Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

CYP3A4 is a crosslink between vitamin D and calcineurin inhibitors in solid organ transplant recipients: implications for bone health

Abstract

The use of calcineurin inhibitors (CNIs) and vitamin D deficiency may contribute to the pathogenesis of post-transplant bone disease. CNIs and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) are substrates of the drug-metabolizing enzyme CYP3A4. This review summarizes the indications for the use of activated vitamin D analogs in post-transplant care and the current knowledge on the impact of CNIs on bone. We searched for clinical evidence of the interaction between CNIs and 1,25(OH)2D3. We also provide an overview of the literature on the interplay between vitamin D metabolism and CYP3A4 in experimental and clinical settings and discuss its possible implications for solid organ transplant recipients. In conclusion, there is a body of evidence on the interplay between vitamin D and the drug-metabolizing enzyme CYP3A4, which may have therapeutic implications.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Leidig-Bruckner G, Hosch S, Dodidou P, Ritschel D, Conradt C, Klose C et al. Frequency and predictors of osteoporotic fractures after cardiac or liver transplantation: a follow-up study. Lancet 2001; 357: 342–347.

    CAS  PubMed  Google Scholar 

  2. Jeon HJ, Kim H, Yang J . Bone disease in post-transplant patients. Curr Opin Endocrinol Diabetes Obes 2015; 22: 452–458.

    CAS  PubMed  Google Scholar 

  3. Yu TM, Lin CL, Chang SN, Sung FC, Huang ST, Kao CH . Osteoporosis and fractures after solid organ transplantation: a nationwide population-based cohort study. Mayo Clin Proc 2014; 89: 888–895.

    PubMed  Google Scholar 

  4. Molnar MZ, Naser MS, Rhee CM, Kalantar-Zadeh K, Bunnapradist S . Bone and mineral disorders after kidney transplantation: therapeutic strategies. Transplant Rev (Orlando) 2014; 28: 56–62.

    Google Scholar 

  5. Stein E, Ebeling P, Shane E . Post-transplantation osteoporosis. Endocrinol Metab Clin North Am 2007; 36: 937–963, viii.

    CAS  PubMed  Google Scholar 

  6. Malluche HH, Monier-Faugere MC, Herberth J . Bone disease after renal transplantation. Nat Rev Nephrol 2010; 6: 32–40.

    PubMed  Google Scholar 

  7. Koch Nogueira PC, David L, Cochat P . Evolution of secondary hyperparathyroidism after renal transplantation. Pediatr Nephrol 2000; 14: 342–346.

    CAS  PubMed  Google Scholar 

  8. Lee CT, Ng HY, Lien YH, Lai LW, Wu MS, Lin CR et al. Effects of cyclosporine, tacrolimus and rapamycin on renal calcium transport and vitamin D metabolism. Am J Nephrol 2011; 34: 87–94.

    CAS  PubMed  Google Scholar 

  9. Dusso AS, Brown AJ, Slatopolsky E . Vitamin D. Am J Physiol Renal Physiol 2005; 289: F8–28.

    CAS  PubMed  Google Scholar 

  10. Courbebaisse M, Souberbielle JC, Thervet E . Potential nonclassical effects of vitamin D in transplant recipients. Transplantation 2010; 89: 131–137.

    CAS  PubMed  Google Scholar 

  11. Holick MF . Vitamin D deficiency. N Engl J Med 2007; 357: 266–281.

    CAS  PubMed  Google Scholar 

  12. Ledger JE, Watson GJ, Ainley CC, Compston JE . Biliary excretion of radioactivity after intravenous administration of 3H-1,25-dihydroxyvitamin D3 in man. Gut 1985; 26: 1240–1245.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kumar R, Nagubandi S, Mattox VR, Londowski JM . Enterohepatic physiology of 1,25-dihydroxyvitamin D3. J Clin Invest 1980; 65: 277–284.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Xu Y, Hashizume T, Shuhart MC, Davis CL, Nelson WL, Sakaki T et al. Intestinal and hepatic CYP3A4 catalyze hydroxylation of 1alpha,25-dihydroxyvitamin D(3): implications for drug-induced osteomalacia. Mol Pharmacol 2006; 69: 56–65.

    CAS  PubMed  Google Scholar 

  15. Wang Z, Lin YS, Zheng XE, Senn T, Hashizume T, Scian M et al. An inducible cytochrome P450 3A4-dependent vitamin D catabolic pathway. Mol Pharmacol 2012; 81: 498–509.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Staatz CE, Tett SE . Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet 2004; 43: 623–653.

    CAS  PubMed  Google Scholar 

  17. Staatz CE, Goodman LK, Tett SE . Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I. Clin Pharmacokinet 2010; 49: 141–175.

    CAS  PubMed  Google Scholar 

  18. De Bruyne R, Bogaert D, De Ruyck N, Lambrecht BN, Van Winckel M, Gevaert P et al. Calcineurin inhibitors dampen humoral immunity by acting directly on naive B cells. Clin Exp Immunol 2015; 180: 542–550.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Spencer CM, Goa KL, Gillis JC . Tacrolimus. An update of its pharmacology and clinical efficacy in the management of organ transplantation. Drugs 1997; 54: 925–975.

    CAS  PubMed  Google Scholar 

  20. Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001; 27: 383–391.

    CAS  PubMed  Google Scholar 

  21. Guengerich FP . Cytochrome P-450 3A4: regulation and role in drug metabolism. Annu Rev Pharmacol Toxicol 1999; 39: 1–17.

    CAS  PubMed  Google Scholar 

  22. Cianferotti L, Cricelli C, Kanis JA, Nuti R, Reginster JY, Ringe JD et al. The clinical use of vitamin D metabolites and their potential developments: a position statement from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the International Osteoporosis Foundation (IOF). Endocrine 2015; 50: 12–26.

    CAS  PubMed  Google Scholar 

  23. Kiattisunthorn K, Wutyam K, Indranoi A, Vasuvattakul S . Randomized trial comparing pulse calcitriol and alfacalcidol for the treatment of secondary hyperparathyroidism in haemodialysis patients. Nephrology (Carlton) 2011; 16: 277–284.

    CAS  Google Scholar 

  24. Courbebaisse M, Thervet E, Souberbielle JC, Zuber J, Eladari D, Martinez F et al. Effects of vitamin D supplementation on the calcium-phosphate balance in renal transplant patients. Kidney Int 2009; 75: 646–651.

    CAS  PubMed  Google Scholar 

  25. Trillini M, Cortinovis M, Ruggenenti P, Reyes Loaeza J, Courville K, Ferrer-Siles C et al. Paricalcitol for secondary hyperparathyroidism in renal transplantation. J Am Soc Nephrol 2015; 26: 1205–1214.

    CAS  PubMed  Google Scholar 

  26. Peppone LJ, Hebl S, Purnell JQ, Reid ME, Rosier RN, Mustian KM et al. The efficacy of calcitriol therapy in the management of bone loss and fractures: a qualitative review. Osteoporos Int 2010; 21: 1133–1149.

    CAS  PubMed  Google Scholar 

  27. Stein EM, Ortiz D, Jin Z, McMahon DJ, Shane E . Prevention of fractures after solid organ transplantation: a meta-analysis. J Clin Endocrinol Metab 2011; 96: 3457–3465.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Elder GJ, Moy C . Bone-protective therapy after kidney and kidney pancreas transplantation. J Bone Miner Res 2004; 19: S476–S476.

    Google Scholar 

  29. El-Agroudy AE, El-Husseini AA, El-Sayed M, Mohsen T, Ghoneim MA . A prospective randomized study for prevention of postrenal transplantation bone loss. Kidney Int 2005; 67: 2039–2045.

    PubMed  Google Scholar 

  30. Shane E, Addesso V, Namerow PB, McMahon DJ, Lo SH, Staron RB et al. Alendronate versus calcitriol for the prevention of bone loss after cardiac transplantation. N Engl J Med 2004; 350: 767–776.

    CAS  PubMed  Google Scholar 

  31. Jeffery JR, Leslie WD, Karpinski ME, Nickerson PW, Rush DN . Prevalence and treatment of decreased bone density in renal transplant recipients: a randomized prospective trial of calcitriol versus alendronate. Transplantation 2003; 76: 1498–1502.

    PubMed  Google Scholar 

  32. Mainra R, Elder GJ . Individualized therapy to prevent bone mineral density loss after kidney and kidney-pancreas transplantation. Clin J Am Soc Nephrol 2010; 5: 117–124.

    PubMed  PubMed Central  Google Scholar 

  33. Cohen A, Addesso V, McMahon DJ, Staron RB, Namerow P, Maybaum S et al. Discontinuing antiresorptive therapy one year after cardiac transplantation: effect on bone density and bone turnover. Transplantation 2006; 81: 686–691.

    CAS  PubMed  Google Scholar 

  34. Moe SM, Drueke TB . Management of secondary hyperparathyroidism: the importance and the challenge of controlling parathyroid hormone levels without elevating calcium, phosphorus, and calcium-phosphorus product. Am J Nephrol 2003; 23: 369–379.

    CAS  PubMed  Google Scholar 

  35. Sprague SM, Llach F, Amdahl M, Taccetta C, Batlle D . Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism. Kidney Int 2003; 63: 1483–1490.

    CAS  PubMed  Google Scholar 

  36. Coyne DW, Goldberg S, Faber M, Ghossein C, Sprague SM . A randomized multicenter trial of paricalcitol versus calcitriol for secondary hyperparathyroidism in stages 3-4 CKD. Clin J Am Soc Nephrol 2014; 9: 1620–1626.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. de Boer IH, Kestenbaum B, Shoben AB, Michos ED, Sarnak MJ, Siscovick DS . 25-hydroxyvitamin D levels inversely associate with risk for developing coronary artery calcification. J Am Soc Nephrol 2009; 20: 1805–1812.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. de Zeeuw D, Agarwal R, Amdahl M, Audhya P, Coyne D, Garimella T 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 2010; 376: 1543–1551.

    CAS  PubMed  Google Scholar 

  39. Chun RF, Liu PT, Modlin RL, Adams JS, Hewison M . Impact of vitamin D on immune function: lessons learned from genome-wide analysis. Front Physiol 2014; 5: 151.

    PubMed  PubMed Central  Google Scholar 

  40. Jirapongsananuruk O, Melamed I, Leung DY . Additive immunosuppressive effects of 1,25-dihydroxyvitamin D3 and corticosteroids on TH1, but not TH2, responses. J Allergy Clin Immunol 2000; 106: 981–985.

    CAS  PubMed  Google Scholar 

  41. Piemonti L, Monti P, Sironi M, Fraticelli P, Leone BE, Dal Cin E et al. Vitamin D3 affects differentiation, maturation, and function of human monocyte-derived dendritic cells. J Immunol 2000; 164: 4443–4451.

    CAS  PubMed  Google Scholar 

  42. Griffin MD, Lutz W, Phan VA, Bachman LA, McKean DJ, Kumar R . Dendritic cell modulation by 1alpha,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo. Proc Natl Acad Sci USA 2001; 98: 6800–6805.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Chessa F, Mathow D, Wang S, Hielscher T, Atzberger A, Porubsky S et al. The renal microenvironment modifies dendritic cell phenotype. Kidney Int 2015; 89: 82–94.

    Google Scholar 

  44. Redaelli CA, Wagner M, Gunter-Duwe D, Tian YH, Stahel PF, Mazzucchelli L et al. 1alpha,25-dihydroxyvitamin D3 shows strong and additive immunomodulatory effects with cyclosporine A in rat renal allotransplants. Kidney Int 2002; 61: 288–296.

    CAS  PubMed  Google Scholar 

  45. Kubisa B, Stammberger U, Gugger M, Uduehi AN, Grodzki T, Schmid RA . 1,25-Dihydroxycholecalciferol with low-calcium diet reduces acute rejection in rat lung allotransplantation. Eur J Cardiothorac Surg 2012; 42: 871–877.

    PubMed  Google Scholar 

  46. Briffa NK, Keogh AM, Sambrook PN, Eisman JA . Reduction of immunosuppressant therapy requirement in heart transplantation by calcitriol. Transplantation 2003; 75: 2133–2134.

    CAS  PubMed  Google Scholar 

  47. Gonzalez E, Rojas-Rivera J, Polanco N, Morales E, Morales JM, Egido J et al. Effects of oral paricalcitol on secondary hyperparathyroidism and proteinuria of kidney transplant patients. Transplantation 2013; 95: e49–e52.

    PubMed  Google Scholar 

  48. Rostand SG, Drueke TB . Parathyroid hormone, vitamin D, and cardiovascular disease in chronic renal failure. Kidney Int 1999; 56: 383–392.

    CAS  PubMed  Google Scholar 

  49. Jones G . Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr 2008; 88: 582S–586S.

    CAS  PubMed  Google Scholar 

  50. Ruebner RL, Reese PP, Denburg MR, Abt PL, Furth SL . End-stage kidney disease after pediatric nonrenal solid organ transplantation. Pediatrics 2013; 132: e1319–e1326.

    PubMed  PubMed Central  Google Scholar 

  51. Levin A, Bakris GL, Molitch M, Smulders M, Tian J, Williams LA 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 2007; 71: 31–38.

    CAS  PubMed  Google Scholar 

  52. Shroff R, Egerton M, Bridel M, Shah V, Donald AE, Cole TJ et al. A bimodal association of vitamin D levels and vascular disease in children on dialysis. J Am Soc Nephrol 2008; 19: 1239–1246.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Keyzer CA, Riphagen IJ, Joosten MM, Navis G, Muller Kobold AC, Kema IP et al. Associations of 25(OH) and 1,25(OH)2 vitamin D with long-term outcomes in stable renal transplant recipients. J Clin Endocrinol Metab 2015; 100: 81–89.

    CAS  PubMed  Google Scholar 

  54. Stein B, Halloran BP, Reinhardt T, Engstrom GW, Bales CW, Drezner MK et al. Cyclosporin-A increases synthesis of 1,25-dihydroxyvitamin D3 in the rat and mouse. Endocrinology 1991; 128: 1369–1373.

    CAS  PubMed  Google Scholar 

  55. Evenepoel P, Naesens M, Claes K, Kuypers D, Vanrenterghem Y . Tertiary 'hyperphosphatoninism' accentuates hypophosphatemia and suppresses calcitriol levels in renal transplant recipients. Am J Transplant 2007; 7: 1193–1200.

    CAS  PubMed  Google Scholar 

  56. Tuchman S, Kalkwarf HJ, Zemel BS, Shults J, Wetzsteon RJ, Foerster D et al. Vitamin D deficiency and parathyroid hormone levels following renal transplantation in children. Pediatr Nephrol 2010; 25: 2509–2516.

    PubMed  Google Scholar 

  57. Filler G, Liu D, Sharma AP, Grimmer J . Are fibroblast growth factor 23 concentrations in renal transplant patients different from non-transplanted chronic kidney disease patients? Pediatr Transplant 2012; 16: 73–77.

    CAS  PubMed  Google Scholar 

  58. Barros X, Fuster D, Rodriguez N, Rodas L, Martinez-Osaba MJ, Campistol JM et al. Rapid calcitriol increase and persistent calcidiol insufficiency in the first 6 months after kidney transplantation. Nucl Med Commun 2015; 36: 489–493.

    CAS  PubMed  Google Scholar 

  59. Wesseling-Perry K, Pereira RC, Tsai E, Ettenger R, Juppner H, Salusky IB . FGF23 and mineral metabolism in the early post-renal transplantation period. Pediatr Nephrol 2013; 28: 2207–2215.

    PubMed  PubMed Central  Google Scholar 

  60. Prytula A, Walle JV, Van Vlierberghe H, Kaufman JM, Fiers T, Dehoorne J et al. Factors associated with 1,25-dihydroxyvitamin D concentrations in liver transplant recipients: a prospective observational longitudinal study. Endocrine 2016; 52: 93–102.

    CAS  PubMed  Google Scholar 

  61. Reese PP, Bloom RD, Feldman HI, Huverserian A, Thomasson A, Shults J et al. Changes in vitamin D binding protein and vitamin D concentrations associated with liver transplantation. Liver Int 2012; 32: 287–296.

    CAS  PubMed  Google Scholar 

  62. Lai CC, Chen WS, Chang DM, Tsao YP, Wu TH, Chou CT et al. Increased serum fibroblast growth factor-23 and decreased bone turnover in patients with systemic lupus erythematosus under treatment with cyclosporine and steroid but not steroid only. Osteoporos Int 2015; 26: 601–610.

    CAS  PubMed  Google Scholar 

  63. Christians U, Jacobsen W, Benet LZ, Lampen A . Mechanisms of clinically relevant drug interactions associated with tacrolimus. Clin Pharmacokinet 2002; 41: 813–851.

    CAS  PubMed  Google Scholar 

  64. Amundsen R, Asberg A, Ohm IK, Christensen H . Cyclosporine A- and tacrolimus-mediated inhibition of CYP3A4 and CYP3A5 in vitro. Drug Metab Dispos 2012; 40: 655–661.

    CAS  PubMed  Google Scholar 

  65. Deb S, Pandey M, Adomat H, Guns ES . Cytochrome P450 3A-mediated microsomal biotransformation of 1alpha,25-dihydroxyvitamin D3 in mouse and human liver: drug-related induction and inhibition of catabolism. Drug Metab Dispos 2012; 40: 907–918.

    CAS  PubMed  Google Scholar 

  66. Deb S, Chin MY, Adomat H, Guns ES . Abiraterone inhibits 1alpha,25-dihydroxyvitamin D3 metabolism by CYP3A4 in human liver and intestine in vitro. J Steroid Biochem Mol Biol 2014; 144 ((Pt A)): 50–58.

    CAS  PubMed  Google Scholar 

  67. Deb S, Chin MY, Adomat H, Guns ES . Ginsenoside-mediated blockade of 1alpha,25-dihydroxyvitamin D3 inactivation in human liver and intestine in vitro. J Steroid Biochem Mol Biol 2014; 141: 94–103.

    CAS  PubMed  Google Scholar 

  68. Wang Z, Schuetz EG, Xu Y, Thummel KE . Interplay between vitamin D and the drug metabolizing enzyme CYP3A4. J Steroid Biochem Mol Biol 2013; 136: 54–58.

    CAS  PubMed  Google Scholar 

  69. Thummel KE, Brimer C, Yasuda K, Thottassery J, Senn T, Lin Y et al. Transcriptional control of intestinal cytochrome P-4503A by 1alpha,25-dihydroxy vitamin D3. Mol Pharmacol 2001; 60: 1399–1406.

    CAS  PubMed  Google Scholar 

  70. Maguire O, Pollock C, Martin P, Owen A, Smyth T, Doherty D et al. Regulation of CYP3A4 and CYP3A5 expression and modulation of "intracrine" metabolism of androgens in prostate cells by liganded vitamin D receptor. Mol Cell Endocrinol 2012; 364: 54–64.

    CAS  PubMed  Google Scholar 

  71. Drocourt L, Ourlin JC, Pascussi JM, Maurel P, Vilarem MJ . Expression of CYP3A4, CYP2B6, and CYP2C9 is regulated by the vitamin D receptor pathway in primary human hepatocytes. J Biol Chem 2002; 277: 25125–25132.

    CAS  PubMed  Google Scholar 

  72. Lindh JD, Andersson ML, Eliasson E, Bjorkhem-Bergman L . Seasonal variation in blood drug concentrations and a potential relationship to vitamin D. Drug Metab Dispos 2011; 39: 933–937.

    CAS  PubMed  Google Scholar 

  73. Awumey EM, Moonga BS, Sodam BR, Koval AP, Adebanjo OA, Kumegawa M et al. Molecular and functional evidence for calcineurin-A alpha and beta isoforms in the osteoclast: novel insights into cyclosporin A action on bone resorption. Biochem Biophys Res Commun 1999; 254: 248–252.

    CAS  PubMed  Google Scholar 

  74. Buchinsky FJ, Ma Y, Mann GN, Rucinski B, Bryer HP, Romero DF et al. T lymphocytes play a critical role in the development of cyclosporin A-induced osteopenia. Endocrinology 1996; 137: 2278–2285.

    CAS  PubMed  Google Scholar 

  75. Spolidorio LC, Marcantonio E Jr., Spolidorio DM, Nassar CA, Nassar PO, Marcantonio RA et al. Alendronate therapy in cyclosporine-induced alveolar bone loss in rats. J Periodontal Res 2007; 42: 466–473.

    CAS  PubMed  Google Scholar 

  76. Erben RG, Stangassinger M, Gartner R . Skeletal effects of low-dose cyclosporin A in aged male rats: lack of relationship to serum testosterone levels. J Bone Miner Res 1998; 13: 79–87.

    CAS  PubMed  Google Scholar 

  77. Jager W, Xu H, Wlcek K, Schuler C, Rubel F, Erben RG . Gender- and dose-related effects of cyclosporin A on hepatic and bone metabolism. Bone 2012; 50: 140–148.

    PubMed  Google Scholar 

  78. Goodman GR, Dissanayake IR, Sodam BR, Gorodetsky E, Lu J, Ma YF et al. Immunosuppressant use without bone loss--implications for bone loss after transplantation. J Bone Miner Res 2001; 16: 72–78.

    CAS  PubMed  Google Scholar 

  79. Yeo H, Beck LH, McDonald JM, Zayzafoon M . Cyclosporin A elicits dose-dependent biphasic effects on osteoblast differentiation and bone formation. Bone 2007; 40: 1502–1516.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Cvetkovic M, Mann GN, Romero DF, Liang XG, Ma Y, Jee WS et al. The deleterious effects of long-term cyclosporine A, cyclosporine G, and FK506 on bone mineral metabolism in vivo. Transplantation 1994; 57: 1231–1237.

    CAS  PubMed  Google Scholar 

  81. Spolidorio LC, Nassar PO, Nassar CA, Spolidorio DM, Muscara MN . Conversion of immunosuppressive monotherapy from cyclosporin a to tacrolimus reverses bone loss in rats. Calcif Tissue Int 2007; 81: 114–123.

    CAS  PubMed  Google Scholar 

  82. Rich GM, Mudge GH, Laffel GL, LeBoff MS, Cyclosporine A . and prednisone-associated osteoporosis in heart transplant recipients. J Heart Lung Transplant 1992; 11: 950–958.

    CAS  PubMed  Google Scholar 

  83. Thiebaud D, Krieg MA, Gillard-Berguer D, Jacquet AF, Goy JJ, Burckhardt P . Cyclosporine induces high bone turnover and may contribute to bone loss after heart transplantation. Eur J Clin Invest 1996; 26: 549–555.

    CAS  PubMed  Google Scholar 

  84. Marcen R, Caballero C, Pascual J, Teruel JL, Tenorio M, Ocana J et al. Lumbar bone mineral density in renal transplant patients on neoral and tacrolimus: a four-year prospective study. Transplantation 2006; 81: 826–831.

    CAS  PubMed  Google Scholar 

  85. Vautour LM, Melton LJ III, Clarke BL, Achenbach SJ, Oberg AL, McCarthy JT . Long-term fracture risk following renal transplantation: a population-based study. Osteoporos Int 2004; 15: 160–167.

    PubMed  Google Scholar 

  86. Patel S, Kwan JT, McCloskey E, McGee G, Thomas G, Johnson D et al. Prevalence and causes of low bone density and fractures in kidney transplant patients. J Bone Miner Res 2001; 16: 1863–1870.

    CAS  PubMed  Google Scholar 

  87. Halleen JM, Tiitinen SL, Ylipahkala H, Fagerlund KM, Vaananen HK . Tartrate-resistant acid phosphatase 5b (TRACP 5b) as a marker of bone resorption. Clin Lab 2006; 52: 499–509.

    CAS  PubMed  Google Scholar 

  88. Luo L, Shi Y, Bai Y, Zou Y, Cai B, Tao Y et al. Impact of tacrolimus on bone metabolism after kidney transplantation. Int Immunopharmacol 2012; 13: 69–72.

    CAS  PubMed  Google Scholar 

  89. Campistol JM, Holt DW, Epstein S, Gioud-Paquet M, Rutault K, Burke JT . Bone metabolism in renal transplant patients treated with cyclosporine or sirolimus. Transplant Int 2005; 18: 1028–1035.

    CAS  Google Scholar 

  90. Goffin E, Devogelaer JP, Lalaoui A, Depresseux G, De Naeyer P, Squifflet JP et al. Tacrolimus and low-dose steroid immunosuppression preserves bone mass after renal transplantation. Transpl Int 2002; 15: 73–80.

    CAS  PubMed  Google Scholar 

  91. Monegal A, Navasa M, Guanabens N, Peris P, Pons F, Martinez de Osaba MJ et al. Bone mass and mineral metabolism in liver transplant patients treated with FK506 or cyclosporine A. Calcif Tissue Int 2001; 68: 83–86.

    CAS  PubMed  Google Scholar 

  92. Josephson MA, Schumm LP, Chiu MY, Marshall C, Thistlethwaite JR, Sprague SM . Calcium and calcitriol prophylaxis attenuates posttransplant bone loss. Transplantation 2004; 78: 1233–1236.

    CAS  PubMed  Google Scholar 

  93. Przybylowski P, Wasilewski G, Janik L, Kozlowska S, Nowak E, Malyszko J . Fibroblast growth factor 23 and Klotho as cardiovascular risk factors in heart transplant recipients. Transplant Proc 2014; 46: 2848–2851.

    CAS  PubMed  Google Scholar 

  94. Diczfalusy U, Nylen H, Elander P, Bertilsson L . 4beta-Hydroxycholesterol, an endogenous marker of CYP3A4/5 activity in humans. Br J Clin Pharmacol 2011; 71: 183–189.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Henderson K, Eisman J, Keogh A, MacDonald P, Glanville A, Spratt P et al. Protective effect of short-term calcitriol or cyclical etidronate on bone loss after cardiac or lung transplantation. J Bone Miner Res 2001; 16: 565–571.

    CAS  PubMed  Google Scholar 

  96. Sambrook P, Henderson NK, Keogh A, Macdonald P, Glanville A, Spratt P et al. Effect of calcitriol on bone loss after cardiac or lung transplantation. J Bone Miner Res 2000; 15: 1818–1824.

    CAS  PubMed  Google Scholar 

  97. De Sevaux RGL, Hoitsma AJ, Corstens FHM, Wetzels JFM . Treatment with vitamin D and calcium reduces bone loss after renal transplantation: a randomized study. J Am Soc Nephrol 2002; 13: 6.

    Google Scholar 

  98. El-Agroudy AE, El-Husseini AA, El-Sayed M, Ghoneim MA . Preventing bone loss in renal transplant recipients with vitamin D. J Am Soc Nephrol 2003; 14: 2975–2979.

    CAS  PubMed  Google Scholar 

  99. Torres A, Garcia S, Gomez A, Gonzalez A, Barrios Y, Concepcion MT et al. Treatment with intermittent calcitriol and calcium reduces bone loss after renal transplantation. Kidney Int 2004; 65: 705–712.

    CAS  PubMed  Google Scholar 

  100. El-Husseini AA, El-Agroudy AE, El-Sayed M, Sobh MA, Ghoneim MA . A prospective randomized study for the treatment of bone loss with vitamin d during kidney transplantation in children and adolescents. Am J Transplant 2004; 4: 2052–2057.

    CAS  PubMed  Google Scholar 

  101. Amer H, Griffin MD, Stegall MD, Cosio FG, Park WD, Kremers WK et al. Oral paricalcitol reduces the prevalence of posttransplant hyperparathyroidism: results of an open label randomized trial. Am J Transplant 2013; 13: 1576–1585.

    CAS  PubMed  Google Scholar 

  102. Perez V, Sanchez-Escuredo A, Lauzurica R, Bayes B, Navarro-Munoz M, Pastor MC et al. Magnetic bead-based proteomic technology to study paricalcitol effect in kidney transplant recipients. Eur J Pharmacol 2013; 709: 72–79.

    CAS  PubMed  Google Scholar 

  103. Li YC, Qiao G, Uskokovic M, Xiang W, Zheng W, Kong J . Vitamin D: a negative endocrine regulator of the renin-angiotensin system and blood pressure. J Steroid Biochem Mol Biol 2004; 89-90: 387–392.

    CAS  PubMed  Google Scholar 

  104. Sigmund CD . Regulation of renin expression and blood pressure by vitamin D(3). J Clin Invest 2002; 110: 155–156.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Zhou C, Lu F, Cao K, Xu D, Goltzman D, Miao D . Calcium-independent and 1,25(OH)2D3-dependent regulation of the renin-angiotensin system in 1alpha-hydroxylase knockout mice. Kidney Int 2008; 74: 170–179.

    CAS  PubMed  Google Scholar 

  106. Martinez-Moreno JM, Herencia C, Montes de Oca A, Munoz-Castaneda JR, Rodriguez-Ortiz ME, Diaz-Tocados JM et al. Vitamin D modulates tissue factor and protease-activated receptor 2 expression in vascular smooth muscle cells. FASEB J 2015; 30: 1367–1376.

    PubMed  Google Scholar 

  107. Gao L, Cao JT, Liang Y, Zhao YC, Lin XH, Li XC et al. Calcitriol attenuates cardiac remodeling and dysfunction in a murine model of polycystic ovary syndrome. Endocrine 2015; 52: 363–373.

    PubMed  Google Scholar 

  108. Mary A, Henaut L, Boudot C, Six I, Brazier M, Massy ZA et al. Calcitriol prevents in vitro vascular smooth muscle cell mineralization by regulating calcium-sensing receptor expression. Endocrinology 2015; 156: 1965–1974.

    CAS  PubMed  Google Scholar 

  109. Bland R, Markovic D, Hills CE, Hughes SV, Chan SL, Squires PE et al. Expression of 25-hydroxyvitamin D3-1alpha-hydroxylase in pancreatic islets. J Steroid Biochem Mol Biol 2004; 89-90: 121–125.

    CAS  PubMed  Google Scholar 

  110. Mitri J, Pittas AG . Vitamin D and diabetes. Endocrinol Metab Clin North Am 2014; 43: 205–232.

    PubMed  Google Scholar 

  111. Takiishi T, Gysemans C, Bouillon R, Mathieu C . Vitamin D and diabetes. Endocrinol Metab Clin North Am 2010; 39: 419–446, table of contents.

    CAS  PubMed  Google Scholar 

  112. Mora JR, Iwata M, von Andrian UH . Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol 2008; 8: 685–698.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 2004; 173: 2909–2912.

    CAS  PubMed  Google Scholar 

  114. Inoue K, Matsui I, Hamano T, Fujii N, Shimomura A, Nakano C et al. Maxacalcitol ameliorates tubulointerstitial fibrosis in obstructed kidneys by recruiting PPM1A/VDR complex to pSmad3. Lab Invest 2012; 92: 1686–1697.

    CAS  PubMed  Google Scholar 

  115. Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ . The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer 2014; 14: 342–357.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

AP was supported by the Clinical Research Grant funded by the University of Ghent.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A Prytuła.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Prytuła, A., Cransberg, K. & Raes, A. CYP3A4 is a crosslink between vitamin D and calcineurin inhibitors in solid organ transplant recipients: implications for bone health. Pharmacogenomics J 17, 481–487 (2017). https://doi.org/10.1038/tpj.2017.15

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2017.15

This article is cited by

Search

Quick links