Skip to main content

Vitamin D Metabolism and Stones

  • Chapter
  • First Online:
Urinary Tract Stone Disease

Abstract

It has been nearly 90 years since the discovery of the antirachitic activity of vitamin D. During that period, vitamin D structure, metabolism, and mechanism of action at target tissues have been delineated. We now recognize that vitamin D acts as a steroid hormone to help maintain normal calcium and phosphate homeostasis. Many diseases characterized by deranged calcium and phosphate metabolism have been explained by dysregulated vitamin D production and/or action. Calcium-containing kidney stones are believed to result from excessive urinary calcium excretion due to increased intestinal absorption of calcium, increased bone resorption, and renal calcium loss. To try and explain the cause of this hypercalciuria, many studies have focused on the role of deranged vitamin D metabolism and action. Much of our understanding of how such derangements in vitamin D metabolism and action can contribute to the development of hypercalciuria and ultimately kidney stones has come from both clinical and basic approaches that are discussed in this chapter. However, some studies have failed to observe any alteration in vitamin D production or action, while others have implicated a role for increased 1,25(OH)2D production or increased tissue sensitivity in the face of normal circulating 1,25(OH)2D concentrations. Resolution of these discrepancies will require additional studies in hypercalciuric stone-forming patients that focus on the genetics of vitamin D metabolism and the cellular and molecular actions of vitamin D at its target tissues.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Mellanby E. An experimental investigation on rickets. Lancet. 1919;1:407-412.

    Google Scholar 

  2. Askew FA, Bourdillon RB, Bruce HM, et al. The distillation of vitamin D. Proc R Soc. 1931;8107:76-90.

    Google Scholar 

  3. Windaus A, Schenk F, vonWerder F. Uber das antirachitisch wirksame Bestrahlungs-produkt aus 7-dehydrocholesterin. Hoppe-Seylers Z Physiol Chem. 1936;241:100-103.

    CAS  Google Scholar 

  4. International Union of Pure and Applied Chemists (IUPAC). IUPAC Commission on the nomenclature of organic chemistry and IUPAC-IUB commission on biochemical nomenclature. Revised tentative rules for nomenclature of steroids. Biochem J. 1969;113:5-28.

    Google Scholar 

  5. Huldshinsky K. Heilung von rachitis durch künstlich hohen-sonne. Deut Med Wochenschr. 1919;45:712-713.

    Article  Google Scholar 

  6. Steenbock H, Black A. Fat soluble vitamins. XXIII. The induction of growth-promoting and calcifying properties in fats and their unsaponifiable constituents by exposure to light. J Biol Chem. 1925;64:263-298.

    CAS  Google Scholar 

  7. Holick MF, Tian XQ, Allen M. Evolutionary importance for the membrane enhancement of the production of vitamin D3 in the skin of poikilothermic animals. Proc Natl Acad Sci USA. 1995;92:3124-3126.

    Article  CAS  PubMed  Google Scholar 

  8. Holick MF, MacLaughlin JA, Doppelt SH. Factors that influence the cutaneous photosynthesis of previtamin D3. Science. 1981;211:590-593.

    Article  CAS  PubMed  Google Scholar 

  9. Matsuoka LY, Wortsman J, Hanifan N, Holick MF. Chronic sunscreen use decreases circulating concentrations of 25-hydroxyvitamin D: a preliminary study. Arch Dermatol. 1988;124:1802-1804.

    Article  CAS  PubMed  Google Scholar 

  10. Bell NH, Greene A, Epstein S, Oexmann MJ, Shaw W, Shary J. Evidence for alteration of the vitamin D endocrine system in Blacks. J Pediatr. 1985;76:470-473.

    CAS  Google Scholar 

  11. Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous synthesis of vitamin D3:exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab. 1988;67:373-378.

    Article  CAS  PubMed  Google Scholar 

  12. Kodicek E. The metabolism of vitamin D. In: Umbreit W, Molitor H, eds. Proceedings of the Fourth International Congress of Biochemistry, vol. 11. London: Pergamon; 1960.

    Google Scholar 

  13. Neville PF, DeLuca HF. The synthesis of [1, 2–3H]vitamin D3 and the tissue localization of a 0.25 mg (10 IU) dose per rat. Biochemistry. 1966;5:2201-2207.

    Article  CAS  PubMed  Google Scholar 

  14. Blunt JW, DeLuca HF, Schnoes HK. 25-Hydroxycholecalciferol. A biologically active metabolite of vitamin D3. Biochemistry. 1968;7:3317-3322.

    Article  CAS  PubMed  Google Scholar 

  15. Holick MF, Schnoes HK, DeLuca HF, Suda T, Cousins RJ. Isolation and identification of 1, 25-dihydroxycholecalciferol A metabolite of vitamin D active in intestine. Biochemistry. 1971;10:2799-2804.

    Article  CAS  PubMed  Google Scholar 

  16. Fraser DR, Kodicek E. Unique biosynthesis by kidney of a biologically active vitamin D metabolite. Nature. 1970;228:764-766.

    Article  CAS  PubMed  Google Scholar 

  17. Boyle IT, Miravet L, Gray RW, Holick MF, DeLuca HF. The response of intestinal calcium transport to 25-hydroxy and 1, 25-dihydroxyvitamin D in nephrectomized rats. Endocrinology. 1972;90:605-608.

    Article  CAS  PubMed  Google Scholar 

  18. Holick MF, Garabedian M, DeLuca HF. 1, 25-Dihydroxycholecalciferol. Metabolite of vitamin D3 active on bone in anephric rats. Science. 1972;176:1146-1147.

    Article  CAS  PubMed  Google Scholar 

  19. Wong RG, Norman AW, Reddy CR, Coburn JW. Biologic effects of 1, 25-dihydroxycholecalciferol (a highly active vitamin D metabolite) in acutely uremic rats. J Clin Invest. 1972;51:1287-1291.

    Article  CAS  PubMed  Google Scholar 

  20. Cheng JB, Motola DL, Mangelsdorf DJ, Russell DW. De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxilase. J Biol Chem. (2003);278

    Google Scholar 

  21. Hollis BW. Circulating 25-hydroxyvitamin D levels indicative of vitamin D insufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr. 2005;135:317-322.

    CAS  PubMed  Google Scholar 

  22. Paulson SK, DeLuca HF. Subcellular location and properties of rat renal 25-hydroxyvitamin D3-1α-hydroxylase. J Biol Chem. 1985;260:11488-11492.

    CAS  PubMed  Google Scholar 

  23. Bouillon R. Vitamin D: from photosynthesis, metabolism and action to clinical applications. In: Degroot LL, Jameson JL, eds. Endocrinology. Vol 2. 4th ed. Philadelphia, PA: Saunders; 2001.

    Google Scholar 

  24. Zerwekh JE, Breslau NA. Human placental production of 1α, 25-dihydroxyvitamin D3: biochemical characterization and production in normal subjects and patients with pseudohypoparathyroidism. J Clin Endocrinol Metab. 1986;62:192-196.

    Article  CAS  PubMed  Google Scholar 

  25. Sharma OP. Hypercalcemia in granulomatous disorders: a clinical review. Curr Opin Pulmon Med. 2000;6:442-447.

    Article  CAS  Google Scholar 

  26. Diaz R, El-Hajj GF, Brown E. Regulation of Parathyroid Function. New York: Oxford University Press; 1998.

    Google Scholar 

  27. Mia D, He B, Lanske B, et al. Skeletal abnormalities in Pth-null mice are influenced by dietary calcium. Endocrinology. 2004;145:2046-2053.

    Article  Google Scholar 

  28. Portale AA, Halloran BP, Morris RC Jr. Physiologic regulation of the serum concentration of 1, 25-dihydroxyvitamin D by phosphorus in normal men. J Clin Invest. 1989;83:1494-1499.

    Article  CAS  PubMed  Google Scholar 

  29. Shimada T, Kakitani M, Yamazaki Y, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest. 2004;113:561-568.

    CAS  PubMed  Google Scholar 

  30. Liu S, Gupta A, Quarles LD. Emerging role of fibroblast growth factor 23 in a bone-kidney axis regulating systemic phosphate homeostasis and extracellular matrix mineralization. Curr Opin Nephrol. 2007;16:329-325.

    Article  CAS  Google Scholar 

  31. Menna C, Vrtovsnik F, Friedlander G, Corvol M, Garabedian M. Insulin-like growth factor I, a unique calcium-dependent stimulator of 1, 25-dihydroxyvitamin D3 production. Studies in cultured mouse kidney cells. J Biol Chem. 1995;270:25461-25467.

    Article  Google Scholar 

  32. Omdahl JL, Morris HA, May BK. Hydroxylase enzymes of the vitamin D pathway: expression, function, and regulation. Annu Rev Nutr. 2002;22:139-166.

    Article  CAS  PubMed  Google Scholar 

  33. Zerwekh JE, Reed BY, Heller HJ, Gonzalez GB, Haussler MR, Pak CYC. Normal vitamin D receptor concentration and responsiveness to 1, 25-dihydroxyvitamin D3 in skin fibroblasts from patients with absorptive hypercalciuria. Min Elec Metab. 1998;24:307-313.

    Article  CAS  Google Scholar 

  34. Pike JW, Shevde NK. The vitamin D receptor. In: Feldman D, Pike JW, Glorieux FH, eds. Vitamin D. 2nd ed. New York: Elsevier; 2005.

    Google Scholar 

  35. Norman AW. 1α, 25(OH)2-vitamin D3-mediated rapid and genomic responses are dependent upon critical structure-function relationships for both the ligand and receptor(s). In: Feldman D, Pike JW, Glorieux FH, eds. Vitamin D. 2nd ed. New York: Elsevier; 2005.

    Google Scholar 

  36. Christakos S, Dhawan P, Liu Y, Peng X, Porta A. New insights into the mechanisms of vitamin D action. J Cell Biochem. 2003;88:695-705.

    Article  CAS  PubMed  Google Scholar 

  37. Shen FH, Baylink DJ, Nielsen RL, Sherrard DJ, Ivey JL, Haussler MR. Increased serum 1, 25-dihydroxyvitamin D in idiopathic hypercalciuria. J Lab Clin Med. 1977;90:955-962.

    CAS  PubMed  Google Scholar 

  38. Gray RW, Wilz DR, Caldas AE, Lemann J Jr. The importance of phosphate in regulating plasma 1, 25-(OH)2-vitamin D levels in humans: studies in healthy subjects, in calcium stone-formers and in patients with primary hyperparathyroidism. J Clin Endocrinol Metab. 1977;45:299-306.

    Article  CAS  PubMed  Google Scholar 

  39. Kaplan RA, Haussler MR, Deftos LJ, Bone H, Pak CYC. The role of 1α, 25-dihydroxyvitamin D in the mediation of intestinal hyperabsorption of calcium in primary hyperparathyroidism and absorptive hypercalciuria. J Clin Invest. 1977;59:756-760.

    Article  CAS  PubMed  Google Scholar 

  40. Broadus AE, Insogna KI, Lang R, Ellison AF, Dreyer BE. Evidence for disordered control of 1, 25-dihydroxyvitamin D production in absorptive hypercalciuria. N Eng J Med. 1984;311:73-80.

    Article  CAS  Google Scholar 

  41. Insogna KL, Broadus AE, Dreyer BE, Ellison AF, Gertner JM. Elevated production rate of 1, 25-dihydroxyvitamin D in patients with absorptive hypercalciuria. J Clin Endocrinol Metab. 1985;61:490-495.

    Article  CAS  PubMed  Google Scholar 

  42. Bordier P, Ryckewart A, Gueris J, Rasmussen H. On the pathogenesis of so-called idiopathic hypercalciuria. Am J Med. 1977;63:398-409.

    Article  CAS  PubMed  Google Scholar 

  43. Lemann J Jr, Dominguez JH, Gray RW. Idiopathic hypercalciuria: a defect in phosphate and vitamin D metabolism. In: Finlayson B, Thomas WC Jr, eds. Colloquium on Renal Lithiasis. Gainesville, FL: University of Florida Press; 1976.

    Google Scholar 

  44. Dominguez JH, Gray RW, Lemann J. Dietary phosphate deprivation in women and men: effects on mineral and acid balances, parathyroid hormone, and the metabolism of 25-OH-vitamin D. J Clin Endocrinol Metab. 1976;43:1056-1068.

    Article  CAS  PubMed  Google Scholar 

  45. Barilla DE, Zerwekh JE, Pak CYC. A critical evaluation of the role of phosphate in the pathogenesis of absorptive hypercalciuria. Min Elect Metab. 1979;2:302-309.

    CAS  Google Scholar 

  46. Pak CYC, Fetner C, Townsend J, et al. Evaluation of calcium urolithiasis in ambulatory patients. Comparison of results with those of inpatient evaluation. Am J Med. 1978;64:979-987.

    Article  CAS  PubMed  Google Scholar 

  47. Scott P, Ouimet D, Proulx Y, et al. The 1 alpha-hydroxylase locus is not linked to calcium stone formation or calciuric phenotypes in French-Canadian families. J Am Soc Nephrol. 1998;9:425-432.

    CAS  PubMed  Google Scholar 

  48. Petrucci M, Scott P, Ouimet D, et al. Evaluation of the calcium-sensing receptor gene in idiopathic hypercalciuria and calcium Nephrolithiasis. Kidney Int. 2000;58:38-42.

    Article  CAS  PubMed  Google Scholar 

  49. Scott P, Ouimet D, Valiquette L, et al. Suggestive evidence for a susceptibility gene near the vitamin D receptor locus in idiopathic calcium stone formation. J Am Soc Nephrol. 1999;105:1007-1013.

    Google Scholar 

  50. McDonnell DP, Mangelsdorf DJ, Pike JW, Haussler MR, O’Malley BW. Molecular cloning of complementary DNA encoding the avian receptor for vitamin D. Science. 1987;235:1214-1217.

    Article  CAS  PubMed  Google Scholar 

  51. Zerwekh JE, Yu X-P, Breslau NA, Manolagas S, Pak CYC. Vitamin D receptor quantitation in human blood mononuclear cells in health & disease. Mol Cell Endocrinol. 1993;96:1-6.

    Article  CAS  PubMed  Google Scholar 

  52. Mangelsdorf DJ, Pike JW, Haussler MR. Avian and mammalian receptors for 1, 25-dihydroxyvitamin D3: in vitro translation to characterize size and hormone-dependent regulation. Proc Natl Acad Sci USA. 1987;84:354-358.

    Article  CAS  PubMed  Google Scholar 

  53. Nun JD, Katz DR, Barker S, et al. Regulation of human tonsillar T-cell proliferation by the active metabolite of vitamin D3. Immunol. 1986;59:479-484.

    Google Scholar 

  54. Rigby WF, Noelle RJ, Krause K, Fanger MW. The effects of 1, 25-dihydroxyvitamin D3 on human T lymphocyte activation and proliferation. J Immunol. 1985;135:2279-2286.

    CAS  PubMed  Google Scholar 

  55. Favus MJ, Karnauskas AJ, Parks JH, Coe FL. Peripheral blood monocyte vitamin D receptor levels are elevated in patients with idiopathic hypercalciuria. J Clin Endocrinol Metab. 2004;89:4937-4943.

    Article  CAS  PubMed  Google Scholar 

  56. Sriussadaporn S, Wong M, Pike JW, Favus MJ. Tissue specificity and mechanism of vitamin D receptor up-regulation during dietary phosphorus restriction in the rat. J Bone Min Res. 1995;10:271-280.

    Article  CAS  Google Scholar 

  57. Feldman D, Chen T, Hirst M, Colston K, Karasek M, Cone C. Demonstration of 1, 25-dihydroxyvitamin D3 receptors in human skin biopsies. J Clin Endocrinol Metab. 1980;51:1463-1465.

    Article  CAS  PubMed  Google Scholar 

  58. Wiese RJ, Uhland-Smith A, Ross TK, Prahl JM, DeLuca HF. Up-regulation of the vitamin D receptor in response to 1, 25-dihydroxyvitamin D3 results from ligand-induced stabilization. J Biol Chem. 1992;267:20082-20086.

    CAS  PubMed  Google Scholar 

  59. Santiso-Mere D, Sore T, Hilliard GM IV, Pike JW, McDonnell DP. Positive regulation of the vitamin D receptor by its cognate ligand in heterologous expression systems. Mol Endocrinol. 1993;7:833-839.

    Article  CAS  PubMed  Google Scholar 

  60. Arbour NC, Prahl JM, DeLuca HF. Stabilization of the vitamin D receptor in rat osteosarcoma cells through the action of 1, 25-dihydroxyvitamin D3. Mol Endocrinol. 1993;7:1307-1312.

    Article  CAS  PubMed  Google Scholar 

  61. Zerwekh JE, Hughes MR, Reed BY, et al. Evidence for normal vitamin D receptor messenger ribonucleic acid and genotype in absorptive hypercalciuria. J Clin Endocrinol Metab. 1995;80:2960-2965.

    Article  CAS  PubMed  Google Scholar 

  62. Coe FL, Parks JA, Moore ES. Familial idiopathic hypercalciuria. N Eng J Med. 1979;300:337-340.

    Article  CAS  Google Scholar 

  63. Pak CYC, McGuire L, Peterson R, Britton F, Harrod MJ. Familial absorptive hyper-calciuria in a large kindred. J Urol. 1981;126:717-719.

    CAS  PubMed  Google Scholar 

  64. Li X-Q, Tembe V, Horwitz GM, Bushinsky DA, Favus MJ. Increased intestinal vitamin D receptor in genetic hypercalciuric rats; a cause of intestinal calcium hyperabsorption. J Clin Invest. 1993;91:661-667.

    Article  CAS  PubMed  Google Scholar 

  65. Pietschmann F, Breslau NA, Pak CYC. Reduced vertebral bone density in hypercalciuric nephrolithiasis. J Bone Min Res. 1992;7:661-667.

    Google Scholar 

  66. Morrison NA, Yeoman R, Kelly PJ, Eisman JA. Contribution of trans-acting alleles to normal physiological variability: vitamin D receptor gene polymorphisms and circulating osteocalcin. Proc Natl Acad Sci USA. 1992;89:6665-6669.

    Article  CAS  PubMed  Google Scholar 

  67. Morrison NA, Qi JC, Tokita A, et al. Prediction of bone density from vitamin D receptor alleles. Nature. 1994;367:284-287.

    Article  CAS  PubMed  Google Scholar 

  68. Bushinsky DA FMJ. Mechanism of hypercalciuria in genetic hypercalciuric rats: inherited defect in intestinal calcium transport. J Clin Invest. 1988;82:1585-1591.

    Article  Google Scholar 

  69. Bushinsky DA, Frick KK, Nehrke K. Genetic hypercalciuric stone-forming rats. Curr Opin Neph Hyperten. 2006;15:403-418.

    Article  CAS  Google Scholar 

  70. Karnauskas AJ, Van Leeuwen JPTM, van den Bemd G-J, et al. Mechanism and function of high vitamin D receptor levels in genetic hypercalciuric stone-forming rats. J Bone Min Res. 2005;20:447-454.

    Article  CAS  Google Scholar 

  71. Hoenderop JG, Nilius B, Bindels RJ. Molecular mechanism of active Ca2+ reabsorption in the distal nephron. Annu Rev Physiol. 2002;64:529-549.

    Article  CAS  PubMed  Google Scholar 

  72. Tsuruoka S, Bushinsky DA, Schwartz GJ. Defective renal calcium reabsorption in genetic hypercalciuric rats. Kidney Int. 1997;51:1540-1547.

    Article  CAS  PubMed  Google Scholar 

  73. Hoenderop JG, Nilius B, Bindels RJ. Calcium absorption across epithelia. Physiol Rev. 2005;85:373-422.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joseph E. Zerwekh .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer London

About this chapter

Cite this chapter

Zerwekh, J.E. (2010). Vitamin D Metabolism and Stones. In: Rao, N., Preminger, G., Kavanagh, J. (eds) Urinary Tract Stone Disease. Springer, London. https://doi.org/10.1007/978-1-84800-362-0_13

Download citation

  • DOI: https://doi.org/10.1007/978-1-84800-362-0_13

  • Published:

  • Publisher Name: Springer, London

  • Print ISBN: 978-1-84800-361-3

  • Online ISBN: 978-1-84800-362-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics