 44669746)
47. Ando, M., Shibuya, A., Tsuchiya, K., Akiba, T. & Nitta, K. Reduced expression of Toll-like receptor 4 contributes to impaired cytokine response of monocytes in uremic patients. Kidney Int. 70, 358-362 (2006). (Pubitemid 44086586)
48. Kuroki, Y. et al. A study of innate immunity in patients with end-stage renal disease: special reference to toll-like receptor-2 and -4 expression in peripheral blood monocytes of hemodialysis patients. Int. J. Mol. Med. 19, 783-790 (2007).
49. Lorenz, E. TLR2 and TLR4 expression during bacterial infections. Curr. Pharm. Des. 12, 4185-4193 (2006). (Pubitemid 44669747)
50. Raj, D. S. et al. Soluble CD14 levels, interleukin 6, and mortality among prevalent hemodialysis patients. Am. J. Kidney Dis. 54, 1072-1080 (2009).
51. Raj, D. S. et al. Skeletal muscle, cytokines, and oxidative stress in end-stage renal disease. Kidney Int. 68, 2338-2344 (2005). (Pubitemid 43117813)
52. Rao, M. et al. Cytokine gene polymorphism and progression of renal and cardiovascular diseases. Kidney Int. 72, 549-556 (2007). (Pubitemid 47312798)
53. Raj, D. S. et al. Haemodialysis induces mitochondrial dysfunction and apoptosis. Eur. J. Clin. Invest. 37, 971-977 (2007). (Pubitemid 350151187)
54. Ulrich, C., Heine, G. H., Seibert, E., Fliser, D. & Girndt, M. Circulating monocyte subpopulations with high expression of angiotensin- converting enzyme predict mortality in patients with end-stage renal disease. Nephrol. Dial. Transplant. 25, 2265-2272 (2010).
55. Chonchol, M. Neutrophil dysfunction and infection risk in end-stage renal disease. Semin. Dial. 19, 291-296 (2006). (Pubitemid 44091703)
56. Kimmel, P. L. Zinc and chronic renal disease. Semin. Dial. 2, 253-259 (1989).
57. Agrawal, S., Gollapudi, P., Elahimehr, R., Pahl, M. V. & Vaziri, N. D. Effects of end-stage renal disease and haemodialysis on dendritic cell subsets and basal and LPS-stimulated cytokine production. Nephrol. Dial. Transplant. 25, 737-746 (2010).
58. Lim, W. H., Kireta, S., Leedham, E., Russ, G. R. & Coates, P. T. Uremia impairs monocyte and monocyte-derived dendritic cell function in hemodialysis patients. Kidney Int. 72, 1138-1148 (2007). (Pubitemid 47609031)
59. Peterson, C.A. & Heffernan, M.E. Serum tumor necrosis factor-alpha concentrations are negatively correlated with serum 25(OH)D concentrations in healthy women. J. Inflamm. 5, 10 (2008).
60. Gelfand, J. M. et al. Vitamin D in African Americans with multiple sclerosis. Neurology 76, 1824-1830 (2011).
61. Ritterhouse, L. L. et al. Vitamin D deficiency is associated with an increased autoimmune response in healthy individuals and in patients with systemic lupus erythematosus. Ann. Rheum. Dis. 70, 1569-1574 (2011).
62. Zhao, G., Ford, E. S., Tsai, J., Li, C. & Croft, J. B. Low concentrations of serum 25-hydroxyvitamin D associated with increased risk for chronic bronchitis among US adults. Br. J. Nutr. 2011, 1-7 (2011).
63. Schwalfenberg, G. Not enough vitamin D: health consequences for Canadians. Can. Fam. Physician 53, 841-854 (2007). (Pubitemid 47164277)
64. Pike, J. W., Meyer, M. B. & Bishop, K. A. Regulation of target gene expression by the vitamin D receptor - an update on mechanisms. Rev. Endocr. Metab. Disord. 13, 45-55 (2012).
65. Brennan, A. et al. Dendritic cells from human tissues express receptors for the immunoregulatory vitamin D3 metabolite, dihydroxycholecalciferol. Immunology 61, 457-461 (1987). (Pubitemid 17127352)
66. Provvedini, D. M., Tsoukas, C. D., Deftos, L. J. & Manolagas, S. C. 1,25-dihydroxyvitamin D3 receptors in human leukocytes. Science 221, 1181-1183 (1983).
67. Liu, P. T. et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311, 1770-1773 (2006).
68. Rigby, W. F., Stacy, T. & Fanger, M. W. Inhibition of T lymphocyte mitogenesis by 1,25-dihydroxyvitamin D3 (calcitriol). J. Clin. Invest. 74, 1451-1455 (1984). (Pubitemid 15200239)
69. Rigby, W. F., Noelle, R. J., Krause, K. & Fanger, M. W. The effects of 1,25-dihydroxyvitamin D3 on human T lymphocyte activation and proliferation: a cell cycle analysis. J. Immunol. 135, 2279-2286 (1985). (Pubitemid 16217108)
70. Lemire, J. M. et al. 1,25-Dihydroxyvitamin D3 suppresses human T helper/inducer lymphocyte activity in vitro. J. Immunol. 134, 3032-3035 (1985). (Pubitemid 15249817)
71. Zhou, C. et al. Calcium-independent and 1,25(OH)2D3-dependent regulation of the renin-angiotensin system in 1?-hydroxylase knockout mice. Kidney Int. 74, 170-179 (2008). (Pubitemid 351915078)
72. Stubbs, J. R., Idiculla, A., Slusser, J., Menard, R. & Quarles, L. D. Cholecalciferol supplementation alters calcitriol-responsive monocyte proteins and decreases inflammatory cytokines in ESRD. J. Am. Soc. Nephrol. 21, 353-361 (2010).
73. Lou, Y. R. et al. 25-Hydroxyvitamin D3 is an agonistic vitamin D receptor ligand. J. Steroid Biochem. Mol. Biol. 118, 162-170 (2010).
74. Brown, A. J., Ritter, C. S., Knutson, J. C. & Strugnell, S. A. The vitamin D prodrugs 1?(OH)D2, 1?(OH)D3 and BCI-210 suppress PTH secretion by bovine parathyroid cells. Nephrol. Dial. Transplant. 21, 644-650 (2006). (Pubitemid 43372909)
75. Kim, M. J. et al. Oral cholecalciferol decreases albuminuria and urinary TGF-?1 in patients with type 2 diabetic nephropathy on established renin-angiotensin-aldosterone system inhibition. Kidney Int. 80, 851-860 (2011).
76. Coronel, F., Rodríguez-Cubillo, B., Cigarrán, S. & Gomis, A. Effects of oral paricalcitol on hyperparathyroidism and proteinuria in peritoneal dialysis patients. Adv. Perit. Dial. 27, 130-133 (2011).
77. de Zeeuw, D. et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet 376, 1543-1551 (2010).
78. Thiem, U. et al. VITA-D: cholecalciferol substitution in vitamin D deficient kidney transplant recipients: a randomized, placebo-controlled study to evaluate the post-transplant outcome. Trials 10, 36 (2009).
79. Fishbane, S. et al. Oral paricalcitol in the treatment of patients with CKD and proteinuria: a randomized trial. Am. J. Kidney Dis. 54, 647-652 (2009).
80. Alborzi, P. et al. Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: a randomized double-blind pilot trial. Hypertension 52, 249-255 (2008).
81. Moe, S. M. et al. A placebo-controlled trial to evaluate immunomodulatory effects of paricalcitol. Am. J. Kidney Dis. 38, 792-802 (2001).
82. Altun, B. et al. Determinants of soluble CD23 antigen levels in hemodialysis patients: effect of 1.25 dihydroxyvitamin D3 and recombinant human erythropoietin treatment. Clin. Nephrol. 52, 230-238 (1999). (Pubitemid 29467098)
83. Antonen, J., Saha, H., Lagerstedt, A., Krohn, K. & Pasternack, A. Intravenous calcitriol therapy restores reduced antigen-induced T-lymphocyte response in 1,25-(OH)2D3-deficient hemodialysis patients. Nephron 74, 680-686 (1996). (Pubitemid 26396184)
84. Quesada, J. M. et al. Calcitriol effect on natural killer cells from hemodialyzed and normal subjects. Calcif. Tissue Int. 56, 113-117 (1995).
85. Riancho, J. A. et al. Vitamin D therapy modulates cytokine secretion in patients with renal failure. Nephron 65, 364-368 (1993). (Pubitemid 23321232)
86. Tabata, T. et al. In vivo effect of 1 alpha-hydroxyvitamin D3 on interleukin-2 production in hemodialysis patients. Nephron 50, 295-298 (1988).
87. Abdelsadik, A. & Trad, A. Toll-like receptors on the fork roads between innate and adaptive immunity. Hum. Immunol. 72, 1188-1193 (2011).
88. Williams, C. On the use and administration of cod-liver oil in pulmonary consumption. Lond. J. Med. 1, 1-18 (1849).
89. Rook, G. A. et al. Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 57, 159-163 (1986). (Pubitemid 16232232)
90. Crowle, A. J., Ross, E. J. & May, M. H. Inhibition by 1,25(OH)2-vitamin D3 of the multiplication of virulent tubercle bacilli in cultured human macrophages. Infect. Immun. 55, 2945-2950 (1987). (Pubitemid 18008262)
91. Krutzik, S. R. et al. IL-15 links TLR2/1-induced macrophage differentiation to the vitamin D-dependent antimicrobial pathway. J. Immunol. 181, 7115-7120 (2008).
92. Nizet, V. et al. Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 414, 454-457 (2001). (Pubitemid 34173727)
93. Dürr, U. H., Sudheendra, U. S. & Ramamoorthy, A. LL-37, the only human member of the cathelicidin family of antimicrobial peptides. Biochim. Biophys. Acta 1758, 1408-1425 (2006). (Pubitemid 44436081)
94. Gordon, Y. J. et al. Human cathelicidin (LL-37), a multifunctional peptide, is expressed by ocular surface epithelia and has potent antibacterial and antiviral activity. Curr. Eye Res. 30, 385-394 (2005). (Pubitemid 40910819)
95. Nijnik, A. & Hancock, R. E. The roles of cathelicidin LL-37 in immune defences and novel clinical applications. Curr. Opin. Hematol. 16, 41-47 (2009).
96. Sørensen, O. E. et al. Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3. Blood 97, 3951-3959 (2001).
97. Wang, T. T. et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J. Immunol. 173, 2909-2912 (2004).
98. Yim, S., Dhawan, P., Ragunath, C., Christakos, S. & Diamond, G. Induction of cathelicidin in normal and CF bronchial epithelial cells by 1,25-dihydroxyvitamin D3. J. Cyst. Fibros. 6, 403-410 (2007). (Pubitemid 350028703)
99. Gombart, A. F., Borregaard, N. & Koeffler, H. P. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J. 19, 1067-1077 (2005). (Pubitemid 40946432)
100. Gombart, A. F. et al. Low plasma level of cathelicidin antimicrobial peptide (hCAP18) predicts increased infectious disease mortality in patients undergoing hemodialysis. Clin. Infect. Dis. 48, 418-424 (2009).
101. Bhalla, A. K., Amento, E. P., Serog, B. & Glimcher, L. H. 1,25-Dihydroxyvitamin D3 inhibits antigen-induced T cell activation. J. Immunol. 133, 1748-1754 (1984). (Pubitemid 14035260)
102. van Etten, E. & Mathieu, C. Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts. J. Steroid Biochem. Mol. Biol. 97, 93-101 (2005).
103. Seibert, E., Levin, N. W. & Kuhlmann, M. K. Immunomodulating effects of vitamin D analogs in hemodialysis patients. Hemodial. Int. 9 (Suppl. 1), S25-S29 (2005). (Pubitemid 41614640)
104. D'Ambrosio, D. et al. Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene. J. Clin. Invest. 101, 252-262 (1998).
105. Takahashi, K. et al. 1?,25-dihydroxyvitamin D3 suppresses interleukin-1?-induced interleukin-8 production in human whole blood: an involvement of erythrocytes in the inhibition. Immunopharmacol. Immunotoxicol. 24, 1-15 (2002). (Pubitemid 34496732)
106. Xu, H., Soruri, A., Gieseler, R. K. & Peters, J. H. 1,25-Dihydroxyvitamin D3 exerts opposing effects to IL-4 on MHC class-II antigen expression, accessory activity, and phagocytosis of human monocytes. Scand. J. Immunol. 38, 535-540 (1993).
107. Bikle, D. Nonclassic actions of vitamin D. J. Clin. Endocrinol. Metab. 94, 26-34 (2009).
108. Sester, U. et al. T-cell activation follows Th1 rather than Th2 pattern in haemodialysis patients. Nephrol. Dial. Transplant. 15, 1217-1223 (2000). (Pubitemid 30487801)
109. Gregori, S. et al. Regulatory T cells induced by 1?,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. J. Immunol. 167, 1945-1953 (2001). (Pubitemid 32747499)
110. Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775-787 (2008). (Pubitemid 351707693)
111. Chen, S. et al. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J. Immunol. 179, 1634-1647 (2007).
112. Equils, O. et al. 1,25-Dihydroxyvitamin D inhibits lipopolysaccharide- induced immune activation in human endothelial cells. Clin. Exp. Immunol. 143, 58-64 (2006).
113. Sadeghi, K. et al. Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns. Eur. J. Immunol. 36, 361-370 (2006). (Pubitemid 43257459)
114. Bukoski, R. D. & Xue, H. On the vascular inotropic action of 1,25-(OH)2 vitamin D3. Am. J. Hypertens. 6, 388-396 (1993). (Pubitemid 23161690)
115. Asakura, H. et al. Beneficial effect of the active form of vitamin D3 against LPS-induced DIC but not against tissue-factor-induced DIC in rat models. Thromb. Haemost. 85, 287-290 (2001). (Pubitemid 32140575)
116. Møller, S., Laigaard, F., Olgaard, K. & Hemmingsen, C. Effect of 1,25-dihydroxy-vitamin D3 in experimental sepsis. Int. J. Med. Sci. 4, 190-195 (2007).
117. Jeng, L. et al. Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis. J. Transl. Med. 7, 28 (2009).
118. Dahl, B. et al. Plasma concentration of Gc-globulin is associated with organ dysfunction and sepsis after injury. Crit. Care Med. 31, 152-156 (2003). (Pubitemid 36151165)
119. Watkins, R. R., Yamshchikov, A. V., Lemonovich, T. L. & Salata, R. A. The role of vitamin D deficiency in sepsis and potential therapeutic implications. J. Infect. 63, 321-326 (2011).
120. Watt, G. H. et al. Alterations in plasma levels and complexing of Gc (vitamin D-binding protein) in rats with endotoxic shock. Circ. Shock 28, 279-291 (1989). (Pubitemid 19186718)
121. Engel, C. et al. Epidemiology of sepsis in Germany: results from a national prospective multicenter study. Intensive Care Med. 33, 606-618 (2007). (Pubitemid 46474888)
122. Forrest, K. Y. & Stuhldreher, W. L. Prevalence and correlates of vitamin D deficiency in US adults. Nutr. Res. 31, 48-54 (2011).
123. Cohen, M. L., Douvdevani, A., Chaimovitz, C. & Shany, S. Regulation of TNF-? by 1?,25-dihydroxyvitamin D3 in human macrophages from CAPD patients. Kidney Int. 59, 69-75 (2001). (Pubitemid 32055215)
124. Giovannini, L. et al. 1,25-dihydroxyvitamin D3 dose-dependently inhibits LPS-induced cytokines production in PBMC modulating intracellular calcium. Transplant. Proc. 33, 2366-2368 (2001). (Pubitemid 33762743)
125. Anders, H. J., Banas, B. & Schlöndorff, D. Signaling danger: toll-like receptors and their potential roles in kidney disease. J. Am. Soc. Nephrol. 15, 854-867 (2004). (Pubitemid 38375304)
126. Kimmel, P. L. et al. Zinc balance in combined zinc deficiency and uremia. Kidney Int. 33, 1091-1099 (1988).
127. Prasad, A. S., Kaplan, J., Brewer, G. J. & Dardenne, M. Immunological effects of zinc deficiency in sickle cell anemia (SCA). Prog. Clin. Biol. Res. 319, 629-647 (1989).
128. Kimmel, P. L., Phillips, T. M., Lew, S. Q. & Langman, C. B. Zinc modulates mononuclear cellular calcitriol metabolism in peritoneal dialysis patients. Kidney Int. 49, 1407-1412 (1996). (Pubitemid 26166415)
129. Kimmel, P. L., Watkins, D. W., Slatopolsky, E. & Langman, C. B. 1,25(OH)2D response to combined zinc and phosphorus depletion in rats. Am. J. Physiol. 259, E319-E326 (1990). (Pubitemid 20320753)
130. Kimmel, P. L., Watkins, D. W., Gubish, C. T., Slatopolsky, E. & Langman, C. B. Zinc nutritional status modulates the 1,25-(OH)2D. Response in uremic rats. Miner. Electrolyte Metab. 17, 307-314 (1991).
131. Yamshchikov, A. V., Desai, N. S., Blumberg, H. M., Ziegler, T. R. & Tangpricha, V. Vitamin D for treatment and prevention of infectious diseases: a systematic review of randomized controlled trials. Endocr. Pract. 15, 438-449 (2009).
132. Rudnicki, M., Kerschbaum, J., Hausdorfer, J., Mayer, G. & König, P. Risk factors for peritoneal dialysis-associated peritonitis: the role of oral active vitamin D. Perit. Dial. Int. 30, 541-548 (2010).
133. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT00892099?term=NCT00892099&rank=1 (2011).
134. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01175798?term=NCT01175798&rank=1 (2011).
135. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01026363?term=NCT01026363&rank=1 (2011).