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Roles of phosphate and fibroblast growth factor 23 in cardiovascular disease

Nature Reviews Nephrology volume 10, pages 268–278 (2014)Cite this article

Subjects

Key Points

  • Higher circulating levels of phosphate and fibroblast growth factor (FGF)-23 are associated with increased risk of cardiovascular disease in populations with or without chronic kidney disease

  • Higher phosphate concentrations induce vascular calcification and endothelial dysfunction in vitro and in animal models; observational studies in humans have corroborated these findings

  • Higher levels of FGF-23 might have direct hypertrophic effects on cardiac myocytes, which could explain their association with left ventricular hypertrophy and congestive heart failure in patients

  • Simultaneous control of FGF-23 and serum phosphate levels might be useful strategies to reduce cardiovascular disease in at-risk populations, including those with chronic kidney disease

Abstract

Disturbances in phosphate homeostasis are common in patients with chronic kidney disease. As kidney function declines, circulating concentrations of phosphate and the phosphate-regulatory hormone, fibroblast growth factor (FGF)-23, rise progressively. Higher serum levels of phosphate and FGF-23 are associated with an increased risk of adverse outcomes, including all-cause mortality and cardiovascular events. The associations between higher FGF-23 levels and adverse cardiovascular outcomes are generally independent of serum phosphate levels, and might be strongest for congestive heart failure. Higher serum phosphate levels are also modestly associated with an increased risk of cardiovascular events even after accounting for FGF-23 levels. This observation suggests that FGF-23 and phosphate might promote distinct mechanisms of cardiovascular toxicity. Indeed, animal models implicate high serum phosphate as a mechanism of vascular calcification and endothelial dysfunction, whereas high levels of FGF-23 are implicated in left ventricular hypertrophy. These seemingly distinct, but perhaps additive, adverse effects of phosphate on the vasculature and FGF-23 on the heart suggest that future population-level and individual-level interventions will need to simultaneously target these molecules to reduce the risk of associated cardiovascular events.

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Figure 1: The physiology of phosphate homeostasis in the context of low-phosphate and high-phosphate diets.
Figure 2: Qualitative interpretation of the evidence supporting causal relationships between circulating levels of phosphate and FGF-23 with CVD.
Figure 3: Proposed mechanisms through which higher circulating levels of phosphate and FGF-23 might contribute separately and additively to clinical CVD events in patients with CKD.
Figure 4: Potential interventions to target phosphate homeostasis at the population, patient and molecular levels.

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References

  1. ADHR Consortium. Autosomal dominant hypophosphatemic rickets is associated with mutations in FGF23. Nat. Genet. 26, 345–348 (2000).

  2. Saito, H. et al. Circulating FGF-23 is regulated by 1α,25-dihydroxyvitamin D3 and phosphorus in vivo. J. Biol. Chem. 280, 2543–2549 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Saji, F. et al. Fibroblast growth factor 23 production in bone is directly regulated by 1α,25-dihydroxyvitamin D, but not PTH. Am. J. Physiol. Renal Physiol. 299, F1212–F1217 (2010).

    Article  CAS  PubMed  Google Scholar 

  4. 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 

  5. Hu, M., Shiizaki, K., Kuro-o, M. & Moe, O. Fibroblast growth factor 23 and Klotho: physiology and pathophysiology of an endocrine network of mineral metabolism. Annu. Rev. Physiol. 75, 503–533 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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 

  7. Burnett, S. et al. Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women. J. Bone Miner. Res. 21, 1187–1196 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Ferrari, S. L., Bonjour, J.-P. & Rizzoli, R. Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men. J. Clin. Endocrinol. Metab. 90, 1519–1524 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Antoniucci, D. M., Yamashita, T. & Portale, A. A. Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men. J. Clin. Endocrinol. Metab. 91, 3144–3149 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Vervloet, M. G. et al. Effects of dietary phosphate and calcium intake on fibroblast growth factor-23. Clin. J. Am. Soc. Nephrol. 6, 383–389 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Isakova, T. et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int. 79, 1370–1378 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Scialla, J. et al. Mineral metabolites and chronic kidney disease progression in African Americans. J. Am. Soc. Nephrol. 24, 125–135 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Scialla, J. et al. Fibroblast growth factor 23 and cardiovascular events in chronic kidney disease. J. Am. Soc. Nephrol. 113, 561–568 (2013).

    Google Scholar 

  14. Ix, J. H. et al. Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study). J. Am. Coll. Cardiol. 60, 200–207 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Parker, B. D. et al. The associations of fibroblast growth factor 23 and uncarboxylated matrix Gla protein with mortality in coronary artery disease: the Heart and Soul Study. Ann. Intern. Med. 152, 640–648 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kendrick, J. et al. FGF-23 associates with death, cardiovascular events, and initiation of chronic dialysis. J. Am. Soc. Nephrol. 22, 1913–1922 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Faul, C. et al. FGF23 induces left ventricular hypertrophy. J. Clin. Invest. 121, 4393–4408 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dhingra, R. et al. Relations of serum phosphorus levels to echocardiographic left ventricular mass and incidence of heart failure in the community. Eur. J. Heart Fail. 12, 812–818 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Dhingra, R. et al. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch. Intern. Med. 167, 879–885 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Foley, R., Collins, A., Ishani, A. & Kalra, P. Calcium-phosphate levels and cardiovascular disese in community-dwelling adults: the Atherosclerosis Risk in Communities (ARIC) Study. Am. Heart J. 156, 556–563 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Dominguez, J. et al. Relationship between serum and urine phosphorus with all-cause and cardiovascular mortality: the osteoporotic fractures in men (MrOS) study. Am. J. Kidney Dis. 61, 555–563 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Tonelli, M. et al. relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation 112, 2627–2633 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Shalhoub, V. et al. FGF23 neutralization improves chronic kidney disease-associated hyperparathyroidism yet increases mortality. J. Clin. Invest. 122, 2543–2553 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Block, G. A., Hulbert-Shearon, T. E., Levin, N. W. & Port, F. K. Association of serum phosphorus and calcium × phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am. J. Kidney Dis. 31, 607–617 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Block, G. A. et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J. Am. Soc. Nephrol. 15, 2208–2218 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Lertdumrongluk, P. et al. Association of serum phosphorus concentration with mortality in elderly and nonelderly hemodialysis patients. J. Ren. Nutr. 23, 411–421 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Voormolen, N. et al. High plasma phosphate as a risk factor for decline in renal function and mortality in pre-dialysis patients. Nephrol. Dial. Transplant. 22, 2909–2916 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Kestenbaum, B. et al. Serum phosphate levels and mortality risk among people with chronic kidney disease. J. Am. Soc. Nephrol. 16, 520–528 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Eddington, H. et al. Serum phosphate and mortality in patients with chronic kidney disease. Clin. J. Am. Soc. Nephrol. 5, 2251–2257 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Palmer, S. C. et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease. JAMA 305, 1119–1127 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Taylor, E., Rimm, E., Stampfer, M. & Curhan, G. Plasma fibroblast growth factor 23, parathyroid hormone, phosphorus, and risk of coronary heart disease. Am. Heart J. 161, 956–962 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gutierrez, O. M. et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N. Engl. J. Med. 359, 584–592 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jean, G. et al. High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients. Nephrol. Dial. Transplant. 24, 2792–2796 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Isakova, T. et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA 305, 2432–2439 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Arnlov, J. et al. Higher fibroblast growth factor-23 increases the risk of all-cause and cardiovascular mortality in the community. Kidney Int. 83, 160–166 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Baia, L. et al. Fibroblast growth factor 23 and cardiovascular mortality after kidney transplantation. Clin. J. Am. Soc. Nephrol. 8, 1968–1978 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Seiler, S. et al. FGF-23 and future cardiovascular events in patients with chronic kidney disease before initiation of dialysis treatment. Nephrol. Dial. Transplant. 35, 3983–3989 (2010).

    Article  CAS  Google Scholar 

  38. Nakano, C. et al. Intact fibroblast growth factor 23 levels predict incident cardiovascular event before but not after the start of dialysis. Bone 50, 1266–1274 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Arnlov, J. et al. Serum FGF23 and risk of cardiovascular events in relation to mineral metabolism and cardiovascular pathology. Clin. J. Am. Soc. Nephrol. 8, 781–786 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Richter, M. et al. Oncostatin M induces FGF23 expression in cardiomyocytes. J. Clin. Exp. Cardiolog. S9, 1–6 (2012).

    Google Scholar 

  41. Voigt, M., Fischer, D.-C., Rimpau, M., Schareck, W. & Haffner, D. Fibroblast growth factor (FGF)-23 and fetuin-A in calcified carotid atheroma. Histopathology 56, 775–788 (2010).

    Article  PubMed  Google Scholar 

  42. Gruson, D. et al. C-terminal FGF23 is a strong predictor of survival in systolic heart failure. Peptides 37, 258–262 (2012).

    Article  CAS  PubMed  Google Scholar 

  43. Plischke, M. et al. Inorganic phosphate and FGF-23 predict outcome in stable systolic heart failure. Eur. J. Clin. Invest. 42, 649–656 (2012).

    Article  CAS  PubMed  Google Scholar 

  44. Zittermann, A. et al. Parameters of mineral metabolism predict midterm clinical outcome in end-stage heart failure patients. Scand. Cardiovasc. J. 45, 342–348 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Hill, A. The environment and disease: association or causation? Proc. R. Soc. Med. 58, 295–300 (1965).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Lucas, R. & McMichael, A. Association or causation: evaluating links between “environment and disease”. Bull. WHO 83, 792–795 (2005).

    PubMed  PubMed Central  Google Scholar 

  47. Isakova, T. et al. Daily variability in mineral metabolites in CKD and effects of dietary calcium and calcitriol. Clin. J. Am. Soc. Nephrol. 7, 820–828 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kuro-o, M. et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45–51 (1997).

    Article  CAS  PubMed  Google Scholar 

  49. Hu, M. C. et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J. Am. Soc. Nephrol. 22, 124–136 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lim, K. et al. Vascular klotho deficiency potentiates the development of human artery calcification and mediates resistance to fibroblast growth factor 23. Circulation 125, 2243–2255 (2012).

    Article  CAS  PubMed  Google Scholar 

  51. Devaraj, S., Syed, B., Chien, A. & Jialal, I. Validation of an immunoassay for soluble Klotho protein: decreased levels in diabetes and increased levels in chronic kidney disease. Am. J. Clin. Pathol. 137, 479–485 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Seiler, S. et al. Plasma klotho is not related to kidney function and does not predict adverse outcome in patients with chronic kidney disease. Kidney Int. 83, 121–128 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Kim, H. et al. Circulating α-klotho levels in CKD and relationship to progression. Am. J. Kidney Dis. 61, 899–909 (2013).

    Article  CAS  PubMed  Google Scholar 

  54. Mirza, M., Larsson, A., Melhus, H., Lind, L. & Larsson, T. Serum intact FGF23 associate with left ventricular mass, hypertrophy and geometry in an elderly population. Atherosclerosis 207, 546–551 (2009).

    Article  CAS  PubMed  Google Scholar 

  55. Mirza, M. A. et al. Relationship between circulating FGF23 and total body atherosclerosis in the community. Nephrol. Dial. Transplant. 24, 3125–3131 (2009).

    Article  CAS  PubMed  Google Scholar 

  56. Six, I. et al. Effects of phosphate on vascular function under normal conditions and influence of the uremic state. Cardiovasc. Res. 96, 130–139 (2012).

    Article  CAS  PubMed  Google Scholar 

  57. Dominguez, J., Shlipak, M., Whooley, M. & Ix, J. Fractional excretion of phosphorus modifies the association between fibroblast growth factor-23 and outcomes. J. Am. Soc. Nephrol. 24, 647–654 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Christov, M. et al. Plasma FGF23 levels increase rapidly after acute kidney injury. Kidney Int. 84, 776–785 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Stubbs, J. et al. Longitudinal evaluation of FGF23 changes and mineral metabolism abnormalities in a mouse model of chronic kidney disease. J. Bone Miner. Res. 27, 38–46 (2012).

    Article  CAS  PubMed  Google Scholar 

  60. Scialla, J. et al. Fibroblast growth factor 23 is not associated with and does not induce arterial calcification. Kidney Int. 83, 1159–1168 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Jono, S. et al. Phosphate regulation of vascular smooth muscle cell calcification. Circ. Res. 87, e10–e17 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. Shroff, R. et al. Chronic mineral dysregulation promotes vascular smooth muscle cell adaptation and extracellular matrix calcification. J. Am. Soc. Nephrol. 21, 103–112 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. El-Abbadi, M. et al. Phosphate feeding induces arterial medial calcification in uremic mice: role of serum phosphorus, fibroblast growth factor-23, and osteopontin. Kidney Int. 75, 1297–1307 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ohnishi, M. & Razzaque, M. Dietary and genetic evidence for phosphate toxicity accelerating mammalian aging. FASEB J. 24, 3562–3571 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Jimbo, R. et al. Fibroblast growth factor 23 accelerates phosphate-induced vascular calcification in the absence of klotho deficiency. Kidney Int. http://dx.doi.org/10.1038/ki.2013.332 (2013).

  66. Saito, H. et al. human fibroblast growth factor-23 mutants suppress na+-dependent phosphate co-transport activity and 1, 25-dihydroxyvitamin D3 production. J. Biol. Chem. 278, 2206–2211 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Larsson, T. et al. transgenic mice expressing fibroblast growth factor 23 under the control of the α1 collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis. Endocrinology 145, 3087–3094 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Shimada, T. et al. FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem. Biophys. Res. Commun. 314, 409–414 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Adeney, K. L. et al. Association of serum phosphate with vascular and valvular calcification in moderate CKD. J. Am. Soc. Nephrol. 20, 381–387 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Linefsky, J. et al. Association of serum phosphate levels with aortic valve sclerosis and annular calcification. J. Am. Coll. Cardiol. 58, 291–297 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Kendrick, J., Ix, J. H., Targher, G., Smits, G. & Chonchol, M. Relation of serum phosphorus levels to ankle brachial pressure index (from the Third National Health and Nutrition Examination Survey). Am. J. Cardiol. 106, 564–568 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ix, J. et al. Serum phosphorus concentrations and arterial stiffness among individuals with normal kidney function to moderate kidney disease in MESA. Clin. J. Am. Soc. Nephrol. 4, 609–615 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Masai, H., Joki, N., Sugi, K. & Moroi, M. A preliminary study of the potential role of FGF-23 in coronary calcification in patients with suspected coronary artery disease. Atherosclerosis 226, 228–233 (2013).

    Article  CAS  PubMed  Google Scholar 

  74. Nasrallah, M. et al. Fibroblast growth factor-23 (FGF-23) is independently correlated to aortic calcification in haemodialysis patients. Nephrol. Dial. Transplant. 25, 2679–2685 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. Srivaths, P., Goldstein, S., Krishnamurthy, R. & Silverstein, D. High serum phosphorus and FGF 23 levels are associated with progression of coronary calcifications. Pediatr. Nephrol. 29, 103–109 (2013).

    Article  PubMed  Google Scholar 

  76. Nakayama, M. et al. Fibroblast growth factor 23 is associated with carotid artery calcification in chronic kidney disease patients not undergoing dialysis: a cross-sectional study. BMC Nephrol. 14, 22 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Desjardins, L. et al. FGF23 is independently associated with vascular calcification but not bone mineral density in patients at various CKD stages. Osteoporos. Int. 23, 2017–2025 (2012).

    Article  CAS  PubMed  Google Scholar 

  78. Jean, G. et al. Increased levels of serum parathyroid hormone and fibroblast growth factor-23 are the main factors associated with the progression of vascular calcification in long-hour hemodialysis patients. Nephron Clin. Pract. 120, 132–138 (2012).

    Article  CAS  Google Scholar 

  79. Cancela, A. et al. Phosphorus is associated with coronary artery disease in patients with preserved renal function. PLoS ONE 7, e36883 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Roos, M. et al. Relation between plasma fibroblast growth factor-23, serum fetuin-A levels and coronary artery calcification evaluated by multislice computed tomography in patients with normal kidney function. Clin. Endocrinol. 68, 660–665 (2008).

    Article  CAS  Google Scholar 

  81. Inaba, M. et al. Role of fibroblast growth factor-23 in peripheral vascular calcification in non-diabetic and diabetic hemodialysis patients. Osteoporos. Int. 17, 1506–1513 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. Di Marco, G. et al. Increased inorganic phosphate induces human endothelial cell apoptosis in vitro. Am. J. Physiol. Renal Physiol. 294, F1387–F1387 (2008).

    Article  CAS  Google Scholar 

  83. Di Marco, G. et al. High phosphate directly affects endothelial function by downregulating annexin II. Kidney Int. 83, 213–222 (2013).

    Article  CAS  PubMed  Google Scholar 

  84. Peng, A. et al. Adverse effects of simulated hyper- and hypo- phosphatemia on endothelial cell function and viability. PLoS ONE 6, e23268 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Shuto, E. et al. Dietary phosphorus acutely impairs endothelial function. J. Am. Soc. Nephrol. 20, 1504–1512 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Crouthamel, M. et al. Sodium-dependent phosphate cotransporters and phosphate-induced calcification of vascular smooth muscle cells: redundant roles for PiT-1 and PiT-2. Arterioscler. Thromb. Vasc. Biol. 33, 2625–2632 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Medici, D. et al. FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis. J. Cell Biol. 182, 459–465 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Foley, R., Collins, A., Herzog, C. A., Ishani, A. & Kalra, P. Serum phosphorus levels associate with coronary atherosclerosis in young adults. J. Am. Soc. Nephrol. 20, 397–404 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ruan, L. et al. Relation of serum phosphorus levels to carotid intima-media thickness in asymptomatic young adults (from the Bogalusa Heart Study). Am. J. Cardiol. 106, 793–797 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Kanbay, M. et al. Fibroblast growth factor 23 and fetuin A are independent predictors for the coronary artery disease extent in mild chronic kidney disease. Clin. J. Am. Soc. Nephrol. 5, 1780–1786 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Yilmaz, M. et al. FGF-23 and vascular dysfunction in patients with stage 3 and 4 chronic kidney disease. Kidney Int. 78, 679–685 (2010).

    Article  CAS  PubMed  Google Scholar 

  92. Mirza, M. A. I., Larsson, A., Lind, L. & Larsson, T. E. Circulating fibroblast growth factor-23 is associated with vascular dysfunction in the community. Atherosclerosis 205, 385–390 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Yilmaz, M. et al. Longitudinal analysis of vascular function and biomarkers of metabolic bone disorders before and after renal transplantation. Am. J. Nephrol. 37, 126–134 (2013).

    Article  CAS  PubMed  Google Scholar 

  94. Yilmaz, M. et al. Comparison of calcium acetate and sevelamer on vascular function and fibroblast growth factor 23 in CKD patients: a randomized clinical trial. Am. J. Kidney Dis. 59, 177–185 (2012).

    Article  CAS  PubMed  Google Scholar 

  95. Gutierrez, O. M. et al. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation 119, 2545–2552 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Touchberry, C. et al. FGF23 is a novel regulator of intracellular calcium and cardiac contractility in addition to cardiac hypertrophy. Am. J. Physiol. Endocrinol. Metab. 304, E863–E873 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Custodio, M. et al. Parathyroid hormone and phosphorus overload in uremia: impact on cardiovascular system. Nephrol. Dial. Transplant. 27, 1437–1445 (2012).

    Article  CAS  PubMed  Google Scholar 

  98. Neves, K. et al. Adverse effects of hyperphosphatemia on myocaridal hypertrophy, renal function, and bone in rats with renal failure. Kidney Int. 66, 2237–2244 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Amann, K. et al. Hyperphosphatemia aggrevates cardiac fibrosis and microvascular disease in experimental uremia. Kidney Int. 63, 1296–1301 (2003).

    Article  PubMed  Google Scholar 

  100. Maizel, J. et al. Effects of sevelamer treatment on cardiovascular abnormalities in mice with chronic renal failure. Kidney Int. 84, 491–500 (2013).

    Article  CAS  PubMed  Google Scholar 

  101. Saab, G., Whooley, M., Schiller, N. & Ix, J. Association of serum phosphorus with left ventricular mass in men and women with stable cardiovascular disease: data from the heart and soul study. Am. J. Kidney Dis. 56, 496–505 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Foley, R., Collins, A., Herzog, C., Ishani, A. & Kalra, P. Serum phosphate and left ventricular hypertrophy in young adults: the coronary artery risk development in young adults study. Kidney Blood Press Res. 32, 37–44 (2009).

    Article  CAS  PubMed  Google Scholar 

  103. Seeherunvong, W. et al. Fibroblast growth factor 23 and left ventricular hypertrophy in children on dialysis. Pediatr. Nephrol. 27, 2129–2136 (2012).

    Article  PubMed  Google Scholar 

  104. Kirkpantur, A. et al. Serum fibroblast growth factor-23 (FGF-23) levels are independently associated with left ventricular mass and myocardial performance index in maintenance haemodialysis patients. Nephrol. Dial. Transplant. 26, 1346–1354 (2011).

    Article  CAS  PubMed  Google Scholar 

  105. Hsu, H. & Wu, M. Fibroblast growth factor 23: a possible cause of left ventricular hypertrophy in hemodialysis patients. Am. J. Med. Sci. 337, 116–122 (2009).

    Article  PubMed  Google Scholar 

  106. Seiler, S. et al. The phosphatonin fibroblast growth factor 23 links calcium-phosphate metabolism with left-ventricular dysfunction and atrial fibrillation. Eur. Heart J. 32, 2688–2696 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. Yamamoto, K. et al. Dietary phosphorus is associated with greater left ventricular mass. Kidney Int. 83, 707–714 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kremsdorf, R. et al. Effects of a high-protein diet on regulation of phosphorus homeostasis. J. Clin. Endocrinol. Metab. 98, 1207–1213 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Di Iorio, B. et al. Acute effects of very-low-protein diet on FGF23 levels: a randomized study. Clin. J. Am. Soc. Nephrol. 7, 581–587 (2012).

    Article  CAS  PubMed  Google Scholar 

  110. Moe, S. et al. Vegetarian compared with meat dietary protein source and phosphorus homeostasis in chronic kidney disease. Clin. J. Am. Soc. Nephrol. 6, 257–264 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Scialla, J. et al. Plant protein intake is associated with fibroblast growth factor 23 and serum bicarbonate levels in patients with chronic kidney disease: the Chronic Renal Insufficiency Cohort study. J. Ren. Nutr. 22, 379–388 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Gutierrez, O., Wolf, M. & Taylor, E. Fibroblast growth factor 23, cardiovascular disease risk factors, and phosphorus intake in the Health Professionals Follow-up Study. Clin. J. Am. Soc. Nephrol. 6, 2871–2878 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Barrett-Connor, E. Nutrition epidemiology: how do we know what they ate? Am. J. Clin. Nutr. 54, 182S–187S (1991).

    Article  CAS  PubMed  Google Scholar 

  114. Gutiérrez, O. Sodium- and phosphorus-based food additives: persistent but surmountable hurdles in the management of nutrition in chronic kidney disease. Adv. Chronic Kidney Dis. 20, 150–156 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Covic, A. et al. A comparison of the calcium acetate/magnesium carbonate and sevelamer-hydrochloride effects on fibroblast growth factor-23 and bone markers: post hoc evaluation from a controlled, randomized study. Nephrol. Dial. Transplant. 28, 2383–2392 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Chue, C. et al. Cardiovascular effects of sevelamer in stage 3 CKD. J. Am. Soc. Nephrol. 24, 842–852 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Gonzalez-Parra, E. et al. Lanthanum carbonate reduces FGF23 in chronic kidney disease stage 3 patients. Nephrol. Dial. Transplant. 26, 2567–2571 (2011).

    Article  CAS  PubMed  Google Scholar 

  118. Isakova, T. et al. Effects of dietary phosphate restriction and phosphate binders on FGF23 levels in CKD. Clin. J. Am. Soc. Nephrol. 8, 1009–1018 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Block, G. et al. Effects of phosphate binders in moderate CKD. J. Am. Soc. Nephrol. 23, 1407–1415 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Seifert, M. et al. Effect of phosphate binder therapy on vascular stiffness in early-stage chronic kidney disease. Am. J. Nephrol. 38, 158–167 (2013).

    Article  CAS  PubMed  Google Scholar 

  121. Spatz, C., Roe, K., Lehman, E. & Verman, N. Effect of a non-calcium-based phosphate binder on fibroblast growth factor 23 in chronic kidney disease. Nephron Clin. Pract. 123, 61–66 (2013).

    Article  CAS  PubMed  Google Scholar 

  122. Isakova, T. et al. Pilot study of dietary phosphorus restriction and phosphorus binders to target fibroblast growth factor 23 in patients with chronic kidney disease. Nephrol. Dial. Transplant. 26, 584–591 (2011).

    Article  CAS  PubMed  Google Scholar 

  123. Ix, J., Ganjoo, P., Tipping, D., Tershakovec, A. & Bostom, A. Sustained hypophosphatemic effect of once-daily niacin/laropiprant in dyslipidemic CKD stage 3 patients. Am. J. Kidney Dis. 57, 963–965 (2011).

    PubMed  Google Scholar 

  124. Maccubbin, D., Tipping, D., Kuznetsova, O., Hanlon, W. & Bostom, A. Hypophosphatemic effect of niacin in patients without renal failure: a randomized trial. Clin. J. Am. Soc. Nephrol. 5, 582–589 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Schiavi, S. et al. Npt2b deletion attenuates hyperphosphatemia associated with CKD. J. Am. Soc. Nephrol. 23, 1691–1700 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Wöhrle, S. et al. Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets. J. Bone Miner. Res. 28, 899–911 (2013).

    Article  CAS  PubMed  Google Scholar 

  127. Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride (National Academies Press, 1997).

  128. Chang, A., Lazo, M., Appel, L., Gutierrez, O. & Grams, M. High dietary phosphorus intake is associated with all-cause mortality: results from NHANES III. Am. J. Clin. Nutr. 99, 320–327 (2014).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

J.J.S. is supported by grant K23DK095949 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). M.W. is supported by grants R01DK076116, R01DK081374, R01DK094796, K24DK093723 and U01DK099930, all from the NIDDK.

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  1. University of Miami Miller School of Medicine, University of Miami, 1120 North West 14th Street, Suite 815, Miami, 33136, FL, USA

    Julia J. Scialla

  2. Feinberg School of Medicine, Northwestern University, 633 North St Clair Street, Suite 18-089, Chicago, 60611, IL, USA

    Myles Wolf

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J.J.S. and M.W. researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and undertook review and/or editing of the manuscript before submission.

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Correspondence to Myles Wolf.

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M.W. declares that he has served as a consultant or received honoraria from Abbott, Amgen, Genzyme, Keryx Biopharmaceuticals, Lutipold Pharmaceuticals, Opko, Pfizer, Shire and Vifor Pharma. J.J.S. declares no competing interests.

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Scialla, J., Wolf, M. Roles of phosphate and fibroblast growth factor 23 in cardiovascular disease. Nat Rev Nephrol 10, 268–278 (2014). https://doi.org/10.1038/nrneph.2014.49

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