International Urology and Nephrology

, Volume 46, Issue 3, pp 577–581 | Cite as

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

Nephrology - Review

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.

Keywords

Chronic kidney disease Fibroblast growth factor 23 Klotho Cardiovascular disease Phosphatonins 

Notes

Conflict of interest

None.

References

  1. 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 390:45–51PubMedCrossRefGoogle Scholar
  2. 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 71:730–737CrossRefGoogle Scholar
  3. 3.
    Kiela PR, Ghishan FK (2009) Recent advances in the renal–skeletal–gut axis that controls phosphate homeostasis. Lab Invest 89:7–14PubMedCrossRefGoogle Scholar
  4. 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 24:3438–3450PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Urakawa I, Yamazaki Y, Shimada T et al (2006) Klotho converts canonical FGF receptor into a specific receptor for FGF-23. Nature 444:770–774PubMedCrossRefGoogle Scholar
  6. 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 70:2141–2147PubMedGoogle Scholar
  7. 7.
    Berndt TJ, Schiavi S, Kumar R (2005) “Phosphatonins” and the regulation of phosphorus homeostasis. Am J Physiol Renal Physiol. 289:F1170–F1182PubMedCrossRefGoogle Scholar
  8. 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 113:561–568PubMedCentralPubMedCrossRefGoogle Scholar
  9. 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 28:821–825PubMedCrossRefGoogle Scholar
  10. 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):3455–3460PubMedCentralPubMedCrossRefGoogle Scholar
  11. 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):956–962PubMedCentralPubMedCrossRefGoogle Scholar
  12. 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):640–648PubMedCentralPubMedCrossRefGoogle Scholar
  13. 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):2545–2552PubMedCentralPubMedCrossRefGoogle Scholar
  14. 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):201–209PubMedCrossRefGoogle Scholar
  15. 15.
    Gutierrez OM, Mannstadt M, Isakova T et al (2008) Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 359:584–592PubMedCentralPubMedCrossRefGoogle Scholar
  16. 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 79:1370–1378PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    John GB, Cheng CY, Kuro-o M (2011) Role of Klotho in aging, phosphate metabolism, and CKD. Am J Kidney Dis 58:127–134PubMedCentralPubMedCrossRefGoogle Scholar
  18. 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):241–247PubMedCentralPubMedGoogle Scholar
  19. 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):3348–3355PubMedCentralPubMedCrossRefGoogle Scholar
  20. 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):311–318PubMedCrossRefGoogle Scholar
  21. 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):383–388PubMedCrossRefGoogle Scholar
  22. 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 24:2792–2796PubMedCrossRefGoogle Scholar
  23. 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 280:1015–1020PubMedCrossRefGoogle Scholar
  24. 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 38:938–942PubMedCrossRefGoogle Scholar
  25. 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):2017–2025PubMedCrossRefGoogle Scholar
  26. 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–E583PubMedCrossRefGoogle Scholar
  27. 27.
    Hsu HJ, Wu MS (2009) Fibroblast growth factor 23: a possible cause of left ventricular hypertrophy in hemodialysis patients. Am J Med Sci 337:116–122PubMedCrossRefGoogle Scholar
  28. 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 18:2116–2124PubMedCrossRefGoogle Scholar
  29. 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):315–322PubMedCrossRefGoogle Scholar
  30. 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):1506–1513CrossRefGoogle Scholar
  31. 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 18:217–223PubMedCrossRefGoogle Scholar
  32. 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):660–665CrossRefGoogle Scholar
  33. 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 40:1067–1074PubMedCrossRefGoogle Scholar
  34. 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 PubMedGoogle Scholar
  35. 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):31–38CrossRefGoogle Scholar
  36. 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 75:88–95PubMedCrossRefGoogle Scholar
  37. 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 5:1717–1722PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Division of Nephrology, Department of MedicineAkdeniz University Medical SchoolAntalyaTurkey

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