Review Article | Published:

Renal and extrarenal effects of fibroblast growth factor 23

Nature Reviews Nephrologyvolume 15pages109120 (2019) | Download Citation


Fibroblast growth factor 23 (FGF23) is a hormone with a central role in the regulation of phosphate homeostasis. This regulation is accomplished by the coordinated modulation of renal phosphate handling, vitamin D metabolism and parathyroid hormone secretion. Patients with kidney disease have increased circulating levels of FGF23 and in other patient populations and in healthy individuals, FGF23 levels also rise following an increase in dietary phosphate intake. Maladaptive increases in FGF23 have a detrimental effect on several organs and tissues and, importantly, these pathological changes most likely contribute to increased morbidity and mortality. For example, in the context of heart disease, FGF23 is involved in the development of pathological hypertrophy that can lead to congestive heart failure. Increased FGF23 concentrations can also lead to microcirculatory changes, in particular reduced vasodilatory capacity, and collectively these cardiovascular changes can compromise tissue perfusion. In addition, FGF23 is associated with inflammation and an increased risk of infection; other potentially detrimental effects of FGF23 are likely to emerge in the future. Most importantly, recent insights demonstrate that FGF23 can be therapeutically targeted, which holds promise for the treatment of many patients in a variety of clinical settings.

Key points

  • Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that functions as the central endocrine factor that regulates phosphate balance.

  • Findings from epidemiological studies, both in the general population and in patients with kidney disease, are remarkably consistent and demonstrate an association of FGF23 with important clinical events related to mortality, cardiovascular disease and inflammation.

  • Biological plausibility for a causal relation between FGF23 and clinical events exists; experimental studies suggest, in particular, a link between FGF23 and left ventricular hypertrophy, and possibly also vasomotor function, inflammation and immunological defence.

  • Given the possibility that residual confounding might have distorted findings from cohort analyses and experimental studies, definite proof that FGF23 induces clinically relevant outcomes is needed.

  • The discovery of therapeutic interventions that can either lower FGF23 concentrations or block its effects should prompt the design of clinical trials that aim to establish whether targeting FGF23 can reduce clinically relevant outcomes.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Schroder, F. H. et al. Screening and prostate-cancer mortality in a randomized European study. N. Engl. J. Med. 360, 1320–1328 (2009).

  2. 2.

    Boulware, L. E., Jaar, B. G., Tarver-Carr, M. E., Brancati, F. L. & Powe, N. R. Screening for proteinuria in US adults: a cost-effectiveness analysis. JAMA 290, 3101–3114 (2003).

  3. 3.

    van der Velde, M. et al. Screening for albuminuria identifies individuals at increased renal risk. J. Am. Soc. Nephrol. 20, 852–862 (2009).

  4. 4.

    Lambers Heerspink, H. J. & Gansevoort, R. T. Albuminuria is an appropriate therapeutic target in patients with CKD: the pro view. Clin. J. Am. Soc. Nephrol. 10, 1079–1088 (2015).

  5. 5.

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

  6. 6.

    Shimada, T. et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc. Natl Acad. Sci. USA 98, 6500–6505 (2001).

  7. 7.

    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).

  8. 8.

    Covic, A. et al. Bone and mineral disorders in chronic kidney disease: implications for cardiovascular health and ageing in the general population. Lancet Diabetes Endocrinol. 6, 319–331 (2018).

  9. 9.

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

  10. 10.

    Quarles, L. D. Endocrine functions of bone in mineral metabolism regulation. J. Clin. Invest. 118, 3820–3828 (2008).

  11. 11.

    Osuka, S. & Razzaque, M. S. Can features of phosphate toxicity appear in normophosphatemia? J. Bone Miner. Metab. 30, 10–18 (2012).

  12. 12.

    Farrow, E. G., Davis, S. I., Summers, L. J. & White, K. E. Initial FGF23-mediated signaling occurs in the distal convoluted tubule. J. Am. Soc. Nephrol. 20, 955–960 (2009).

  13. 13.

    Shimada, T. et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J. Bone Miner. Res. 19, 429–435 (2004).

  14. 14.

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

  15. 15.

    Richter, B. & Faul, C. FGF23 actions on target tissues-with and without Klotho. Front. Endocrinol. 9, 189 (2018).

  16. 16.

    Olauson, H., Mencke, R., Hillebrands, J. L. & Larsson, T. E. Tissue expression and source of circulating αKlotho. Bone 100, 19–35 (2017).

  17. 17.

    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).

  18. 18.

    Jimbo, R. et al. Fibroblast growth factor 23 accelerates phosphate-induced vascular calcification in the absence of Klotho deficiency. Kidney Int. 85, 1103–1111 (2014).

  19. 19.

    Mencke, R. et al. Membrane-bound Klotho is not expressed endogenously in healthy or uraemic human vascular tissue. Cardiovasc. Res. 108, 220–231 (2015).

  20. 20.

    Lau, W. L. et al. Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet. Kidney Int. 82, 1261–1270 (2012).

  21. 21.

    Olauson, H. et al. Targeted deletion of Klotho in kidney distal tubule disrupts mineral metabolism. J. Am. Soc. Nephrol. 23, 1641–1651 (2012).

  22. 22.

    Lindberg, K. et al. The kidney is the principal organ mediating klotho effects. J. Am. Soc. Nephrol. 25, 2169–2175 (2014).

  23. 23.

    Chen, G. et al. alpha-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling. Nature 553, 461–466 (2018).

  24. 24.

    Ornitz, D. M. & Itoh, N. Fibroblast growth factors. Genome Biol. 2, 3005.1–3005.12 (2001).

  25. 25.

    Grabner, A. et al. Activation of cardiac fibroblast growth factor receptor 4 causes left ventricular hypertrophy. Cell Metab. 22, 1020–1032 (2015).

  26. 26.

    Singh, S. et al. Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney Int. 90, 985–996 (2016).

  27. 27.

    Rossaint, J. et al. FGF23 signaling impairs neutrophil recruitment and host defense during CKD. J. Clin. Invest. 126, 962–974 (2016).

  28. 28.

    Han, X. et al. Counter-regulatory paracrine actions of FGF-23 and 1,25(OH)2 D in macrophages. FEBS Lett. 590, 53–67 (2016).

  29. 29.

    Masuda, Y. et al. Expression of Fgf23 in activated dendritic cells and macrophages in response to immunological stimuli in mice. Biol. Pharm. Bull. 38, 687–693 (2015).

  30. 30.

    Bacchetta, J. et al. Fibroblast growth factor 23 inhibits extrarenal synthesis of 1,25-dihydroxyvitamin D in human monocytes. J. Bone Miner. Res. 28, 46–55 (2013).

  31. 31.

    Vervloet, M. G. et al. The role of phosphate in kidney disease. Nat. Rev. Nephrol. 13, 27–38 (2017).

  32. 32.

    Qi, Z., Liu, W. & Lu, J. The mechanisms underlying the beneficial effects of exercise on bone remodeling: roles of bone-derived cytokines and microRNAs. Prog. Biophys. Mol. Biol. 122, 131–139 (2016).

  33. 33.

    Temiyasathit, S. & Jacobs, C. R. Osteocyte primary cilium and its role in bone mechanotransduction. Ann. NY Acad. Sci. 1192, 422–428 (2010).

  34. 34.

    Andrukhova, O. et al. FGF23 regulates renal sodium handling and blood pressure. EMBO Mol. Med. 6, 744–759 (2014).

  35. 35.

    Krajisnik, T. et al. Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells. J. Endocrinol. 195, 125–131 (2007).

  36. 36.

    Ben-Dov, I. Z. et al. The parathyroid is a target organ for FGF23 in rats. J. Clin. Invest. 117, 4003–4008 (2007).

  37. 37.

    Olauson, H. et al. Parathyroid-specific deletion of Klotho unravels a novel calcineurin-dependent FGF23 signaling pathway that regulates PTH secretion. PLOS Genet. 9, e1003975 (2013).

  38. 38.

    Kawakami, K. et al. Persistent fibroblast growth factor 23 signalling in the parathyroid glands for secondary hyperparathyroidism in mice with chronic kidney disease. Sci. Rep. 7, 40534 (2017).

  39. 39.

    Galitzer, H., Ben-Dov, I. Z., Silver, J. & Naveh-Many, T. Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease. Kidney Int. 77, 211–218 (2010).

  40. 40.

    Carpenter, T. O. et al. Burosumab therapy in children with X-linked hypophosphatemia. N. Engl. J. Med. 378, 1987–1998 (2018).

  41. 41.

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

  42. 42.

    Marthi, A. et al. Fibroblast growth factor-23 and risks of cardiovascular and noncardiovascular diseases: a meta-analysis. J. Am. Soc. Nephrol. 29, 2015–2027 (2018).

  43. 43.

    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).

  44. 44.

    Ikeda, K. et al. Macrophages play a unique role in the plaque calcification by enhancing the osteogenic signals exerted by vascular smooth muscle cells. Biochem. Biophys. Res. Commun. 425, 39–44 (2012).

  45. 45.

    Nowak, K. L. et al. Fibroblast growth factor 23 and the risk of infection-related hospitalization in older adults. J. Am. Soc. Nephrol. 28, 1239–1246 (2017).

  46. 46.

    Mehta, R. et al. Association of fibroblast growth factor 23 with atrial fibrillation in chronic kidney disease, from the chronic renal insufficiency cohort study. JAMA Cardiol. 1, 548–556 (2016).

  47. 47.

    Leaf, D. E. et al. Fibroblast growth factor 23 associates with death in critically ill patients. Clin. J. Am. Soc. Nephrol. 13, 531–541 (2018).

  48. 48.

    Isakova, T. et al. Longitudinal FGF23 trajectories and mortality in patients with CKD. J. Am. Soc. Nephrol. 29, 579–590 (2018).

  49. 49.

    Takashi, Y. et al. Patients with FGF23-related hypophosphatemic rickets/osteomalacia do not present with left ventricular hypertrophy. Endocr. Res. 42, 132–137 (2017).

  50. 50.

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

  51. 51.

    Sarmento-Dias, M. et al. Fibroblast growth factor 23 is associated with left ventricular hypertrophy, not with uremic vasculopathy in peritoneal dialysis patients. Clin. Nephrol. 85, 135–141 (2016).

  52. 52.

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

  53. 53.

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

  54. 54.

    Mitsnefes, M. M. et al. FGF23 and left ventricular hypertrophy in children with CKD. Clin. J. Am. Soc. Nephrol. 13, 45–52 (2018).

  55. 55.

    Sinha, M. D. et al. Relationship of FGF23 to indexed left ventricular mass in children with non-dialysis stages of chronic kidney disease. Pediatr. Nephrol. 30, 1843–1852 (2015).

  56. 56.

    Unsal, A. et al. Relationship of fibroblast growth factor 23 with left ventricle mass index and coronary calcificaton in chronic renal disease. Kidney Blood Press Res. 36, 55–64 (2012).

  57. 57.

    Jovanovich, A. et al. Fibroblast growth factor 23, left ventricular mass, and left ventricular hypertrophy in community-dwelling older adults. Atherosclerosis 231, 114–119 (2013).

  58. 58.

    Shibata, K. et al. Association between circulating fibroblast growth factor 23, alpha-Klotho, and the left ventricular ejection fraction and left ventricular mass in cardiology inpatients. PLOS ONE 8, e73184 (2013).

  59. 59.

    Tanaka, S., Fujita, S., Kizawa, S., Morita, H. & Ishizaka, N. Association between FGF23, alpha-Klotho, and cardiac abnormalities among patients with various chronic kidney disease stages. PLOS ONE 11, e0156860 (2016).

  60. 60.

    Grabner, A. et al. FGF23/FGFR4-mediated left ventricular hypertrophy is reversible. Sci. Rep. 7, 1993 (2017).

  61. 61.

    Verkaik, M. et al. High fibroblast growth factor 23 concentrations in experimental renal failure impair calcium handling in cardiomyocytes. Physiol. Rep. 6, e13591 (2018).

  62. 62.

    Wald, R. et al. Correlates of left ventricular mass in chronic hemodialysis recipients. Int. J. Cardiovasc. Imag. 30, 349–356 (2014).

  63. 63.

    Nassiri, A. A. et al. Association of serum intact fibroblast growth factor 23 with left ventricular mass and different echocardiographic findings in patients on hemodialysis. J. Transl Int. Med. 4, 135–141 (2016).

  64. 64.

    Liu, E. S. et al. Increased circulating FGF23 does not lead to cardiac hypertrophy in the male hyp mouse model of XLH. Endocrinology 159, 2165–2172 (2018).

  65. 65.

    Pastor-Arroyo, E. M. et al. The elevation of circulating fibroblast growth factor 23 without kidney disease does not increase cardiovascular disease risk. Kidney Int. 94, 49–59 (2018).

  66. 66.

    Faul, C. FGF23 effects on the heart-levels, time, source, and context matter. Kidney Int. 94, 7–11 (2018).

  67. 67.

    Marsell, R. et al. Gene expression analysis of kidneys from transgenic mice expressing fibroblast growth factor-23. Nephrol. Dial. Transplant. 23, 827–833 (2008).

  68. 68.

    Xie, J. et al. Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart. Nat. Commun. 3, 1238 (2012).

  69. 69.

    Xie, J., Yoon, J., An, S. W., Kuro-o M. & Huang, C. L. Soluble klotho protects against uremic cardiomyopathy independently of fibroblast growth factor 23 and phosphate. J. Am. Soc. Nephrol. 26, 1150–1160 (2015).

  70. 70.

    Leifheit-Nestler, M. et al. Vitamin D treatment attenuates cardiac FGF23/FGFR4 signaling and hypertrophy in uremic rats. Nephrol. Dial. Transplant. 32, 1493–1503 (2017).

  71. 71.

    Slavic, S. et al. Genetic ablation of Fgf23 or klotho does not modulate experimental heart hypertrophy induced by pressure overload. Sci. Rep. 7, 11298 (2017).

  72. 72.

    Andrukhova, O., Slavic, S., Odorfer, K. I. & Erben, R. G. Experimental myocardial infarction upregulates circulating fibroblast growth factor 23. J. Bone Miner. Res. 30, 1831–1839 (2015).

  73. 73.

    Matsui, I. et al. Cardiac hypertrophy elevates serum levels of fibroblast growth factor 23. Kidney Int. 94, 60–71 (2018).

  74. 74.

    Andersen, I. A. et al. Elevation of circulating but not myocardial FGF23 in human acute decompensated heart failure. Nephrol. Dial. Transplant. 31, 767–772 (2016).

  75. 75.

    Leaf, D. E. et al. Fibroblast growth factor 23 levels are elevated and associated with severe acute kidney injury and death following cardiac surgery. Kidney Int. 89, 939–948 (2016).

  76. 76.

    Hum, J. M. et al. The metabolic bone disease associated with the Hyp mutation is independent of osteoblastic HIF1alpha expression. Bone Rep. 6, 38–43 (2017).

  77. 77.

    Flamme, I., Ellinghaus, P., Urrego, D. & Kruger, T. FGF23 expression in rodents is directly induced via erythropoietin after inhibition of hypoxia inducible factor proline hydroxylase. PLOS ONE 12, e0186979 (2017).

  78. 78.

    Udell, J. A. et al. Fibroblast growth factor-23, cardiovascular prognosis, and benefit of angiotensin-converting enzyme inhibition in stable ischemic heart disease. J. Am. Coll. Cardiol. 63, 2421–2428 (2014).

  79. 79.

    Vervloet, M. & Cozzolino, M. Vascular calcification in chronic kidney disease: different bricks in the wall? Kidney Int. 91, 808–817 (2016).

  80. 80.

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

  81. 81.

    Scialla, J. J. et al. Fibroblast growth factor-23 and cardiovascular events in CKD. J. Am. Soc. Nephrol. 25, 349–360 (2014).

  82. 82.

    Nasrallah, M. 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).

  83. 83.

    Faul, C. & Wolf, M. Hunt for the culprit of cardiovascular injury in kidney disease. Cardiovasc. Res. 108, 209–211 (2015).

  84. 84.

    Lindberg, K. et al. Arterial klotho expression and FGF23 effects on vascular calcification and function. PLOS ONE 8, e60658 (2013).

  85. 85.

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

  86. 86.

    Mirza, M. A., 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).

  87. 87.

    Haring, R. et al. Plasma fibroblast growth factor 23: clinical correlates and association with cardiovascular disease and mortality in the framingham heart study. J. Am. Heart Assoc. 5, e003486 (2016).

  88. 88.

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

  89. 89.

    Tripepi, G. et al. Competitive interaction between fibroblast growth factor 23 and asymmetric dimethylarginine in patients with CKD. J. Am. Soc. Nephrol. 26, 935–944 (2015).

  90. 90.

    Six, I. et al. Direct, acute effects of Klotho and FGF23 on vascular smooth muscle and endothelium. PLOS ONE 9, e93423 (2014).

  91. 91.

    Richter, B., Haller, J., Haffner, D. & Leifheit-Nestler, M. Klotho modulates FGF23-mediated NO synthesis and oxidative stress in human coronary artery endothelial cells. Pflugers Arch. 468, 1621–1635 (2016).

  92. 92.

    Silswal, N. et al. FGF23 directly impairs endothelium-dependent vasorelaxation by increasing superoxide levels and reducing nitric oxide bioavailability. Am. J. Physiol. Endocrinol. Metab. 307, E426–E436 (2014).

  93. 93.

    Verkaik, M. et al. FGF23 impairs peripheral microvascular function in renal failure. Am. J. Physiol. Heart Circ. Physiol. 315, H1414–H1424 (2018).

  94. 94.

    Mason, J. C. & Libby, P. Cardiovascular disease in patients with chronic inflammation: mechanisms underlying premature cardiovascular events in rheumatologic conditions. Eur. Heart J. 36, 482–489 (2015).

  95. 95.

    Munoz Mendoza, J. et al. Fibroblast growth factor 23 and Inflammation in CKD. Clin. J. Am. Soc. Nephrol. 7, 1155–1162 (2012).

  96. 96.

    Ito, N. et al. Regulation of FGF23 expression in IDG-SW3 osteocytes and human bone by pro-inflammatory stimuli. Mol. Cell Endocrinol. 399, 208–218 (2015).

  97. 97.

    Pathak, J. L. et al. Systemic inflammation affects human osteocyte-specific protein and cytokine expression. Calcif. Tissue Int. 98, 596–608 (2016).

  98. 98.

    Durlacher, S. H. & Winternitz, M. C. Studies on the relation of the kidney to cardiovascular disease: V. lesions of the myocardium. 14, 269–278 (1942).

  99. 99.

    David, V. et al. Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int. 89, 135–146 (2016).

  100. 100.

    Hanudel, M., Juppner, H. & Salusky, I. B. Fibroblast growth factor 23: fueling the fire. Kidney Int. 90, 928–930 (2016).

  101. 101.

    Munoz Mendoza, J. et al. Inflammation and elevated levels of fibroblast growth factor 23 are independent risk factors for death in chronic kidney disease. Kidney Int. 91, 711–719 (2017).

  102. 102.

    Go, A. S., Chertow, G. M., Fan, D., McCulloch, C. E. & Hsu, C. Y. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N. Engl. J. Med. 351, 1296–1305 (2004).

  103. 103.

    de Jager, D. J., Vervloet, M. G. & Dekker, F. W. Noncardiovascular mortality in CKD: an epidemiological perspective. Nat. Rev. Nephrol. 10, 208–214 (2014).

  104. 104.

    Chonchol, M., Greene, T., Zhang, Y., Hoofnagle, A. N. & Cheung, A. K. Low vitamin D and high fibroblast growth factor 23 serum levels associate with infectious and cardiac deaths in the HEMO study. J. Am. Soc. Nephrol. 27, 227–237 (2016).

  105. 105.

    Ishigami, J. et al. Biomarkers of mineral and bone metabolism and 20-year risk of hospitalization with infection: the atherosclerosis risk in communities study. J. Clin. Endocrinol. Metab. 102, 4648–4657 (2017).

  106. 106.

    Zarbock, A., Deem, T. L., Burcin, T. L. & Ley, K. Gαi2 is required for chemokine-induced neutrophil arrest. Blood 110, 3773–3779 (2007).

  107. 107.

    Beenken, A. & Mohammadi, M. The structural biology of the FGF19 subfamily. Adv. Exp. Med. Biol. 728, 1–24 (2012).

  108. 108.

    Fitzpatrick, E. A., Han, X., Xiao, Z. & Quarles, L. D. Role of fibroblast growth factor-23 in innate immune responses. Front. Endocrinol. 9, 320 (2018).

  109. 109.

    Medrano, M., Carrillo-Cruz, E., Montero, I. & Perez-Simon, J. A. Vitamin D: effect on haematopoiesis and immune system and clinical applications. Int. J. Mol. Sci. 19, 2663 (2018).

  110. 110.

    Koeffler, H. P., Amatruda, T., Ikekawa, N., Kobayashi, Y. & DeLuca, H. F. Induction of macrophage differentiation of human normal and leukemic myeloid stem cells by 1,25-dihydroxyvitamin D3 and its fluorinated analogues. Cancer Res. 44, 5624–5628 (1984).

  111. 111.

    Liu, P. T. et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311, 1770–1773 (2006).

  112. 112.

    Mehta, R. et al. Fibroblast growth factor 23 and anemia in the chronic renal insufficiency cohort study. Clin. J. Am. Soc. Nephrol. 12, 1795–1803 (2017).

  113. 113.

    Coe, L. M. et al. FGF-23 is a negative regulator of prenatal and postnatal erythropoiesis. J. Biol. Chem. 289, 9795–9810 (2014).

  114. 114.

    Agoro, R. et al. Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia. FASEB J. 32, 3752–3764 (2018).

  115. 115.

    Yashiro, M. et al. FGF23 modulates the effects of erythropoietin on gene expression in renal epithelial cells. Int. J. Nephrol. Renovasc Dis. 11, 125–136 (2018).

  116. 116.

    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).

  117. 117.

    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).

  118. 118.

    Tsai, W. C. et al. Effects of lower versus higher phosphate diets on fibroblast growth factor-23 levels in patients with chronic kidney disease: a systematic review and meta-analysis. Nephrol. Dial. Transplant. (2018).

  119. 119.

    Ketteler, M. et al. Effects of sucroferric oxyhydroxide and sevelamer carbonate on chronic kidney disease-mineral bone disorder parameters in dialysis patients. Nephrol. Dial. Transplant. (2018).

  120. 120.

    Koizumi, M., Komaba, H., Nakanishi, S., Fujimori, A. & Fukagawa, M. Cinacalcet treatment and serum FGF23 levels in haemodialysis patients with secondary hyperparathyroidism. Nephrol. Dial. Transplant. 27, 784–790 (2012).

  121. 121.

    Wetmore, J. B., Liu, S., Krebill, R., Menard, R. & Quarles, L. D. Effects of cinacalcet and concurrent low-dose vitamin D on FGF23 levels in ESRD. Clin J. Am. Soc. Nephrol. 5, 110–116 (2010).

  122. 122.

    Investigators, E. T. et al. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N. Engl. J. Med. 367, 2482–2494 (2012).

  123. 123.

    Moe, S. M. et al. Cinacalcet, fibroblast growth factor-23, and cardiovascular disease in hemodialysis: the evaluation of cinacalcet HCl therapy to lower cardiovascular events (EVOLVE) trial. Circulation 132, 27–39 (2015).

  124. 124.

    Wolf, M., Koch, T. A. & Bregman, D. B. Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women. J. Bone Miner. Res. 28, 1793–1803 (2013).

Download references


The author’s work on FGF23 is supported by the Dutch Kidney Foundation.

Reviewer information

Nature Reviews Nephrology thanks M. Fukugawa, A. Zarbock and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information


  1. Amsterdam Cardiovascular Sciences and Department of Nephrology, Amsterdam University Medical Center, Amsterdam, Netherlands

    • Marc Vervloet


  1. Search for Marc Vervloet in:

Competing interests

The author declares no competing interests.

Corresponding author

Correspondence to Marc Vervloet.



Bone disease that leads to softening or weakening of the bones and is characterized by abnormal mineralization of osteoid, which is the unmineralized matrix produced by osteoblasts.

Uraemic syndrome

Set of clinical features that result from the metabolic abnormalities induced by kidney failure.

Fractional excretion of phosphate

The percentage of phosphate that is filtered at the glomerulus and is eventually secreted in the urine.

Diastolic heart failure

Impaired cardiac dilatation, especially of the left ventricle, during diastole that typically leads to congestive heart failure.

Mediation analysis

Statistical analysis technique that aims to unravel a causal path of sequential events.

Phosphate binders

Drugs that bind phosphate derived from diet, thereby impairing phosphate absorption from the gastrointestinal tract and lowering serum phosphate concentrations; frequently prescribed in end-stage renal disease.


Drug prescribed for secondary hyperparathyroidism in patients treated by dialysis that enhances the sensitivity of the calcium-sensing receptor in the parathyroid gland, thereby inhibiting parathyroid hormone secretion.

About this article

Publication history