Skip to main content
Log in

A short story of Klotho and FGF23: a deuce of dark side or the savior?

  • Nephrology - Review
  • Published:
International Urology and Nephrology Aims and scope Submit manuscript

Abstract

Fibroblast growth factor 23 (FGF23) is an osteocyte and osteoblast derived peptide hormone, which requires Klotho as a cofactor for its biologic actions. FGF23 acts as a phosphaturic agent and it is capable of reducing serum inorganic phosphate (Pi) via direct inhibition of renal NaPi-2a transporter in the proximal tubuli, as well as indirectly, via the suppression of calcitriol synthesis. In patients with chronic kidney disease (CKD), circulating FGF23 levels are markedly elevated, while Klotho production is decreased. Experimental observations indicating that lack of activities of both Klotho and FGF23 may cause decreased life span, premature aging and accelerated atherosclerosis and generalized vascular calcifications have raised the question whether FGF23 could be a new risk factor and predictor of cardiovascular (CV) disease in both renal and non-renal patient groups. Clinical studies, however, have yielded conflicting results. Some of these studies have found that serum FGF23 is independently associated with mortality and CV events in CKD patients, while others have failed to show any relationship. Furthermore, some studies have even suggested that FGF23 may have a protective role against vascular calcifications and CV disease. Thus, there is clearly a need for further research in this area, and special interest should be paid to the physiologic consequences of high FGF23/low Klotho state, which is typical for patients with CKD.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsuki T et al (1997) Mutation of the mouse Klotho gene leads to a syndrome resembling ageing. Nature 390:45–51

    Article  CAS  PubMed  Google Scholar 

  2. Ureña Torres D, Prié V Molina-Blétry, Beck L, Silve C, Friedlander G (2007) An antiaging protein involved in mineral and vitamin D metabolism. Kidney Int 71:730–737

    Article  Google Scholar 

  3. Kiela PR, Ghishan FK (2009) Recent advances in the renal–skeletal–gut axis that controls phosphate homeostasis. Lab Invest 89:7–14

    Article  CAS  PubMed  Google Scholar 

  4. Hu MC, Shi M, Zhang J, Pastor J, Nakatani T et al (2010) Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J 24:3438–3450

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Urakawa I, Yamazaki Y, Shimada T et al (2006) Klotho converts canonical FGF receptor into a specific receptor for FGF-23. Nature 444:770–774

    Article  CAS  PubMed  Google Scholar 

  6. Nishida Y, Taketani Y, Yamanaka-Okumura H et al (2006) Acute effect of oral phosphate loading on serum fibroblast growth factor 23 levels in healthy men. Kidney Int 70:2141–2147

    CAS  PubMed  Google Scholar 

  7. Berndt TJ, Schiavi S, Kumar R (2005) “Phosphatonins” and the regulation of phosphorus homeostasis. Am J Physiol Renal Physiol. 289:F1170–F1182

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Ketteler M, Patrick Biggar H, Liangos O (2013) FGF23 antagonism:the thin line between adaptation and maladaptation in chronic kidney disease. Nephrol Dial Transplant 28:821–825

    Article  CAS  PubMed  Google Scholar 

  10. Brownstein CA, Adler F, Nelson-Williams C, Iijima J, Li P, Imura A, Nabeshima Y, Reyes Mugica M, Carpenter TO, Lifton RP (2008) A translocation causing increased alpha-Klotho level results in hypophosphatemic rickets and hyperparathyroidism. PNAS 105(9):3455–3460

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Taylor EN, Rimm EB, Stampfer MJ, Curhan GC (2011) Plasma fibroblast growth factor 23, parathyroid hormone, phosphorus, and risk of coronary heart disease. Am Heart J 161(5):956–962

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Parker BD, Schurgers LJ, Brandenburg VM, Christenson RH, Vermeer C, Ketteler M et al (2010) 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(10):640–648

    Article  PubMed Central  PubMed  Google Scholar 

  13. Gutiérrez OM, Januzzi JL, Isakova T, Laliberte K, Smith K, Collerone G et al (2009) Fibroblast growth factor-23 and left ventricular hypertrophy in chronic kidney disease. Circulation 119(19):2545–2552

    Article  PubMed Central  PubMed  Google Scholar 

  14. Jongbloed F, Galassi A, Cozzolino M, Zietse R, Chiarelli G, Cusi D, Brancaccio D, Gallieni M (2011) Clinical significance of FGF-23 measurement in dialysis patients. Clin Nephrol 76(3):201–209

    Article  CAS  PubMed  Google Scholar 

  15. Gutierrez OM, Mannstadt M, Isakova T et al (2008) Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 359:584–592

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. John GB, Cheng CY, Kuro-o M (2011) Role of Klotho in aging, phosphate metabolism, and CKD. Am J Kidney Dis 58:127–134

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Titan SM, Zatz R, Graciolli FG, dos Reis LM, Barros RT, Jorgetti V, Moysés RM (2011) FGF-23 as a predictor of renal outcome in diabetic nephropathy. CJASN 6(2):241–247

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Bostrom MA, Hicks PJ, Lu L, Langefeld CD, Freedman BI, Bowden DW (2010) Association of polymorphisms in the Klotho gene with severity of non-diabetic ESRD in African Americans. Nephrol Dial Transplant 25(10):3348–3355

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Oguro R, Kamide K, Kokubo Y, Shimaoka I, Congrains A, Horio T et al (2010) Association of carotid atherosclerosis with genetic polymorphisms of the Klotho gene in patients with hypertension. Geriatr Gerontol Int. 10(4):311–318

    Article  PubMed  Google Scholar 

  21. Shimoyama Y, Taki K, Mitsuda Y, Tsuruta Y, Hamajima N, Niwa T (2009) Klotho gene polymorphisms G-395A and C1818T are associated with low-density lipoprotein cholesterol and uric acid in Japanese hemodialysis patients. Am J Nephrol 30(4):383–388

    Article  CAS  PubMed  Google Scholar 

  22. Jean G, Terrat JC, Vanel T et al (2009) High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long hemodialysis patients. Nephrol Dial Transplant 24:2792–2796

    Article  CAS  PubMed  Google Scholar 

  23. Koh N, Fujimori T, Nishiguchi S, Tamori A, Shiomi S, Nakatani T, Sugimura K, Kishimoto T, Kinoshita S, Kuroki T, Nabeshima Y (2001) Severely reduced production of Klotho in human chronic renal failure kidney. Biochem Biophys Res Commun 280:1015–1020

    Article  CAS  PubMed  Google Scholar 

  24. Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM (2001) Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 38:938–942

    Article  CAS  PubMed  Google Scholar 

  25. Desjardins L, Liabeuf S, Renard C, Lenglet A, Lemke HD, Choukroun G, Drueke TB, Massy ZA (2012) European uremic toxin (EUTox) Work Group. FGF23 is independently associated with vascular calcification but not bone mineral density in patients at various CKD stages. Osteoporos Int 23(7):2017–2025

    Article  CAS  PubMed  Google Scholar 

  26. Schoppet M, Hofbauer LC, Brinskelle-Schmal N, Varennes A, Goudable J, Richard M, Hawa G, Chapurlat R, Szulc P (2012) Serum level of the phosphaturic factor FGF23 is associated with abdominal aortic calcification in men: the STRAMBO study. J Clin Endocrinol Metab 97(4):E575–E583

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  28. Stubbs JR, Liu S, Tang W et al (2007) Role of hyperphosphatemia and 1,25-dihydroxyvitamin D in vascular calcification and mortality in fibroblastic growth factor 23 null mice. J Am Soc Nephrol 18:2116–2124

    Article  CAS  PubMed  Google Scholar 

  29. Ashikaga E, Honda H, Suzuki H et al (2010) Impact of fibroblast growth factor 23 on lipids and atherosclerosis in hemodialysis patients. Ther Apher Dial 14(3):315–322

    Article  CAS  PubMed  Google Scholar 

  30. Inaba M, Okuno S, Imanishi Y et al (2006) Role of fibroblast growth factor-23 in peripheral vascular calcification in non-diabetic and diabetic hemodialysis patients. Osteoporosis Int 17(10):1506–1513

    Article  CAS  Google Scholar 

  31. Tamei N, Ogawa T, Ishida H et al (2011) Serum fibroblast growth factor-23 levels and progression of aortic arch calcification in non-diabetic patients on chronic hemodialysis. J Atheroscler Thromb 18:217–223

    Article  CAS  PubMed  Google Scholar 

  32. Roos M, Lutz J, Salmhofer H et al (2008) 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(4):660–665

    Article  CAS  Google Scholar 

  33. Kojima F, Uchida K, Ogawa T et al (2008) Plasma levels of fibroblast growth factor-23 and mineral metabolism in diabetic and non-diabetic patients on chronic hemodialysis. Int Urol Nephrol 40:1067–1074

    Article  CAS  PubMed  Google Scholar 

  34. Moldovan D, Moldovan I, Rusu C, Kacso I, Patiu IM, Gherman-Caprioara M (2013) FGF-23, vascular calcification and cardiovascular diseases in chronic hemodialysis patients. Int Urol Nephrol. doi:10.1007/s11255-013-0422-2

    PubMed  Google Scholar 

  35. Levin A, Bakris GL, Molitch M, Smulders M, Tian J, Williams LA, Andress DL (2007) Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int 1(1):31–38

    Article  Google Scholar 

  36. Ravani P, Malberti F, Tripepi G, Pecchini P, Cutrupi S, Pizzini P, Mallamaci F, Zoccali C (2009) Vitamin D levels and patient outcome in chronic kidney disease. Kidney Int 75:88–95

    Article  CAS  PubMed  Google Scholar 

  37. Prié D, Friedlander G (2010) Reciprocal Control of 1,25-Dihydroxyvitamin D and FGF23 Formation Involving the FGF23/Klotho System. Clin J Am Soc Nephrol 5:1717–1722

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to F. Fevzi Ersoy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ersoy, F.F. A short story of Klotho and FGF23: a deuce of dark side or the savior?. Int Urol Nephrol 46, 577–581 (2014). https://doi.org/10.1007/s11255-013-0536-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11255-013-0536-6

Keywords

Navigation