Seminars in Nephrology
Volume 29, Issue 1 , Pages 85-93 , January 2009

Vitamin D Therapy for Chronic Kidney Disease

  • Ishir Bhan, MD

      Affiliations

    • Department of Medicine, Renal Unit, Massachusetts General Hospital, Boston, MA
    • ,
  • Ravi Thadhani, MD, MPH

      Affiliations

    • Department of Medicine, Renal Unit, Massachusetts General Hospital, Boston, MA
    • Center for D-Receptor Activation Research (CeDAR) at the Massachusetts General Hospital, Boston, MA
    • Corresponding Author InformationAddress reprint requests to Ravi Thadhani, MD, MPH, Bulfinch 127, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114

References 

  1. Brunette MG, Chan M, Ferriere C, Roberts KD. Site of 1,25(OH)2 vitamin D3 synthesis in the kidney. Nature. 1978;276:287–289
  2. Takeyama K, Kitanaka S, Sato T, et al. 25-Hydroxyvitamin D3 1alpha-hydroxylase and vitamin D synthesis. Science. 1997;277:1827–1830
  3. Holick MF, Schnoes HK, DeLuca HF. Identification of 1,25-dihydroxycholecalciferol, a form of vitamin D3 metabolically active in the intestine. Proc Natl Acad Sci U S A. 1971;68:803–804
  4. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–281
  5. Suda T, Ueno Y, Fujii K, Shinki T. Vitamin D and bone. J Cell Biochem. 2003;88:259–266
  6. DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr. 2004;80(Suppl):1689S–1696S
  7. Gal-Moscovici A, Sprague SM. Role of vitamin D deficiency in chronic kidney disease. J Bone Miner Res. 2007;22(Suppl 2):V91–V94
  8. Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis. 1998;31:607–617
  9. US Renal Data System. USRDS 2007 annual data report. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2007;
  10. Steddon SJ, Cunningham J. Calcimimetics and calcilytics—fooling the calcium receptor. Lancet. 2005;365:2237–2239
  11. Li YC, Kong J, Wei M, et al. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest. 2002;110:229–238
  12. Zhou CL, Lu FX, Cao KX, et al. Calcium-independent and 1,25(OH)(2)D(3)-dependent regulation of the renin-angiotensin system in 1alpha-hydroxylase knockout mice. Kidney Int. 2008;74:141–143
  13. Yamamoto T, Kozawa O, Tanabe K, et al. 1,25-dihydroxyvitamin D3 stimulates vascular endothelial growth factor release in aortic smooth muscle cells: role of p38 mitogen-activated protein kinase. Arch Biochem Biophys. 2002;398:1–6
  14. Teng M, Wolf M, Ofsthun MN, et al. Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol. 2005;16:1115–1125
  15. Teng M, Wolf M, Lowrie E, et al. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med. 2003;349:446–456
  16. Shoji T, Shinohara K, Kimoto E, et al. Lower risk for cardiovascular mortality in oral 1alpha-hydroxy vitamin D3 users in a haemodialysis population. Nephrol Dial Transplant. 2004;19:179–184
  17. Melamed ML, Eustace JA, Plantinga L, et al. Changes in serum calcium, phosphate, and PTH and the risk of death in incident dialysis patients: a longitudinal study. Kidney Int. 2006;70:351–357
  18. Tentori F, Hunt WC, Stidley CA, et al. Mortality risk among hemodialysis patients receiving different vitamin D analogs. Kidney Int. 2006;70:1858–1865
  19. Kalantar-Zadeh K, Kuwae N, Regidor DL, et al. Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients. Kidney Int. 2006;70:771–780
  20. Kovesdy CP, Ahmadzadeh S, Anderson JE, Kalantar-Zadeh K. Association of activated vitamin D treatment and mortality in chronic kidney disease. Arch Intern Med. 2008;168:397–403
  21. Wolf M, Betancourt J, Chang Y, et al. Impact of activated vitamin D and race on survival among hemodialysis patients. J Am Soc Nephrol. 2008;19:1379–1388
  22. Palmer SC, McGregor DO, Macaskill P, et al. Meta-analysis: vitamin D compounds in chronic kidney disease. Ann Intern Med. 2007;147:840–853
  23. Goodman WG, Goldin J, Kuizon BD, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2000;342:1478–1483
  24. Goldsmith DJ, Covic A, Sambrook PA, Ackrill P. Vascular calcification in long-term haemodialysis patients in a single unit: a retrospective analysis. Nephron. 1997;77:37–43
  25. Milliner DS, Zinsmeister AR, Lieberman E, Landing B. Soft tissue calcification in pediatric patients with end-stage renal disease. Kidney Int. 1990;38:931–936
  26. Jono S, Nishizawa Y, Shioi A, Morii H. 1,25-Dihydroxyvitamin D3 increases in vitro vascular calcification by modulating secretion of endogenous parathyroid hormone-related peptide. Circulation. 1998;98:1302–1306
  27. Zittermann A, Schleithoff SS, Koerfer R. Putting cardiovascular disease and vitamin D insufficiency into perspective. Br J Nutr. 2005;94:483–492
  28. Detrano R, Guerci AD, Carr JJ, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med. 2008;358:1136–1145
  29. Blacher J, Guerin AP, Pannier B, et al. Impact of aortic stiffness on survival in end-stage renal disease. Circulation. 1999;99:2434–2439
  30. London GM, Guerin AP, Marchais SJ, et al. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant. 2003;18:1731–1740
  31. Moe SM, O'Neill KD, Reslerova M, et al. Natural history of vascular calcification in dialysis and transplant patients. Nephrol Dial Transplant. 2004;19:2387–2393
  32. Merx MW, Schafer C, Westenfeld R, et al. Myocardial stiffness, cardiac remodeling, and diastolic dysfunction in calcification-prone fetuin-A-deficient mice. J Am Soc Nephrol. 2005;16:3357–3364
  33. Ahmed A, Rich MW, Sanders PW, et al. Chronic kidney disease associated mortality in diastolic versus systolic heart failure: a propensity matched study. Am J Cardiol. 2007;99:393–398
  34. Mizobuchi M, Finch JL, Martin DR, Slatopolsky E. Differential effects of vitamin D receptor activators on vascular calcification in uremic rats. Kidney Int. 2007;72:709–715
  35. Tukaj C, Kubasik-Juraniec J, Kraszpulski M. Morphological changes of aortal smooth muscle cells exposed to calcitriol in culture. Med Sci Monit. 2000;6:668–674
  36. Andress DL. Vitamin D in chronic kidney disease: a systemic role for selective vitamin D receptor activation. Kidney Int. 2006;69:33–43
  37. Drissi H, Pouliot A, Koolloos C, et al. 1,25-(OH)2-vitamin D3 suppresses the bone-related Runx2/Cbfa1 gene promoter. Exp Cell Res. 2002;274:323–333
  38. Andersson P, Rydberg E, Willenheimer R. Primary hyperparathyroidism and heart disease—a review. Eur Heart J. 2004;25:1776–1787
  39. Rostand SG, Drueke TB. Parathyroid hormone, vitamin D, and cardiovascular disease in chronic renal failure. Kidney Int. 1999;56:383–392
  40. Amann K, Ritz E, Wiest G, Klaus G, Mall G. A role of parathyroid hormone for the activation of cardiac fibroblasts in uremia. J Am Soc Nephrol. 1994;4:1814–1819
  41. Davies MR, Hruska KA. Pathophysiological mechanisms of vascular calcification in end-stage renal disease. Kidney Int. 2001;60:472–479
  42. Xiang W, Kong J, Chen S, et al. Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems. Am J Physiol. 2005;288:E125–E132
  43. Wu J, Garami M, Cheng T, Gardner DG. 1,25(OH)2 vitamin D3, and retinoic acid antagonize endothelin-stimulated hypertrophy of neonatal rat cardiac myocytes. J Clin Invest. 1996;97:1577–1588
  44. Bodyak N, Ayus JC, Achinger S, et al. Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals. Proc Natl Acad Sci U S A. 2007;104:16810–16815
  45. Park CW, Oh YS, Shin YS, et al. Intravenous calcitriol regresses myocardial hypertrophy in hemodialysis patients with secondary hyperparathyroidism. Am J Kidney Dis. 1999;33:73–81
  46. Zhang Z, Sun L, Wang Y, et al. Renoprotective role of the vitamin D receptor in diabetic nephropathy. Kidney Int. 2008;73:163–171
  47. Kautzky-Willer A, Pacini G, Barnas U, et al. Intravenous calcitriol normalizes insulin sensitivity in uremic patients. Kidney Int. 1995;47:200–206
  48. Aihara K, Azuma H, Akaike M, et al. Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice. J Biol Chem. 2004;279:35798–35802
  49. Mak RH. 1,25-Dihydroxyvitamin D3 corrects insulin and lipid abnormalities in uremia. Kidney Int. 1998;53:1353–1357
  50. 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
  51. Martins D, Wolf M, Pan D, et al. Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2007;167:1159–1165
  52. Edfeldt K, Agerberth B, Rottenberg ME, et al. Involvement of the antimicrobial peptide LL-37 in human atherosclerosis. Arterioscler Thromb Vasc Biol. 2006;26:1551–1557
  53. Zasloff M. Inducing endogenous antimicrobial peptides to battle infections. Proc Natl Acad Sci U S A. 2006;103:8913–8914
  54. Zasloff M. Innate immunity, antimicrobial peptides, and protection of the oral cavity. Lancet. 2002;360:1116–1117
  55. Ganz T. Immunology (Versatile defensins). Science. 2002;298:977–979
  56. Hancock RE, Scott MG. The role of antimicrobial peptides in animal defenses. Proc Natl Acad Sci U S A. 2000;97:8856–8861
  57. Andreu D, Rivas L. Animal antimicrobial peptides: an overview. Biopolymers. 1998;47:415–433
  58. Sorensen O, Cowland JB, Askaa J, Borregaard N. An ELISA for hCAP-18, the cathelicidin present in human neutrophils and plasma. J Immunol Methods. 1997;206:53–59
  59. Nizet V, Ohtake T, Lauth X, et al. Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature. 2001;414:454–457
  60. Bals R, Weiner DJ, Moscioni AD, Meegalla RL, Wilson JM. Augmentation of innate host defense by expression of a cathelicidin antimicrobial peptide. Infect Immun. 1999;67:6084–6089
  61. Wang TT, Nestel FP, Bourdeau V, et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol. 2004;173:2909–2912
  62. Martineau AR, Wilkinson KA, Newton SM, et al. IFN-gamma- and TNF-independent vitamin D-inducible human suppression of mycobacteria: the role of cathelicidin LL-37. J Immunol. 2007;178:7190–7198
  63. Gombart AF, Borregaard N, Koeffler HP. 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. 2005;19:1067–1077
  64. Yim S, Dhawan P, Ragunath C, Christakos S, Diamond G. Induction of cathelicidin in normal and CF bronchial epithelial cells by 1,25-dihydroxyvitamin D(3). J Cyst Fibros. 2007;6:403–410
  65. Gombart AF, O'Kelly J, Saito T, Koeffler HP. Regulation of the CAMP gene by 1,25(OH)2D3 in various tissues. J Steroid Biochem Mol Biol. 2007;103:552–557
  66. Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311:1770–1773
  67. Gombart AF, Bhan I, Borregaard N, et al. Low plasma cathelicidin antimicrobial peptide (hCAP18) predicts increased infectious disease mortality in hemodialysis. Clin Infect Dis. 2008;(in press)
  68. Yu S, Cantorna MT. The vitamin D receptor is required for iNKT cell development. Proc Natl Acad Sci U S A. 2008;105:5207–5212
  69. Chen S, Sims GP, Chen XX, et al. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol. 2007;179:1634–1647
  70. Reichel H, Koeffler HP, Tobler A, Norman AW. 1 alpha,25-Dihydroxyvitamin D3 inhibits gamma-interferon synthesis by normal human peripheral blood lymphocytes. Proc Natl Acad Sci U S A. 1987;84:3385–3389
  71. Tsoukas CD, Provvedini DM, Manolagas SC. 1,25-dihydroxyvitamin D3: a novel immunoregulatory hormone. Science. 1984;224:1438–1440
  72. Schwarz U, Amann K, Orth SR, et al. Effect of 1,25 (OH)2 vitamin D3 on glomerulosclerosis in subtotally nephrectomized rats. Kidney Int. 1998;53:1696–1705
  73. Hirata M, Makibayashi K, Katsumata K, et al. 22-Oxacalcitriol prevents progressive glomerulosclerosis without adversely affecting calcium and phosphorus metabolism in subtotally nephrectomized rats. Nephrol Dial Transplant. 2002;17:2132–2137
  74. Kuhlmann A, Haas CS, Gross ML, et al. 1,25-Dihydroxyvitamin D3 decreases podocyte loss and podocyte hypertrophy in the subtotally nephrectomized rat. Am J Physiol Renal Physiol. 2004;286:F526–F533
  75. Uyar M, Sezer S, Arat Z, et al. 1,25-dihydroxyvitamin D(3) therapy is protective for renal function and prevents hyperparathyroidism in renal allograft recipients. Transplant Proc. 2006;38:2069–2073
  76. LaClair RE, Hellman RN, Karp SL, et al. Prevalence of calcidiol deficiency in CKD: a cross-sectional study across latitudes in the United States. Am J Kidney Dis. 2005;45:1026–1033
  77. Wolf M, Shah A, Gutierrez O, et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int. 2007;72:1004–1013
  78. 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
  79. London GM, Guérin AP, Verbeke FH, et al. Mineral metabolism and arterial functions in end-stage renal disease: potential role of 25-hydroxyvitamin D deficiency. J Am Soc Nephrol. 2007;18:613–620

 R. Thadhani has received grant support from Abbott Laboratories, and speaking honoraria from Abbott Laboratories and Genzyme.

PII: S0270-9295(08)00174-5

doi: 10.1016/j.semnephrol.2008.10.010

Seminars in Nephrology
Volume 29, Issue 1 , Pages 85-93 , January 2009

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