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Possible renoprotection by vitamin D in chronic renal disease: beyond mineral metabolism

Nature Reviews Nephrology volume 5, pages 691–700 (2009)Cite this article

Abstract

Vitamin D is typically viewed as a key player in the regulation of calcium and phosphate levels and the control of bone metabolism; however, growing evidence suggests that vitamin D deficiency may also have an important role in the progressive loss of renal function. Vitamin D deficiency is particularly frequent in patients with chronic kidney disease, in whom it is associated with increased mortality. Studies indicate that treatment with vitamin D analogues reduces proteinuria, suppresses the renin–angiotensin–aldosterone system (RAAS), and exerts anti-inflammatory and immunomodulatory effects. These pleiotropic effects render vitamin D a potentially interesting treatment modality for renoprotection in patients with chronic kidney disease. Whether vitamin D has clinically relevant renoprotective effects in addition to RAAS blockade is currently under investigation.

Key Points

  • Inadequate vitamin D levels are present in the majority of Western populations, but vitamin D deficiency is more prevalent and severe in patients with chronic kidney disease (CKD)

  • Decreased circulating levels of active vitamin D in patients with CKD may be explained by suppression of renal 1α-hydroxylase activity

  • Vitamin D deficiency has been associated with increased mortality, increased cardiovascular disease and increased risk of fracture

  • Vitamin D analogues might ameliorate the reactive rise in renin observed in patients with CKD treated with suppression of the renin–angiotensin–aldosterone system

  • The antiproteinuric effect of active vitamin D has been confirmed in preclinical studies of CKD and clinical trials to investigate this effect are ongoing

  • Vitamin D has anti-inflammatory and immunomodulatory effects, suggesting that treatment with vitamin D analogues may be particularly beneficial in patients with glomerulonephritis, autoimmune diseases, and renal transplant recipients

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Figure 1: Vitamin D physiology.
Figure 2: Prevalence of vitamin D deficiency in the general population and in patients with chronic kidney disease.
Figure 3: Possible mechanisms of vitamin D deficiency in proteinuric renal disease.
Figure 4: Overview of the potential renoprotective effects of active vitamin D in the damaged kidney.

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References

  1. Holick, M. F. Vitamin D deficiency. N. Engl. J. Med. 357, 266–281 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Nykjaer, A. et al. An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell 96, 507–515 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Zhong, Y., Armbrecht, H. J. & Christakos, S. Calcitonin, a regulator of the 25-hydroxyvitamin D3 1alpha-hydroxylase gene. J. Biol. Chem. 284, 11059–11069 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Turunen, M. M., Dunlop, T. W., Carlberg, C. & Vaisanen, S. Selective use of multiple vitamin D response elements underlies the 1 alpha, 25-dihydroxyvitamin D3-mediated negative regulation of the human CYP27B1 gene. Nucleic Acids Res. 35, 2734–2747 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Liu, S. et al. Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J. Am. Soc. Nephrol. 17, 1305–1315 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Urakawa, I. et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444, 770–774 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Shimada, T. et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J. Clin. Invest. 113, 561–568 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Carlberg, C. & Seuter, S. A genomic perspective on vitamin D signaling. Anticancer Res. 29, 3485–3493 (2009).

    CAS  PubMed  Google Scholar 

  9. Christakos, S., Raval-Pandya, M., Wernyj, R. P. & Yang, W. Genomic mechanisms involved in the pleiotropic actions of 1,25-dihydroxyvitamin D3. Biochem. J. 316 (Pt 2), 361–371 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ginde, A. A., Liu, M. C. & Camargo, C. A. Jr. Demographic differences and trends of vitamin D insufficiency in the US population, 1988–2004. Arch. Intern. Med. 169, 626–632 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. White, J. H. Profiling 1,25-dihydroxyvitamin D3-regulated gene expression by microarray analysis. J. Steroid Biochem. Mol. Biol. 89–90, 239–244 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Bosse, Y., Maghni, K. & Hudson, T. J. 1alpha, 25-dihydroxy-vitamin D3 stimulation of bronchial smooth muscle cells induces autocrine, contractility, and remodeling processes. Physiol. Genomics 29, 161–168 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Ellis, B. C., Gattoni-Celli, S., Mancia, A. & Kindy, M. S. The vitamin D3 transcriptomic response in skin cells derived from the Atlantic bottlenose dolphin. Dev. Comp. Immunol. 33, 901–912 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Towsend, K. et al. Identification of VDR-responsive gene signatures in breast cancer cells. Oncology 71, 111–123 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Wu-Wong, J. R., Nakane, M., Ma, J., Ruan, X. & Kroeger, P. E. VDR-mediated gene expression patterns in resting human coronary artery smooth muscle cells. J. Cell Biochem. 100, 1395–1405 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Tan, X., Wen, X. & Liu, Y. Paricalcitol inhibits renal inflammation by promoting vitamin D receptor-mediated sequestration of NF-kappaB signaling. J. Am. Soc. Nephrol. 19, 1741–1752 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Norman, A. W. Minireview: vitamin D receptor: new assignments for an already busy receptor. Endocrinology 147, 5542–5548 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Dusso, A. S., Brown, A. J. & Slatopolsky, E. Vitamin D. Am. J. Physiol. Renal Physiol. 289, F8–F28 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Holick, M. F. & Garabedian, M. in Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism (ed. Favus, M. J.) 129–137 (Lippincott Williams & Wilkins, Washington, DC, 2006).

    Google Scholar 

  20. Holick, M. F. Resurrection of vitamin D deficiency and rickets. J. Clin. Invest. 116, 2062–2072 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kumar, R., Schaefer, J., Grande, J. P. & Roche, P. C. Immunolocalization of calcitriol receptor, 24-hydroxylase cytochrome P-450, and calbindin D28k in human kidney. Am. J. Physiol. 266, F477–F485 (1994).

    CAS  PubMed  Google Scholar 

  22. Zhang, Z. et al. 1,25-Dihydroxyvitamin D3 targeting of NF-kappaB suppresses high glucose-induced MCP-1 expression in mesangial cells. Kidney Int. 72, 193–201 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Zhang, Z. et al. Renoprotective role of the vitamin D receptor in diabetic nephropathy. Kidney Int. 73, 163–171 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Vieth, R. The role of vitamin D in the prevention of osteoporosis. Ann. Med. 37, 278–285 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Bischoff-Ferrari, H. A., Giovannucci, E., Willett, W. C., Dietrich, T. & Dawson-Hughes, B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am. J. Clin. Nutr. 84, 18–28 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Lips, P. Which circulating level of 25-hydroxyvitamin D is appropriate? J. Steroid Biochem. Mol. Biol. 89–90, 611–614 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Malabanan, A., Veronikis, I. E. & Holick, M. F. Redefining vitamin D insufficiency. Lancet 351, 805–806 (1998).

    Article  CAS  PubMed  Google Scholar 

  28. Jones, G. Pharmacokinetics of vitamin D toxicity. Am. J. Clin. Nutr. 88, 582S–586S (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Matsuoka, L. Y., Ide, L., Wortsman, J., MacLaughlin, J. A. & Holick, M. F. Sunscreens suppress cutaneous vitamin D3 synthesis. J. Clin. Endocrinol. Metab. 64, 1165–1168 (1987).

    Article  CAS  PubMed  Google Scholar 

  30. Scragg, R. & Camargo, C. A. Jr. Frequency of leisure-time physical activity and serum 25-hydroxyvitamin D levels in the US population: results from the Third National Health and Nutrition Examination Survey. Am. J. Epidemiol. 168, 577–586 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Wortsman, J., Matsuoka, L. Y., Chen, T. C., Lu, Z. & Holick, M. F. Decreased bioavailability of vitamin D in obesity. Am. J. Clin. Nutr. 72, 690–693 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Binkley, N. et al. Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization. J. Clin. Endocrinol. Metab. 89, 3152–3157 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Singh, R. J. Are clinical laboratories prepared for accurate testing of 25-hydroxy vitamin D? Clin. Chem. 54, 221–223 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Yates, A. M. et al. Interlaboratory variation in 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 is significantly improved if common calibration material is used. Clin. Chem. 54, 2082–2084 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Looker, A. C. et al. Serum 25-hydroxyvitamin D status of the US population: 1988–1994 compared with 2000–2004. Am. J. Clin. Nutr. 88, 1519–1527 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Carter, G. D. 25-Hydroxyvitamin D assays: the quest for accuracy. Clin. Chem. 55, 1300–1302 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Gonzalez, E. A., Sachdeva, A., Oliver, D. A. & Martin, K. J. Vitamin D insufficiency and deficiency in chronic kidney disease. A single center observational study. Am. J. Nephrol. 24, 503–510 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Jean, G., Charra, B. & Chazot, C. Vitamin D deficiency and associated factors in hemodialysis patients. J. Ren. Nutr. 18, 395–399 (2008).

    Article  PubMed  Google Scholar 

  39. LaClair, R. E. et al. Prevalence of calcidiol deficiency in CKD: a cross-sectional study across latitudes in the United States. Am. J. Kidney Dis. 45, 1026–1033 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Levin, A. 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. 71, 31–38 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Barreto, D. V. et al. Vitamin D affects survival independently of vascular calcification in chronic kidney disease. Clin. J. Am. Soc. Nephrol. 4, 1128–1135 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cuppari, L., Carvalho, A. B. & Draibe, S. A. Vitamin D status of chronic kidney disease patients living in a sunny country. J. Ren. Nutr. 18, 408–414 (2008).

    Article  PubMed  Google Scholar 

  43. Wolf, M. et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int. 72, 1004–1013 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Wang, A. Y. et al. Serum 25-hydroxyvitamin D status and cardiovascular outcomes in chronic peritoneal dialysis patients: a 3-y prospective cohort study. Am. J. Clin. Nutr. 87, 1631–1638 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. Zittermann, A., Gummert, J. F. & Borgermann, J. Vitamin D deficiency and mortality. Curr. Opin. Clin. Nutr. Metab. Care doi:10.1097/MCO.0b013e3283310767

    Article  CAS  PubMed  Google Scholar 

  46. Autier, P. & Gandini, S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch. Intern. Med. 167, 1730–1737 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Melamed, M. L., Michos, E. D., Post, W. & Astor, B. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch. Intern. Med. 168, 1629–1637 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Wang, T. J. et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation 117, 503–511 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Dobnig, H. et al. Independent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch. Intern. Med. 168, 1340–1349 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Hsia, J. et al. Calcium/vitamin D supplementation and cardiovascular events. Circulation 115, 846–854 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Wallis, D. E. & Penckofer, S. Letter by Wallis and Penckofer regarding article, “Calcium/vitamin D supplementation and cardiovascular events”. Circulation 116, e86 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Pettifor, J. M. in Vitamin D (eds Feldman, D., Pike, J. W. & Glorieux, F. H.) 1065–1084 (Elsevier Academic Press, Boston, 2005).

    Book  Google Scholar 

  53. Avenell, A., Gillespie, W. J., Gillespie, L. D. & O'Connell, D. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database of Systematic Reviews Issue 2. Art. No.: CD000227 doi:10.1002/14651858.CD000227.pub3 (2009).

    Google Scholar 

  54. Tang, B. M., Eslick, G. D., Nowson, C., Smith, C. & Bensoussan, A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 370, 657–666 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Chapuy, M. C. et al. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N. Engl. J. Med. 327, 1637–1642 (1992).

    Article  CAS  PubMed  Google Scholar 

  56. Dawson-Hughes, B., Harris, S. S., Krall, E. A. & Dallal, G. E. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N. Engl. J. Med. 337, 670–676 (1997).

    Article  CAS  PubMed  Google Scholar 

  57. Grant, A. M. et al. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet 365, 1621–1628 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. de Boer, I. H., Ioannou, G. N., Kestenbaum, B., Brunzell, J. D. & Weiss, N. S. 25-Hydroxyvitamin D levels and albuminuria in the Third National Health and Nutrition Examination Survey (NHANES III). Am. J. Kidney Dis. 50, 69–77 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Lambers Heerspink, H. J. et al. The Selective Vitamin D Receptor Activator for Albuminuria Lowering (VITAL) Study: study design and baseline characteristics. Am. J. Nephrol. 30, 280–286 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Inaguma, D. et al. Relationship between serum 1,25-dihydroxyvitamin D and mortality in patients with pre-dialysis chronic kidney disease. Clin. Exp. Nephrol. 12, 126–131 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Ravani, P. et al. Vitamin D levels and patient outcome in chronic kidney disease. Kidney Int. 75, 88–95 (2009).

    Article  CAS  PubMed  Google Scholar 

  62. de Boer, I. et al. 25-Hydroxyvitamin D levels inversely associate with risk for developing coronary artery calcification. J. Am. Soc. Nephrol. 20, 1805–1812 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Chonchol, M. & Scragg, R. 25-Hydroxyvitamin D, insulin resistance, and kidney function in the Third National Health and Nutrition Examination Survey. Kidney Int. 71, 134–139 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Martins, 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. 167, 1159–1165 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Marcen, R. et al. Prevalence of osteoporosis, osteopenia, and vertebral fractures in long-term renal transplant recipients. Transplant. Proc. 39, 2256–2258 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Pichette, V. et al. Long-term bone loss in kidney transplant recipients: a cross-sectional and longitudinal study. Am. J. Kidney Dis. 28, 105–114 (1996).

    Article  CAS  PubMed  Google Scholar 

  67. Kidney Disease Outcomes Quality Initiative Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease [online].

  68. Yuan, W. et al. 1,25-dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter. J. Biol. Chem. 282, 29821–29830 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Tan, X., Li, Y. & Liu, Y. Paricalcitol attenuates renal interstitial fibrosis in obstructive nephropathy. J. Am. Soc. Nephrol. 17, 3382–3393 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Leheste, J. R. et al. Megalin knockout mice as an animal model of low molecular weight proteinuria. Am. J. Pathol. 155, 1361–1370 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Leheste, J. R. et al. Hypocalcemia and osteopathy in mice with kidney-specific megalin gene defect. FASEB J. 17, 247–249 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Matsui, I. et al. Active vitamin D and its analogue, 22-oxacalcitriol, ameliorate puromycin aminonucleoside-induced nephrosis in rats. Nephrol. Dial. Transplant. 24, 2354–2361 (2009).

    Article  CAS  PubMed  Google Scholar 

  73. Jacob, A. I., Sallman, A., Santiz, Z. & Hollis, B. W. Defective photoproduction of cholecalciferol in normal and uremic humans. J. Nutr. 114, 1313–1319 (1984).

    Article  CAS  PubMed  Google Scholar 

  74. Andress, D. L. Vitamin D in chronic kidney disease: a systemic role for selective vitamin D receptor activation. Kidney Int. 69, 33–43 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Li, Y., Spataro, B. C., Yang, J., Dai, C. & Liu, Y. 1,25-dihydroxyvitamin D inhibits renal interstitial myofibroblast activation by inducing hepatocyte growth factor expression. Kidney Int. 68, 1500–1510 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Schwarz, U. et al. Effect of 1,25 (OH)2 vitamin D3 on glomerulosclerosis in subtotally nephrectomized rats. Kidney Int. 53, 1696–1705 (1998).

    Article  CAS  PubMed  Google Scholar 

  77. Xiao, H. et al. 1,25-Dihydroxyvitamin D(3) prevents puromycin aminonucleoside-induced apoptosis of glomerular podocytes by activating the phosphatidylinositol 3-kinase/Akt-signaling pathway. Am. J. Nephrol. 30, 34–43 (2009).

    Article  CAS  PubMed  Google Scholar 

  78. Okamura, M., Takano, Y., Saito, Y., Yao, J. & Kitamura, M. Induction of nephrin gene expression by selective cooperation of the retinoic acid receptor and the vitamin D receptor. Nephrol. Dial. Transplant. 24, 3006–3012 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. Yamauchi, K. et al. Screening and identification of substances that regulate nephrin gene expression using engineered reporter podocytes. Kidney Int. 70, 892–900 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Wang, Y. et al. Altered vitamin D metabolism in type II diabetic mouse glomeruli may provide protection from diabetic nephropathy. Kidney Int. 70, 882–891 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Kuhlmann, A. et al. 1,25-Dihydroxyvitamin D3 decreases podocyte loss and podocyte hypertrophy in the subtotally nephrectomized rat. Am. J. Physiol. Renal Physiol. 286, F526–F533 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Li, Y. C. et al. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J. Clin. Invest. 110, 229–238 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Pilz, S., Tomaschitz, A., Ritz, E. & Pieber, T. R. Vitamin D status and arterial hypertension: a systematic review. Nat. Rev. Cardiol. 6, 621–630 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Morris, K. L. & Zemel, M. B. 1,25-Dihydroxyvitamin D3 modulation of adipocyte glucocorticoid function. Obes. Res. 13, 670–677 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. de Borst, M. H. et al. Specific MAP-kinase blockade protects against renal damage in homozygous TGR(mRen2)27 rats. Lab. Invest. 83, 1761–1770 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. van Veldhuisen, D. J. et al. High- versus low-dose ACE inhibition in chronic heart failure: a double-blind, placebo-controlled study of imidapril. J. Am. Coll. Cardiol. 32, 1811–1818 (1998).

    Article  CAS  PubMed  Google Scholar 

  87. Krikken, J. A., Laverman, G. D. & Navis, G. Benefits of dietary sodium restriction in the management of chronic kidney disease. Curr. Opin. Nephrol. Hypertens. doi:10.1097/MNH.0b013e3283312fc8

    Article  CAS  PubMed  Google Scholar 

  88. Vogt, L., Waanders, F., Boomsma, F., de Zeeuw, D. & Navis, G. Effects of dietary sodium and hydrochlorothiazide on the antiproteinuric efficacy of losartan. J. Am. Soc. Nephrol. 19, 999–1007 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kramer, A. B., van der Meulen, E. F., van Goor, H. & Navis, G. Effect of combining ACE inhibition with aldosterone blockade on proteinuria and renal damage in experimental nephrosis. Kidney Int. 71, 417–424 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Nguyen, G. et al. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J. Clin. Invest. 109, 1417–1427 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hamming, I., Navis, G., Kocks, M. J. & van Goor, H. ACE inhibition has adverse renal effects during dietary sodium restriction in proteinuric and healthy rats. J. Pathol. 209, 129–139 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Mizobuchi, M. et al. Combination therapy with an angiotensin-converting enzyme inhibitor and a vitamin D analog suppresses the progression of renal insufficiency in uremic rats. J. Am. Soc. Nephrol. 18, 1796–1806 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. van Paassen, P., de Zeeuw, D., Navis, G. & de Jong, P. E. Renal and systemic effects of continued treatment with renin inhibitor remikiren in hypertensive patients with normal and impaired renal function. Nephrol. Dial. Transplant. 15, 637–643 (2000).

    Article  CAS  PubMed  Google Scholar 

  94. Parving, H. H., Persson, F., Lewis, J. B., Lewis, E. J. & Hollenberg, N. K. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N. Engl. J. Med. 358, 2433–2446 (2008).

    Article  CAS  PubMed  Google Scholar 

  95. Persson, F. et al. Renal effects of aliskiren compared to and in combination with irbesartan in patients with type 2 diabetes, hypertension and albuminuria. Diabetes Care 32, 1873–1879 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Yamamoto, E. et al. Aliskiren enhances the protective effects of valsartan against cardiovascular and renal injury in endothelial nitric oxide synthase-deficient mice. Hypertension 54, 633–638 (2009).

    Article  CAS  PubMed  Google Scholar 

  97. Batenburg, W. W. et al. Aliskiren-binding increases the half life of renin and prorenin in rat aortic vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 28, 1151–1157 (2008).

    Article  CAS  PubMed  Google Scholar 

  98. Zhang, Z. et al. Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: blockade of compensatory renin increase. Proc. Natl Acad. Sci. USA 105, 15896–15901 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Kramer, A. B., Laverman, G. D., van Goor, H. & Navis, G. Inter-individual differences in anti-proteinuric response to ACEi in established adriamycin nephrotic rats are predicted by pretreatment renal damage. J. Pathol. 201, 160–167 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. Remuzzi, G. et al. Combining an antiproteinuric approach with mycophenolate mofetil fully suppresses progressive nephropathy of experimental animals. J. Am. Soc. Nephrol. 10, 1542–1549 (1999).

    CAS  PubMed  Google Scholar 

  101. Panichi, V. et al. Effects of 1,25(OH)2D3 in experimental mesangial proliferative nephritis in rats. Kidney Int. 60, 87–95 (2001).

    Article  CAS  PubMed  Google Scholar 

  102. Lemire, J. M., Adams, J. S., Sakai, R. & Jordan, S. C. 1 Alpha, 25-dihydroxyvitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. J. Clin. Invest. 74, 657–661 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Adams, J. S. & Hewison, M. Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nat. Clin. Pract. Endocrinol. Metab. 4, 80–90 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Zehnder, D. et al. Reduction of the vitamin D hormonal system in kidney disease is associated with increased renal inflammation. Kidney Int. 74, 1343–1353 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Cohen-Lahav, M., Douvdevani, A., Chaimovitz, C. & Shany, S. The anti-inflammatory activity of 1,25-dihydroxyvitamin D3 in macrophages. J. Steroid Biochem. Mol. Biol. 103, 558–562 (2007).

    Article  CAS  PubMed  Google Scholar 

  107. Sigmundsdottir, H. et al. DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27. Nat. Immunol. 8, 285–293 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Fritsche, J., Mondal, K., Ehrnsperger, A., Andreesen, R. & Kreutz, M. Regulation of 25-hydroxyvitamin D3–1 alpha-hydroxylase and production of 1 alpha, 25-dihydroxyvitamin D3 by human dendritic cells. Blood 102, 3314–3316 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. van Etten, E. & Mathieu, C. Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts. J. Steroid Biochem. Mol. Biol. 97, 93–101 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. Mora, J. R., Iwata, M. & von Andrian, U. H. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat. Rev. Immunol. 8, 685–698 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Penna, G. & Adorini, L. 1 Alpha, 25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J. Immunol. 164, 2405–2411 (2000).

    Article  CAS  PubMed  Google Scholar 

  112. Adorini, L. & Penna, G. Dendritic cell tolerogenicity: a key mechanism in immunomodulation by vitamin D receptor agonists. Hum. Immunol. 70, 345–352 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Ghoreishi, M. et al. Expansion of antigen-specific regulatory T cells with the topical vitamin D analog calcipotriol. J. Immunol. 182, 6071–6078 (2009).

    Article  CAS  PubMed  Google Scholar 

  114. Redaelli, C. A. et al. 1Alpha, 25-dihydroxyvitamin D3 shows strong and additive immunomodulatory effects with cyclosporine A in rat renal allotransplants. Kidney Int. 61, 288–296 (2002).

    Article  CAS  PubMed  Google Scholar 

  115. Courbebaisse, M. et al. Effects of vitamin D supplementation on the calcium-phosphate balance in renal transplant patients. Kidney Int. 75, 646–651 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. Heymann, F. et al. Kidney dendritic cell activation is required for progression of renal disease in a mouse model of glomerular injury. J. Clin. Invest. 119, 1286–1297 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

M. H. de Borst is supported by research grants from the Dutch Kidney Foundation (KJPB.08.07) and the University Medical Center Groningen (Mandema stipend).

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  1. Department of Internal Medicine, Division of Nephrology, University Medical Centre Groningen, University of Groningen, The Netherlands

    Carolina R. C. Doorenbos, Jacob van den Born, Gerjan Navis & Martin H. de Borst

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Correspondence to Martin H. de Borst.

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Doorenbos, C., van den Born, J., Navis, G. et al. Possible renoprotection by vitamin D in chronic renal disease: beyond mineral metabolism. Nat Rev Nephrol 5, 691–700 (2009). https://doi.org/10.1038/nrneph.2009.185

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