Pediatric Nephrology

, Volume 27, Issue 12, pp 2167–2173 | Cite as

Can vitamin D slow down the progression of chronic kidney disease?



Pharmacological blockade of the renin–angiotensin–aldosterone system (RAAS) is the cornerstone of renoprotective therapy, and the reduction of persistent RAAS activation is considered to be an important target in the treatment of chronic kidney disease (CKD). Vitamin D is a steroid hormone that controls a broad range of metabolic and cell regulatory functions. It acts as a transcription factor and can suppress the renin gene, thereby acting as a negative endocrine regulator of RAAS. RAAS activation can reduce renal Klotho expression, and the Klotho–fibroblast growth factor 23 interaction may further reduce the production of active vitamin D. Results from both clinical and experimental studies suggest that vitamin D therapy is associated with a reduction in blood pressure and left ventricular hypertrophy and improves cardiovascular outcomes. In addition, a reduction in angiotensin II through RAAS blockade may have anti-proteinuric and anti-fibrotic effects. Vitamin D has also been shown to modulate the immune system, regulate inflammatory responses, improve insulin sensitivity and reduce high-density lipoprotein cholesterol. Taken together, these pleiotropic effects of vitamin D may slow down the progression of CKD. In this review, we discuss the experimental and early clinical findings that suggest a renoprotective effect of vitamin D, thereby providing an additional rationale beyond mineral metabolism for the close monitoring of, and supplemention with vitamin D from the earliest stages of CKD.


Chronic kidney disease Cardiovascular disease 25-Hydroxyvitamin D [25(OH)D] 1,25-Dihydroxyvitamin D [1,25(OH)2D] 


  1. 1.
    Holick MF (2007) Vitamin D deficiency. N Engl J Med 357:266–281PubMedCrossRefGoogle Scholar
  2. 2.
    Shroff R, Knott C, Rees L (2010) The virtues of vitamin D—but how much is too much? Pediatr Nephrol 25:1607–1620PubMedCrossRefGoogle Scholar
  3. 3.
    Zittermann A, Schleithoff SS, Koerfer R (2005) Putting cardiovascular disease and vitamin D insufficiency into perspective. Br J Nutr 94:483–492PubMedCrossRefGoogle Scholar
  4. 4.
    Melamed ML, Michos ED, Post W, Astor B (2008) 25-Hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med 168:1629–1637PubMedCrossRefGoogle Scholar
  5. 5.
    Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R (2003) Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med 349:446–456PubMedCrossRefGoogle Scholar
  6. 6.
    Tentori F, Hunt WC, Stidley CA, Rohrscheib MR, Bedrick EJ, Meyer KB, Johnson HK, Zager PG (2006) Mortality risk among hemodialysis patients receiving different vitamin D analogs. Kidney Int 70:1858–1865PubMedCrossRefGoogle Scholar
  7. 7.
    Wolf M, Shah A, Gutierrez O, Ankers E, Monroy M, Tamez H, Steele D, Chang Y, Camargo CA Jr, Tonelli M, Thadhani R (2007) Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int 72:1004–1013PubMedCrossRefGoogle Scholar
  8. 8.
    Fogo AB (2007) Mechanisms of progression of chronic kidney disease. Pediatr Nephrol 22:2011–2022PubMedCrossRefGoogle Scholar
  9. 9.
    Wingen AM, Fabian-Bach C, Schaefer F, Mehls O (1997) Randomised multicentre study of a low-protein diet on the progression of chronic renal failure in children. European Study Group of Nutritional Treatment of Chronic Renal Failure in Childhood. Lancet 349:1117–1123PubMedCrossRefGoogle Scholar
  10. 10.
    Peterson JC, Adler S, Burkart JM, Greene T, Hebert LA, Hunsicker LG, King AJ, Klahr S, Massry SG, Seifter JL (1995) Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Intern Med 123:754–762PubMedGoogle Scholar
  11. 11.
    Wuhl E, Trivelli A, Picca S, Litwin M, Peco-Antic A, Zurowska A, Testa S, Jankauskiene A, Emre S, Caldas-Afonso A, Anarat A, Niaudet P, Mir S, Bakkaloglu A, Enke B, Montini G, Wingen AM, Sallay P, Jeck N, Berg U, Caliskan S, Wygoda S, Hohbach-Hohenfellner K, Dusek J, Urasinski T, Arbeiter K, Neuhaus T, Gellermann J, Drozdz D, Fischbach M, Moller K, Wigger M, Peruzzi L, Mehls O, Schaefer F (2009) Strict blood-pressure control and progression of renal failure in children. N Engl J Med 361:1639–1650PubMedCrossRefGoogle Scholar
  12. 12.
    Volpe M, Savoia C, De PP, Ostrowska B, Tarasi D, Rubattu S (2002) The renin-angiotensin system as a risk factor and therapeutic target for cardiovascular and renal disease. J Am Soc Nephrol 13(Suppl 3):S173–S178PubMedCrossRefGoogle Scholar
  13. 13.
    Levin A, Bakris GL, Molitch M, Smulders M, Tian J, Williams LA, Andress DL (2007) 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 71:31–38PubMedCrossRefGoogle Scholar
  14. 14.
    Verstuyf A, Carmeliet G, Bouillon R, Mathieu C (2010) Vitamin D: a pleiotropic hormone. Kidney Int 78:140–145PubMedCrossRefGoogle Scholar
  15. 15.
    Cardus A, Parisi E, Gallego C, Aldea M, Fernandez E, Valdivielso JM (2006) 1,25-Dihydroxyvitamin D3 stimulates vascular smooth muscle cell proliferation through a VEGF-mediated pathway. Kidney Int 69:1377–1384PubMedGoogle Scholar
  16. 16.
    Hsu JJ, Tintut Y, Demer LL (2008) Vitamin D and osteogenic differentiation in the artery wall. Clin J Am Soc Nephrol 3:1542–1547PubMedCrossRefGoogle Scholar
  17. 17.
    Mathew S, Lund RJ, Chaudhary LR, Geurs T, Hruska KA (2008) Vitamin D receptor activators can protect against vascular calcification. J Am Soc Nephrol 19:1509–1519PubMedCrossRefGoogle Scholar
  18. 18.
    London GM, Guerin AP, Verbeke FH, Pannier B, Boutouyrie P, Marchais SJ, Metivier F (2007) Mineral metabolism and arterial functions in end-stage renal disease: potential role of 25-hydroxyvitamin D deficiency. J Am Soc Nephrol 18:613–620PubMedCrossRefGoogle Scholar
  19. 19.
    Shroff R, Egerton M, Bridel M, Shah V, Donald AE, Cole TJ, Hiorns MP, Deanfield JE, Rees L (2008) A bimodal association of vitamin D levels and vascular disease in children on dialysis. J Am Soc Nephrol 19:1239–1246PubMedCrossRefGoogle Scholar
  20. 20.
    Thadhani R, Wolf M (2007) Vitamin D in patients with kidney disease: cautiously optimistic. Adv Chronic Kidney Dis 14:22–26PubMedCrossRefGoogle Scholar
  21. 21.
    Wolf M, Thadhani R (2005) Beyond minerals and parathyroid hormone: role of active vitamin D in end-stage renal disease. Semin Dial 18:302–306PubMedCrossRefGoogle Scholar
  22. 22.
    Bikle D (2009) Nonclassic actions of vitamin D. J Clin Endocrinol Metab 94:26–34PubMedCrossRefGoogle Scholar
  23. 23.
    Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002) 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 110:229–238PubMedGoogle Scholar
  24. 24.
    Xiang W, Kong J, Chen S, Cao LP, Qiao G, Zheng W, Liu W, Li X, Gardner DG, Li YC (2005) Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems. Am J Physiol Endocrinol Metab 288:E125–E132PubMedCrossRefGoogle Scholar
  25. 25.
    Yuan W, Pan W, Kong J, Zheng W, Szeto FL, Wong KE, Cohen R, Klopot A, Zhang Z, Li YC (2007) 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 282:29821–29830PubMedCrossRefGoogle Scholar
  26. 26.
    Tiosano D, Schwartz Y, Braver Y, Hadash A, Gepstein V, Weisman Y, Lorber A (2011) The renin-angiotensin system, blood pressure, and heart structure in patients with hereditary vitamin D-resistance rickets (HVDRR). J Bone Miner Res 26:2252–2260PubMedCrossRefGoogle Scholar
  27. 27.
    Zhou C, Lu F, Cao K, Xu D, Goltzman D, Miao D (2008) Calcium-independent and 1,25(OH)2D3-dependent regulation of the renin-angiotensin system in 1-alpha-hydroxylase knockout mice. Kidney Int 74:170–179PubMedCrossRefGoogle Scholar
  28. 28.
    Zhang Z, Zhang Y, Ning G, Deb DK, Kong J, Li YC (2008) Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: blockade of compensatory renin increase. Proc Natl Acad Sci USA 105:15896–15901PubMedCrossRefGoogle Scholar
  29. 29.
    Mizobuchi M, Morrissey J, Finch JL, Martin DR, Liapis H, Akizawa T, Slatopolsky E (2007) 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 18:1796–1806PubMedCrossRefGoogle Scholar
  30. 30.
    Tan X, Li Y, Liu Y (2006) Paricalcitol attenuates renal interstitial fibrosis in obstructive nephropathy. J Am Soc Nephrol 17:3382–3393PubMedCrossRefGoogle Scholar
  31. 31.
    Tan X, Wen X, Liu Y (2008) Paricalcitol inhibits renal inflammation by promoting vitamin D receptor-mediated sequestration of NF-kappaB signaling. J Am Soc Nephrol 19:1741–1752PubMedCrossRefGoogle Scholar
  32. 32.
    Feneis JF, Arora RR (2010) Role of vitamin D in blood pressure homeostasis. Am J Ther 17:e221–e229PubMedCrossRefGoogle Scholar
  33. 33.
    Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K, Benjamin EJ, D'Agostino RB, Wolf M, Vasan RS (2008) Vitamin D deficiency and risk of cardiovascular disease. Circulation 117:503–511PubMedCrossRefGoogle Scholar
  34. 34.
    Rostand SG (2010) Vitamin D, blood pressure, and African Americans: toward a unifying hypothesis. Clin J Am Soc Nephrol 5:1697–1703PubMedCrossRefGoogle Scholar
  35. 35.
    Kim HW, Park CW, Shin YS, Kim YS, Shin SJ, Kim YS, Choi EJ, Chang YS, Bang BK (2006) Calcitriol regresses cardiac hypertrophy and QT dispersion in secondary hyperparathyroidism on hemodialysis. Nephron Clin Pract 102:c21–c29PubMedCrossRefGoogle Scholar
  36. 36.
    Park CW, Oh YS, Shin YS, Kim CM, Kim YS, Kim SY, Choi EJ, Chang YS, Bang BK (1999) Intravenous calcitriol regresses myocardial hypertrophy in hemodialysis patients with secondary hyperparathyroidism. Am J Kidney Dis 33:73–81PubMedCrossRefGoogle Scholar
  37. 37.
    Mak RH (1992) Amelioration of hypertension and insulin resistance by 1,25-dihydroxycholecalciferol in hemodialysis patients. Pediatr Nephrol 6:345–348PubMedCrossRefGoogle Scholar
  38. 38.
    Wang AY, Lam CW, Sanderson JE, Wang M, Chan IH, Lui SF, Sea MM, Woo J (2008) Serum 25-hydroxyvitamin D status and cardiovascular outcomes in chronic peritoneal dialysis patients: a 3-y prospective cohort study. Am J Clin Nutr 87:1631–1638PubMedGoogle Scholar
  39. 39.
    Shroff R, Knott C, Gullett A, Wells D, Marks S, Rees L (2011) Vitamin D deficiency is associated with short stature and hypertension in paediatric renal transplant recipients. Pediatr Nephrol 26:2227–2233PubMedCrossRefGoogle Scholar
  40. 40.
    Lee BK, Lee GS, Stewart WF, Ahn KD, Simon D, Kelsey KT, Todd AC, Schwartz BS (2001) Associations of blood pressure and hypertension with lead dose measures and polymorphisms in the vitamin D receptor and delta-aminolevulinic acid dehydratase genes. Environ Health Perspect 109:383–389PubMedGoogle Scholar
  41. 41.
    Nakano Y, Oshima T, Sasaki S, Yamaoka K, Matsumoto T, Hirao H, Ozono R, Matsuura H, Kajiyama G, Kambe M (2000) Vitamin D receptor gene polymorphism is associated with serum total and ionized calcium concentration. J Mol Med (Berl) 78:575–579CrossRefGoogle Scholar
  42. 42.
    Vaidya A, Sun B, Forman JP, Hopkins PN, Brown NJ, Kolatkar NS, Williams GH, Williams JS (2011) The Fok1 vitamin D receptor gene polymorphism is associated with plasma renin activity in Caucasians. Clin Endocrinol (Oxf) 74:783–790CrossRefGoogle Scholar
  43. 43.
    Agarwal R (2009) Vitamin D, proteinuria, diabetic nephropathy, and progression of CKD. Clin J Am Soc Nephrol 4:1523–1528PubMedCrossRefGoogle Scholar
  44. 44.
    de Zeeuw D, Agarwal R, Amdahl M, Audhya P, Coyne D, Garimella T, Parving HH, Pritchett Y, Remuzzi G, Ritz E, Andress D (2010) Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet 376:1543–1551PubMedCrossRefGoogle Scholar
  45. 45.
    Shroff RC, McNair R, Figg N, Skepper JN, Schurgers L, Gupta A, Hiorns M, Donald AE, Deanfield J, Rees L, Shanahan CM (2008) Dialysis accelerates medial vascular calcification in part by triggering smooth muscle cell apoptosis. Circulation 118:1748–1757PubMedCrossRefGoogle Scholar
  46. 46.
    Shroff RC, Donald AE, Hiorns MP, Watson A, Feather S, Milford D, Ellins EA, Storry C, Ridout D, Deanfield J, Rees L (2007) Mineral metabolism and vascular damage in children on dialysis. J Am Soc Nephrol 18:2996–3003PubMedCrossRefGoogle Scholar
  47. 47.
    Shroff RC, Shanahan CM (2007) The vascular biology of calcification. Semin Dial 20:103–109PubMedCrossRefGoogle Scholar
  48. 48.
    Carthy EP, Yamashita W, Hsu A, Ooi BS (1989) 1,25-Dihydroxyvitamin D3 and rat vascular smooth muscle cell growth. Hypertension 13:954–959PubMedCrossRefGoogle Scholar
  49. 49.
    Becker LE, Koleganova N, Piecha G, Noronha ID, Zeier M, Geldyyev A, Kokeny G, Ritz E, Gross ML (2010) Effect of paricalcitol and calcitriol on aortic wall remodeling in uninephrectomized ApoE knockout mice. Am J Physiol Renal Physiol 300:F772–F782PubMedCrossRefGoogle Scholar
  50. 50.
    Wu-Wong JR, Noonan W, Ma J, Dixon D, Nakane M, Bolin AL, Koch KA, Postl S, Morgan SJ, Reinhart GA (2006) Role of phosphorus and vitamin D analogs in the pathogenesis of vascular calcification. J Pharmacol Exp Ther 318:90–98PubMedCrossRefGoogle Scholar
  51. 51.
    Baeke F, Gysemans C, Korf H, Mathieu C (2010) Vitamin D insufficiency: implications for the immune system. Pediatr Nephrol 25:1597–1606PubMedCrossRefGoogle Scholar
  52. 52.
    Zehnder D, Quinkler M, Eardley KS, Bland R, Lepenies J, Hughes SV, Raymond NT, Howie AJ, Cockwell P, Stewart PM, Hewison M (2008) Reduction of the vitamin D hormonal system in kidney disease is associated with increased renal inflammation. Kidney Int 74:1343–1353PubMedCrossRefGoogle Scholar
  53. 53.
    Inaguma D, Nagaya H, Hara K, Tatematsu M, Shinjo H, Suzuki S, Mishima T, Kurata K (2008) Relationship between serum 1,25-dihydroxyvitamin D and mortality in patients with pre-dialysis chronic kidney disease. Clin Exp Nephrol 12:126–131PubMedCrossRefGoogle Scholar
  54. 54.
    Teng M, Wolf M, Ofsthun MN, Lazarus JM, Hernan MA, Camargo CA Jr, Thadhani R (2005) Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol 16:1115–1125PubMedCrossRefGoogle Scholar
  55. 55.
    Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zugel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL (2006) Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311:1770–1773PubMedCrossRefGoogle Scholar
  56. 56.
    de Boer I (2008) Vitamin D and glucose metabolism in chronic kidney disease. Curr Opin Nephrol Hypertens 17:566–572PubMedCrossRefGoogle Scholar
  57. 57.
    Zhang Z, Sun L, Wang Y, Ning G, Minto AW, Kong J, Quigg RJ, Li YC (2008) Renoprotective role of the vitamin D receptor in diabetic nephropathy. Kidney Int 73:163–171PubMedCrossRefGoogle Scholar
  58. 58.
    Praga M, Hernandez E, Morales E, Campos AP, Valero MA, Martinez MA, Leon M (2001) Clinical features and long-term outcome of obesity-associated focal segmental glomerulosclerosis. Nephrol Dial Transplant 16:1790–1798PubMedCrossRefGoogle Scholar
  59. 59.
    Alemzadeh R, Kichler J, Babar G, Calhoun M (2008) Hypovitaminosis D in obese children and adolescents: relationship with adiposity, insulin sensitivity, ethnicity, and season. Metabolism 57:183–191PubMedCrossRefGoogle Scholar
  60. 60.
    Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF (2000) Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 72:690–693PubMedGoogle Scholar
  61. 61.
    Sneve M, Figenschau Y, Jorde R (2008) Supplementation with cholecalciferol does not result in weight reduction in overweight and obese subjects. Eur J Endocrinol 159:675–684PubMedCrossRefGoogle Scholar
  62. 62.
    Rodriguez-Rodriguez E, Ortega RM, Gonzalez-Rodriguez LG, Lopez-Sobaler AM (2011) Vitamin D deficiency is an independent predictor of elevated triglycerides in Spanish school children. Eur J Nutr 50:373–378PubMedCrossRefGoogle Scholar
  63. 63.
    Zittermann A, Gummert JF, Borgermann J (2011) The role of vitamin d in dyslipidemia and cardiovascular disease. Curr Pharm Des 17:933–942PubMedCrossRefGoogle Scholar
  64. 64.
    Mitani H, Ishizaka N, Aizawa T, Ohno M, Usui S, Suzuki T, Amaki T, Mori I, Nakamura Y, Sato M, Nangaku M, Hirata Y, Nagai R (2002) In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage. Hypertension 39:838–843PubMedCrossRefGoogle Scholar
  65. 65.
    Yoon HE, Ghee JY, Piao S, Song JH, Han DH, Kim S, Ohashi N, Kobori H, Kuro-o M, Yang CW (2011) Angiotensin II blockade upregulates the expression of Klotho, the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy. Nephrol Dial Transplant 26:800–813PubMedCrossRefGoogle Scholar
  66. 66.
    Shroff R, Shanahan CM (2011) Klotho: an elixir of youth for the vasculature? J Am Soc Nephrol 22:5–7PubMedCrossRefGoogle Scholar

Copyright information

© IPNA 2011

Authors and Affiliations

  1. 1.Renal UnitGreat Ormond Street Hospital for Children NHS TrustLondonUK

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