Download PDF
Dialyse aktuell 2013; 17(8): 409-416
DOI: 10.1055/s-0033-1359375
Nephrologie
© Georg Thieme Verlag Stuttgart · New York

Die neuen Player in der Pathogenese chronischer Nierenerkrankungen – FGF-23 und Klotho

New players in pathogenesis of chronic kidney disease – FGF-23 and Klotho
Sarah Seiler
1   Klinik für Innere Medizin IV – Nieren- und Hochdruckkrankheiten, Universitätsklinikum des Saarlandes, Homburg (Leitung: Prof. Dr. Danilo Fliser)
› Author Affiliations
Further Information

Publication History

Publication Date:
15 October 2013 (online)

Also available at
    Permissions and Reprints

Der sogenannte „fibroblast growth factor 23“, kurz FGF-23, ist ein zentraler Regulator der Kalzium-Phosphat-Homöostase, da das Hormon zum einen die renale Phosphatexkretion fördert und zum anderen durch die Hemmung der Calcitriolsynthese die intestinale Phosphataufnahme vermindert. In klinischen Studien erwiesen sich erhöhte FGF-23-Spiegel als unabhängiger Prädiktor des kardiovaskulären, des renalen und des Gesamtüberlebens chronisch nierenkranker Menschen. Rezente experimentelle Arbeiten suggerieren einen direkten kardiotoxischen Effekt von FGF-23. Der FGF-23-Korezeptor Klotho wiederum wird als membranständiges Protein in physiologischen Zielorganen von FGF-23 exprimiert. Darüber hinaus existiert eine lösliche Form von Klotho (sKlotho), der eigenständige vaskulo- und renoprotektive Eigenschaften zugesprochen werden. Die potenzielle Eignung von FGF-23 und Klotho als mögliche neue Therapieziele zur Behandlung der „chronic kidney disease – mineral bone disorder“ (CKD-MBD) ist Gegenstand aktueller klinischer und experimenteller Studien.

Fibroblast growth factor 23 (FGF-23) is a central regulator of calcium phosphate homeostasis by increasing renal phosphate excretion and decreasing gastrointestinal phosphate absorption via inhibition of calcitriol synthesis. In clinical trials, elevated FGF-23 levels were associated with impaired cardiovascular, renal and total survival in chronic kidney disease patients. Recent experimental data suggest a direct cardiotoxic effect of FGF-23. The FGF-23 co-receptor Klotho is expressed as a membrane standing form in physiological target organs of FGF-23. Additionally, a soluble form of sKlotho exists, which is thought to exert vasculo- and renoprotective functions. The meaning of FGF-23 and Klotho as potential therapeutic targets in the treatment of Chronic Kidney Disease – Mineral and Bone Disorder remains to be defined in clinical and experimental studies.

Key words

calcium - phosphate - chronic kidney disease (CKD) - FGF-23 - Klotho
 

  • Literatur

  • 1 Gutierrez O, Isakova T, Rhee E et al. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 2005; 16: 2205-2215
    CrossrefGoogle Scholar
  • 2 Larsson T, Nisbeth U, Ljunggren G et al. Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney Int 2003; 64: 2272-2279
    CrossrefGoogle Scholar
  • 3 Koh N, Fujimori T, Nishiguchi S et al. Severely reduced production of klotho in human chronic renal failure kidney. Biochem Biophys Res Commun 2001; 280: 1015-1020
    CrossrefGoogle Scholar
  • 4 Hu MC, Shi M, Zhang J et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 2011; 22: 124-136
    CrossrefGoogle Scholar
  • 5 Olauson H, Lindberg K, Amin R et al. Targeted deletion of Klotho in kidney distal tubule disrupts mineral metabolism. J Am Soc Nephrol 2012; 23: 1641-1651
    CrossrefGoogle Scholar
  • 6 Isakova T, Xie H, Yang W et al. Fibroblast groth factor 23 and risks of mortality and end stage renal disease in patients with chronic kidney disease. JAMA 2011; 305: 2432-2439
    CrossrefGoogle Scholar
  • 7 Fliser D, Kollents B, Never U et al. Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol 2007; 18: 2600-2608
    CrossrefGoogle Scholar
  • 8 Kendrick J, Cheung AK, Kaufman JS et al. FGF-23 associates with death, cardiovascular events, and initiation of chronic dialysis. J Am Soc Nephrol 2011; 22: 1913-1922
    CrossrefGoogle Scholar
  • 9 Gutiérrez OM, Mannstadt M, Isakova T et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialyis. N Engl J Med 2008; 359: 584-592
    CrossrefGoogle Scholar
  • 10 Seiler S, Reichert B, Roth D et al. FGF-23 and future cardiovascular events in patients with chronic kidney disease before initiation of dialysis treatment. Nephrol Dial Transplant 2010; 25: 3983-3989
    CrossrefGoogle Scholar
  • 11 Parker BD, Schurgers LJ, Brandenburg VM 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 2010; 152: 640-648
    CrossrefGoogle Scholar
  • 12 Ix JH, Katz R, Kestenbaum BR et al. Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-lining individuals: CHS (Cardiovascular Health Study). J Am Coll Cardiol 2012; 60: 200-207
    CrossrefGoogle Scholar
  • 13 Seiler S, Cremers B, Rebling NM et al. The phosphatonin fibroblast growth factor 23 links calcium-phosphate metabolism with left-ventricular dysfunction and atrial fibrillation. Eur Heart J 2011; 32: 2688-2696
    CrossrefGoogle Scholar
  • 14 Faul C, Amarai AP, Oskouei B et al. FGF23 induces left ventricular hypertrophy. J Clin Invest 2011; 121: 4393-4408
    CrossrefGoogle Scholar
  • 15 Yamazaki Y, Imuary A, Urakawa I et al. Establishment of sandwich ELISA for soluble alpha-Klotho measurement: Age-dependent change of soluble alpha-Klotho levels in healthy subjects. Biochem Biophys Res Commun 2010; 398: 513-518
    CrossrefGoogle Scholar
  • 16 Semba RD, Cappola AR, Sun K et al. Plasma klotho and mortality risk in older community-dwelling adults. J Gerontol A Biol Sci Med Sci 2011; 6: 794-800
    Google Scholar
  • 17 Seiler S, Wen M, Roth HJ et al. Plasma Klotho is not related to kidney function and does not predict adverse outcome in patients with chronic kidney disease. Kidney Int 2013; 83: 121-128
    CrossrefGoogle Scholar
  • 18 Akimoto T, Yoshizawa H, Watanabe Y et al. Characteristics of urinary and serum soluble Klotho protein in patients with different degrees of chronic kidney disease. BMC Nephrol 2012; 13: 155-155
    CrossrefGoogle Scholar
  • 19 Isakova T, Gutiérrez OM, Chang Y et al. Phosphorus binders and survival on hemodialysis. J Am Soc Nephrol 2009; 20: 388-396
    CrossrefGoogle Scholar
  • 20 Shalboub V, Shalzen EM, Ward SC et al. FGF23 neutralization improves chronic kidney disease-associated hyperparathyroidism yet increases mortality. J Clin Invest 2012; 122: 2543-2553
    CrossrefGoogle Scholar
  • 21 Nakano C, Hamano T, Fujii N et al. Intact fibroblast growth factor 23 levels predict incident cardiovascular event before but not after the start of dialysis. Bone 2012; 50: 1266-1274
    CrossrefGoogle Scholar
  • 22 Jean G, Terrat JC, Vanel T et al. High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients. Nephrol Dialysis Transplant 2009; 24: 2792-2796
    CrossrefGoogle Scholar
  • 23 Sugiura H, Tsuchiya K, Nitta K. Circulating levels of soluble α-Klotho in patients with chronic kidney disease. Clin Exp Nephrol 2011; 15: 795-796
    CrossrefGoogle Scholar
  • 24 Shimamura Y, Hamada K, Inoue K et al. Clin Exp Nephrol 2012; 16: 722-729
    Crossref
  • 25 Devaraj S, Syed B, Chien A et al. Validation of an immunoassay for soluble Klotho protein: decreased levels in diabetes and increased levels in chronic kidney disease. Am J Clin Pathol 2012; 137: 479-485
    CrossrefGoogle Scholar
  • 26 Pavik I, Jaeger P, Ebner L et al. Soluble klotho and autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2012; 7: 248-257
    CrossrefGoogle Scholar
  • 27 Pavik I, Jaeger P, Ebner L et al. Secreted Klotho and FGF23 in chronic kidney disease Stage 1 to 5: a sequence suggested from a cross-sectional study. Nephrol Dial Transplant 2013; 28: 352-359
    CrossrefGoogle Scholar
  • 28 Akimoto T, Shiizaki K, Sugase T et al. The relationship between the soluble Klotho protein and the residual renal function among peritoneal dialysis patients. Clin Exp Nephrol 2012; 16: 442-447
    CrossrefGoogle Scholar