FGF23 and Klotho in chronic kidney disease

Current Opinion in Nephrology and Hypertension

Volumn 22, Issue 4, 2013, Pages 397-404

  Olauson, Hannes ^a   Larsson, Tobias E ^a,b  

^a KAROLINSKA INSTITUTE   (Sweden)

^b KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

Author keywords

Calcium; Cardiovascular disease; Fibroblast growth factor 23; Hyperparathyroidism; Parathyroid hormone; Phosphorous; PTH; Vitamin D

Indexed keywords

FIBROBLAST GROWTH FACTOR 23; FIBROBLAST GROWTH FACTOR RECEPTOR; KLOTHO PROTEIN; NEUTRALIZING ANTIBODY; PARATHYROID HORMONE; TRANSFORMING GROWTH FACTOR BETA; VANILLOID RECEPTOR 5; VITAMIN D RECEPTOR; WNT PROTEIN;

ACUTE KIDNEY FAILURE; BLOOD VESSEL CALCIFICATION; BONE METABOLISM; CARBOXY TERMINAL SEQUENCE; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CELL FUNCTION; CHRONIC KIDNEY DISEASE; CORONARY ARTERY CALCIFICATION; ENZYME LINKED IMMUNOSORBENT ASSAY; HEART LEFT VENTRICLE HYPERTROPHY; HUMAN; HYPERPHOSPHATEMIA; INFLAMMATION; KIDNEY FIBROSIS; KIDNEY PARENCHYMA; MINERAL METABOLISM; MORTALITY; OSTEOCYTE; OSTEOMALACIA; OUTCOME ASSESSMENT; OXIDATIVE STRESS; PARATHYROID HORMONE RELEASE; PREDICTIVE VALUE; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN DOMAIN; PROTEIN EXPRESSION; REVIEW; RICKETS; SENESCENCE;

ANIMALS; BIOLOGICAL MARKERS; DISEASE PROGRESSION; FIBROBLAST GROWTH FACTORS; GLUCURONIDASE; HUMANS; KIDNEY; PROGNOSIS; RENAL INSUFFICIENCY, CHRONIC; SIGNAL TRANSDUCTION;

EID: 84879205889     PISSN: 10624821     EISSN: 14736543     Source Type: Journal    
DOI: 10.1097/MNH.0b013e32836213ee     Document Type: Review

References (93)

1. Block GA, Klassen PS, Lazarus JM, et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 2004; 15:2208-2218.
2. Wald R, Sarnak MJ, Tighiouart H, et al. Disordered mineral metabolism in hemodialysis patients: an analysis of cumulative effects in the Hemodialysis (HEMO) Study. Am J Kidney Dis 2008; 52:531-540.
3. Tentori F, Blayney MJ, Albert JM, et al. Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2008; 52:519-530.
4. Ravani P, Malberti F, Tripepi G, et al. Vitamin D levels and patient outcome in chronic kidney disease. Kidney Int 2009; 75:88-95.
5. Wolf M, Shah A, Gutierrez O, et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int 2007; 72:1004-1013.
6. Larsson T, Nisbeth U, Ljunggren O, 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.
7. Wolf M. Fibroblast growth factor 23 and the future of phosphorus management. Curr Opin Nephrol Hypertens 2009; 18:463-468.
8. Isakova T, Wahl P, Vargas GS, et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int 2011; 79:1370-1378.
9. Quarles LD. Role of FGF23 in vitamin D and phosphate metabolism: implications in chronic kidney disease. Exp Cell Res 2012; 318:1040-1048.
10. Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006; 444:770-774.
11. Kato Y, Arakawa E, Kinoshita S, et al. Establishment of the anti-Klotho monoclonal antibodies and detection of Klotho protein in kidneys. Biochem Biophys Res Commun 2000; 267:597-602.
12. Hu MC, Shi M, Zhang J, et al. Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J 2010; 24:3438-3450.
13. Matsumura Y, Aizawa H, Shiraki-Iida T, et al. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun 1998; 242:626-630.
14. Chang Q, Hoefs S, van der Kemp AW, et al. The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel. Science 2005; 310:490-493.
15. Liu S, Tang W, Zhou J, et al. Fibroblast growth factor 23 is a counterregulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol 2006; 17:1305-1315.
16. Shimada T, Yamazaki Y, Takahashi M, et al. Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism. Am J Physiol Renal Physiol 2005; 289:F1088-F1095.
17. Yu X, Sabbagh Y, Davis SI, et al. Genetic dissection of phosphate- and vitamin D-mediated regulation of circulating Fgf23 concentrations. Bone 2005; 36:971-977.
18. Antoniucci DM, Yamashita T, Portale AA. Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men. J Clin Endocrinol Metab 2006; 91:3144-3149.
19. Isakova T, Gutierrez O, Shah A, et al. Postprandial mineral metabolism and secondary hyperparathyroidism in early CKD. J Am Soc Nephrol 2008; 19:615-623.
20. Nishida Y, Taketani Y, Yamanaka-Okumura H, et al. Acute effect of oral phosphate loading on serum fibroblast growth factor 23 levels in healthy men. Kidney Int 2006; 70:2141-2147.
21. Vervloet MG, van Ittersum FJ, Buttler RM, et al. Effects of dietary phosphate and calcium intake on fibroblast growth factor-23. Clin J Am Soc Nephrol 2011; 6:383-389.
22. Lavi-Moshayoff V, Wasserman G, Meir T, et al. PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop. Am J Physiol Renal Physiol 2010; 299:F882-F889.
23. Rhee Y, Bivi N, Farrow E, et al. Parathyroid hormone receptor signaling in osteocytes increases the expression of fibroblast growth factor-23 in vitro and in vivo. Bone 2011; 49:636-643.
24. Lopez I, Rodriguez-Ortiz ME, Almaden Y, et al. Direct and indirect effects of parathyroid hormone on circulating levels of fibroblast growth factor 23 in vivo. Kidney Int 2011; 80:475-482.
25. Gutierrez OM, Wolf M, Taylor EN. Fibroblast growth factor 23, cardiovascular disease risk factors, and phosphorus intake in the health professionals follow-up study. Clin J Am Soc Nephrol 2011; 6:2871-2878.
26. Di Iorio B, Di Micco L, Torraca S, et al. Acute effects of very-low-protein diet on FGF23 levels: arandomized study. Clin J Am Soc Nephrol 2012; 7:581-587.
27. Moe SM, Zidehsarai MP, Chambers MA, et al. Vegetarian comparedwith meat dietary protein source and phosphorus homeostasis in chronic kidney disease. Clin J Am Soc Nephrol 2011; 6:257-264.
28. Farrow EG, Yu X, Summers LJ, et al. Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice. Proc Natl Acad Sci U S A 2011; 108:E1146-E1155.
29. Imel EA, Peacock M, Gray AK, et al. Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. J Clin Endocrinol Metab 2011; 96:3541-3549.
30. Schouten BJ, Hunt PJ, Livesey JH, et al. FGF23 elevation and hypopho-sphatemia after intravenous iron polymaltose: a prospective study. J Clin Endocrinol Metab 2009; 94:2332-2337.
31. Tsuji K, Maeda T, Kawane T, et al. Leptin stimulates fibroblast growth factor 23 expression in bone and suppresses renal 1alpha, 25-dihydroxyvitamin D3 synthesis in leptin-deficient mice. J Bone Miner Res 2010; 25:1711-1723.
32. Carrillo-Lopez N, Roman-Garcia P, Rodriguez-Rebollar A, et al. Indirect regulation of PTH by estrogens may require FGF23. J Am Soc Nephrol 2009; 20:2009-2017.
33. Yamazaki Y, Imura A, Urakawa I, et al. Establishment of sandwich ELISA for soluble alpha-Klotho measurement: Age-dependent change of soluble alpha-Klotho levelsinhealthy subjects. Biochem Biophys Res Commun 2010; 398:513-518.
34. Carpenter TO, Insogna KL, Zhang JH, et al. Circulating levels of soluble klotho and FGF23 in X-linked hypophosphatemia: circadian variance, effects of treatment, and relationship to parathyroid status. J Clin Endocrinol Metab 2010; 95:E352-E357.
35. 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.
36. Shimamura Y, Hamada K, Inoue K, et al. Serum levels of soluble secreted alpha-Klotho are decreased in the early stages of chronic kidney disease, making it a probable novel biomarker for early diagnosis. Clin Exp Nephrol 2012; 16:722-729.
37. 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.
38. Yokoyama K, Imura A, Ohkido I, et al. Serum soluble alpha-klotho in hemo-dialysis patients. Clin Nephrol 2012; 77:347-351.
39. Wan M, Smith C, Shah V, et al. Fibroblast growth factor 23 and soluble klotho in children with chronic kidney disease. Nephrol Dial Transplant 2013; 28:153-161.
40. 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.
41. 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.
42. Hu MC, Shi M, Zhang J, et al. Klotho deficiency is an early biomarker of renal ischemia-reperfusion injury and its replacement is protective. Kidney Int 2010; 78:1240-1251.
43. Wolf M. Forging forward with 10 burning questions on FGF23 in kidney disease. J Am Soc Nephrol 2010; 21:1427-1435.
44. 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.
45. Asai O, Nakatani K, Tanaka T, et al. Decreased renal alpha-Klotho expression in early diabetic nephropathy in humans and mice and its possible role in urinary calcium excretion. Kidney Int 2012; 81:539-547.
46. Yu J, Deng M, Zhao J, Huang L. Decreased expression of klotho gene in uremic atherosclerosis in apolipoprotein E-deficient mice. Biochem Biophys Res Commun 2010; 391:261-266.
47. Shimada T, Urakawa I, Isakova T, et al. Circulating fibroblast growth factor 23 in patients with end-stage renal disease treated by peritoneal dialysis is intact and biologically active. J Clin Endocrinol Metab 2010; 95:578-585.
48. Goetz R, Nakada Y, Hu MC, et al. Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation. Proc Natl Acad Sci U S A 2010; 107:407-412.
49. Gutierrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 2008; 359:584-592.
50. 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 Dial Transplant 2009; 24:2792-2796.
51. Isakova T, Xie H, Yang W, et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA 2011; 305:2432-2439.
52. Wolf M, Molnar MZ, Amaral AP, et al. Elevated fibroblast growth factor 23 is a risk factor for kidney transplant loss and mortality. J Am Soc Nephrol 2011; 22:956-966.
53. Ix JH, Katz R, Kestenbaum BR, 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 2012; 60:200-207.
54. Arnlov J, Carlsson AC, Sundstrom J, et al. Higher fibroblast growth factor-23 increases the risk of all-cause and cardiovascular mortality in the community. Kidney Int 2013; 83:160-166.
55. Arnlov J, Carlsson AC, Sundstrom J, et al. Serum FGF23 and risk of cardiovascular events in relation to mineral metabolism and cardiovascular pathology. Clin J Am Soc Nephrol 2013. [Epub ahead of print]
56. Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest 2011; 121:4393-4408.
57. Khan AM, Chirinos JA, Litt H, et al. FGF-23 and the progression of coronary arterial calcification in patients new to dialysis. Clin J Am Soc Nephrol 2012; 7:2017-2022.
58. Larsson TE. FGF23 beyond mineral metabolism: a bridge to cardiovascular disease. Clin J Am Soc Nephrol 2011; 6:2735-2737.
59. Lim K, Lu TS, Molostvov G, et al. Vascular Klotho deficiency potentiates the development of human artery calcification and mediates resistance to fibroblast growth factor 23. Circulation 2012; 125:2243-2255.
60. Lindberg K, Olauson H, Amin R, et al. Arterial Klotho expression and FGF23 effects on vascular calcification and function. PLoS One 2013; 8:e60658.
61. Scialla JJ, Lau WL, Reilly MP, et al. Fibroblast growth factor 23 is not associated with and does not induce arterial calcification. Kidney Int 2013. doi: 10.1038/ki.2013.3. [Epub ahead of print]
62. Kawai M, Kinoshita S, Kimoto A, et al. FGF23 suppresses chondrocyte proliferation in the presence of soluble alpha-Klotho both in vitro and in vivo. J Biol Chem 2013; 288:2414-2427.
63. Martin A, David V, Quarles LD. Regulation and function of the FGF23/klotho endocrine pathways. Physiol Rev 2012; 92:131-155.
64. Bacchetta J, Sea JL, Chun RF, et al. Fibroblast growth factor 23 inhibits extrarenal synthesis of 1,25-dihydroxyvitamin D in human monocytes. J Bone Miner Res 2013; 28:46-55.
65. Kuroo M. Klotho and beta Klotho. Adv Exp Med Biol 2012; 728:25-40.
66. Hu MC, Kuroo M, Moe OW. Secreted klotho and chronic kidney disease. Adv Exp Med Biol 2012; 728:126-157.
67. Seitz S, Rendenbach C, Barvencik F, et al. Retinol deprivation partially rescues the skeletal mineralization defects of Phex-deficient Hyp mice. Bone 2013; 53:231-238.
68. Martin A, Liu S, David V, et al. Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling. FASEBJ 2011; 25:2551-2562.
69. Wang X, Wang S, Li C, et al. Inactivation of a novel FGF23 regulator, FAM20C, leads to hypophosphatemic rickets in mice. PLoS Genet 2012; 8:e1002708.
70. Huitema LF, Apschner A, Logister I, et al. Entpd5 is essential for skeletal mineralization and regulates phosphate homeostasis in zebrafish. Proc Natl Acad Sci U S A 2012; 109:21372-21377.
71. 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.
72. Smith RC, O'Bryan LM, Farrow EG, et al. Circulating alphaKlotho influences phosphate handling by controlling FGF23 production. J Clin Invest 2012; 122:4710-4715. Pivotal study demonstrating soluble Klotho as a potent stimulus for FGF23 expression.
73. Pathare G, Foller M, Michael D, et al. Enhanced FGF23 serum concentrations and phosphaturia in gene targeted mice expressing WNK-resistant spak. Kidney Blood Press Res 2012; 36:355-364.
74. Bjorklund P, Krajisnik T, Akerstrom G, et al. Type I membrane klotho expression is decreased and inversely correlated to serum calcium in primary hyperparathyroidism. J Clin Endocrinol Metab 2008; 93:4152-4157.
75. Moreno JA, Izquierdo MC, Sanchez-Nino MD, et al. The inflammatory cytokines TWEAK and TNFalpha reduce renal klotho expression through NFkappaB. J Am Soc Nephrol 2011; 22:1315-1325.
76. Young GH, Wu VC. KLOTHO methylation is linked to uremic toxins and chronic kidney disease. Kidney Int 2012; 81:611-612.
77. Sun CY, Chang SC, Wu MS. Suppression of Klotho expression by protein-bound uremic toxins is associated with increased DNA methyltransferase expression and DNA hypermethylation. Kidney Int 2012; 81:640-650.
78. Gonzalez-Parra E, Gonzalez-Casaus ML, Galan A, et al. Lanthanum carbonate reduces FGF23 in chronic kidney disease Stage 3 patients. Nephrol Dial Transplant 2011; 26:2567-2571.
79. Oliveira RB, Cancela AL, Graciolli FG, et al. Early control of PTH and FGF23 in normophosphatemicCKD patients: a new target in CKD-MBD therapy? Clin J Am Soc Nephrol 2010; 5:286-291.
80. Hansen D. A randomised clinical study of alfacalcidol and paricalcitol. Dan Med J 2012; 59:B4400.
81. Burnett-Bowie SA, Leder BZ, Henao MP, et al. Randomized trial assessing the effects of ergocalciferol administration on circulating FGF23. Clin J Am Soc Nephrol 2012; 7:624-631.
82. Wesseling-Perry K, Pereira RC, Sahney S, et al. Calcitriol and doxercalciferol are equivalent in controlling bone turnover, suppressing parathyroid hormone, and increasing fibroblast growth factor-23 in secondary hyperparathyroidism. Kidney Int 2011; 79:112-119.
83. Wetmore JB, Liu S, Krebill R, et al. Effects of cinacalcet and concurrent lowdose vitamin D on FGF23 levels in ESRD. Clin J Am Soc Nephrol 2010; 5:110-116.
84. Kitaoka T, Namba N, Miura K, et al. Decrease in serum FGF23 levels after intravenous infusion of pamidronate in patients with osteogenesis imperfecta. J Bone Miner Metab 2011; 29:598-605.
85. Koizumi M, Komaba H, Nakanishi S, et al. Cinacalcet treatment and serum FGF23 levels in haemodialysis patients with secondary hyperparathyroidism. Nephrol Dial Transplant 2012; 27:784-790.
86. Wang Y, Sun Z. Klotho gene delivery prevents the progression of spontaneous hypertension and renal damage. Hypertension 2009; 54:810-817.
87. Haruna Y, Kashihara N, Satoh M, et al. Amelioration of progressive renal injury by genetic manipulation of Klotho gene. Proc Natl Acad Sci U S A 2007; 104:2331-2336.
88. Doi S, Zou Y, Togao O, et al. Klotho inhibits transforming growth factor-beta1 (TGF-beta1) signaling and suppresses renal fibrosis and cancer metastasis in mice. J Biol Chem 2011; 286:8655-8665.
89. Carracedo J, Buendia P, Merino A, et al. Klotho modulates the stress response in human senescent endothelial cells. Mech Ageing Dev 2012; 133:647-654.
90. Chen TH, Kuro OM, Chen CH, et al. The secreted Klotho protein restores phosphate retention and suppresses accelerated aging in Klotho mutant mice. Eur J Pharmacol 2013; 698:67-73.
91. Shalhoub V, Shatzen EM, Ward SC, et al. FGF23 neutralization improves chronic kidney disease-associated hyperparathyroidism yet increases mortality. J Clin Invest 2012; 122:2543-2553.
92. Wohrle S, Henninger C, Bonny O, et al. Pharmacological inhibition of FGFR signaling ameliorates FGF23-mediated hypophosphatemic rickets. J Bone Miner Res 2013; 28:899-911.
93. Wu X, Weiszmann J, Ge H, et al. A unique FGF23 with the ability to activate FGFR signaling through both alphaKlotho and betaKlotho. J Mol Biol 2012; 418:82-89.