Background/Aims: Fibroblast growth factor (FGF)-23 and parathyroid hormone (PTH) are both potent phosphaturic hormones. Since they exert opposite effects on vitamin D metabolism, the measurement of 3 vitamin D metabolites; 25-hydroxyvitamin D (25-OH-D), 1,25-dihydroxyvitamin D (1,25(OH)2D), and 24,25-dihydroxyvitamin D (24,25(OH)2D), allows the distinction of the effects of FGF-23 from those of PTH. The aim of this study was to elucidate which factor, FGF-23 or PTH, plays a more important role in the regulation of vitamin D metabolites in subjects with estimated glomerular filtration (eGFR) ≥60 ml/min/1.73 m2. Methods: Subjects with eGFR ≥60 ml/min/1.73 m2 (n = 20) were enrolled and their serum levels of FGF-23, intact PTH, and vitamin D metabolites were determined. Results: Serum FGF-23 correlated inversely with 1,25(OH)2D (r = -0.717, p = 0.0004) and the 1,25(OH)2D/25-OH-D ratio (r = -0.518, p = 0.019), compared with a significant positive correlation between serum intact PTH and the 1,25(OH)2D/25-OH-D ratio (r = 0.562, p = 0.010). Multiple regression analyses revealed serum FGF-23 as a significant factor that was associated with serum 1,25(OH)2D (β = -0.593, p = 0.018), 1,25(OH)2D/25-OH-D ratio (β = -0.521, p = 0.025), and the 24,25(OH)2D/1,25(OH)2D ratio (β = 0.632, p = 0.008), and intact PTH as a significant factor associated with the 1,25(OH)2D/25-OH-D ratio (β = 0.445, p = 0.028). Conclusions: This study demonstrated that, even in subjects with eGFR ≥60 ml/min/1.73 m2, FGF-23 might play an important role in the regulation of vitamin D metabolism. In addition to the established role of PTH, the association between FGF-23 and indices of vitamin D metabolism suggested the potential role of FGF-23 on phosphate metabolism in such patients.

Keywords:
FGF-23, Vitamin D, Intact PTH, CKD-MBD
1.
Moe S, Drüeke T, Cunningham J, Goodman W, Martin K, Olgaard K, Ott S, Sprague S, Lameire N, Eknoyan G: Definition, evaluation, and classification of renal osteodystrophy: a position statement from kidney disease: improving global outcomes (KDIGO). Kidney Int 2006;69:1945-1953.
2.
London GM, Guérin AP, Marchais SJ, Métivier F, Pannier B, Adda H: Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 2003;18:1731-1740.
3.
Oliveira RB, Cancela AL, Graciolli FG, Dos Reis LM, Draibe SA, Cuppari L, Carvalho AB, Jorgetti V, Canziani ME, Moysés RM: Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy? Clin J Am Soc Nephrol 2010;5:286-291.
4.
Nakano C, Hamano T, Fujii N, Matsui I, Tomida K, Mikami S, Inoue K, Obi Y, Okada N, Tsubakihara Y, Isaka Y, Rakugi H: Combined use of vitamin D status and FGF23 for risk stratification of renal outcome. Clin J Am Soc Nephrol 2012;7:810-819.
5.
Isakova T, Wahl P, Vargas GS, Gutiérrez OM, Scialla J, Xie H, Appleby D, Nessel L, Bellovich K, Chen J, Hamm L, Gadegbeku C, Horwitz E, Townsend RR, Anderson CA, Lash JP, Hsu CY, Leonard MB, Wolf M: Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int 2011;79:1370-1378.
6.
Uchikawa T, Borle AB, Midgett RJ: Parathyroid hormone and phosphaturia. Calcif Tissue Res 1976;21(suppl):284-287.
7.
Peacock M: Calcium metabolism in health and disease. Clin J Am Soc Nephrol 2010;5(suppl 1):S23-S30.
8.
Garabedian M, Holick MF, Deluca HF, Boyle IT: Control of 25-hydroxycholecalciferol metabolism by parathyroid glands. Proc Natl Acad Sci U S A 1972;69:1673-1676.
9.
Brenza HL, Kimmel-Jehan C, Jehan F, Shinki T, Wakino S, Anazawa H, Suda T, DeLuca HF: Parathyroid hormone activation of the 25-hydroxyvitamin D3-1alpha-hydroxylase gene promoter. Proc Natl Acad Sci U S A 1998;95:1387-1391.
10.
Zierold C, Mings JA, DeLuca HF: Parathyroid hormone regulates 25-hydroxyvitamin D(3)-24-hydroxylase mRNA by altering its stability. Proc Natl Acad Sci U S A 2001;98:13572-13576.
11.
Anderson PH, O'Loughlin PD, May BK, Morris HA: Quantification of mRNA for the vitamin D metabolizing enzymes CYP27B1 and CYP24 and vitamin D receptor in kidney using real-time reverse transcriptase - polymerase chain reaction. J Mol Endocrinol 2003;31:123-132.
12.
Hoenderop JG, Chon H, Gkika D, Bluyssen HA, Holstege FC, St-Arnaud R, Braam B, Bindels RJ: Regulation of gene expression by dietary Ca2+ in kidneys of 25-hydroxyvitamin D3-1 alpha-hydroxylase knockout mice. Kidney Int 2004;65:531-539.
13.
Shigematsu T, Kazama JJ, Yamashita T, Fukumoto S, Hosoya T, Gejyo F, Fukagawa M: Possible involvement of circulating fibroblast growth factor 23 in the development of secondary hyperparathyroidism associated with renal insufficiency. Am J Kidney Dis 2004;44:250-256.
14.
Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, Fujita T, Nakahara K, Fukumoto S, Yamashita T: FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004;19:429-435.
15.
Yuan B, Xing Y, Horst RL, Drezner MK: Evidence for abnormal translational regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase activity in the hyp-mouse. Endocrinology 2004;145:3804-3812.
16.
Gutierrez O, Isakova T, Rhee E, Shah A, Holmes J, Collerone G, Jüppner H, Wolf M: Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 2005;16:2205-2215.
17.
Shimada T, Yamazaki Y, Takahashi M, Hasegawa H, Urakawa I, Oshima T, Ono K, Kakitani M, Tomizuka K, Fujita T, Fukumoto S, Yamashita T: Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism. Am J Physiol Renal Physiol 2005;289:F1088-F1095.
18.
Chanakul A, Zhang MY, Louw A, Armbrecht HJ, Miller WL, Portale AA, Perwad F: FGF-23 regulates CYP27B1 transcription in the kidney and in extra-renal tissues. PLoS One 2013;8:e72816.
19.
Ishimura E, Nishizawa Y, Inaba M, Matsumoto N, Emoto M, Kawagishi T, Shoji S, Okuno S, Kim M, Miki T, Morii H: Serum levels of 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D, and 25-hydroxyvitamin D in nondialyzed patients with chronic renal failure. Kidney Int 1999;55:1019-1027.
20.
Kurajoh M, Inaba M, Yamada S, Imanishi Y, Tsuchida T, Ishimura E, Nishizawa Y: Association of increased active PTH(1-84) fraction with decreased GFR and serum Ca in predialysis CRF patients: modulation by serum 25-OH-D. Osteoporos Int 2008;19:709-716.
21.
Yamada S, Inaba M, Kurajoh M, Shidara K, Imanishi Y, Ishimura E, Nishizawa Y: Utility of serum tartrate-resistant acid phosphatase (TRACP5b) as a bone resorption marker in patients with chronic kidney disease: independence from renal dysfunction. Clin Endocrinol (Oxf) 2008;69:189-196.
22.
Inaba M, Hayashino Y, Shoji T, Akiba T, Akizawa T, Saito A, Kurokawa K, Fukuhara S: Disappearance of association in diabetic patients on hemodialysis between anemia and mortality risk: the Japan dialysis outcomes and practice pattern study. Nephron Clin Pract 2012;120:c91-c100.
23.
Nakatani S, Ishimura E, Mori K, Fukumoto S, Yamano S, Wei M, Emoto M, Wanibuchi H, Inaba M: Nephronectin expression in glomeruli of renal biopsy specimens from various kidney diseases: nephronectin is expressed in the mesangial matrix expansion of diabetic nephropathy. Nephron Clin Pract 2012;122:114-121.
24.
Masuda M, Ishimura E, Ochi A, Tsujimoto Y, Tahahra H, Okuno S, Tabata T, Nishizawa Y, Inaba M: Serum β2-microglobulin correlates positively with left ventricular hypertrophy in long-term hemodialysis patients. Nephron Clin Pract 2014;128:101-106.
25.
Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A: Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 2009;53:982-992.
26.
Shimizu Y, Fukumoto S, Fujita T: Evaluation of a new automated chemiluminescence immunoassay for FGF23. J Bone Miner Metab 2012;30:217-221.
27.
Inaba M, Nakatsuka K, Imanishi Y, Watanabe M, Mamiya Y, Ishimura E, Nishizawa Y: Technical and clinical characterization of the Bio-PTH (1-84) immunochemiluminometric assay and comparison with a second-generation assay for parathyroid hormone. Clin Chem 2004;50:385-390.
28.
Ishii A, Imanishi Y, Kurajoh M, Nagata Y, Kobayashi K, Miki T, Inaba M, Nishizawa Y: The administration of an active vitamin D(3) analogue reduced the serum concentrations of 1-84 and truncated parathyroid hormone in pseudohypoparathyroidism type Ib patients. Endocr J 2010;57:609-614.
29.
Higashi T, Awada D, Shimada K: Simultaneous determination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 in human plasma by liquid chromatography-tandem mass spectrometry employing derivatization with a Cookson-type reagent. Biol Pharm Bull 2001;24:738-743.
30.
Tsugawa N, Suhara Y, Kamao M, Okano T: Determination of 25-hydroxyvitamin D in human plasma using high-performance liquid chromatography - tandem mass spectrometry. Anal Chem 2005;77:3001-3007.
31.
Harinarayan CV: Prevalence of vitamin D insufficiency in postmenopausal south indian women. Osteoporos Int 2005;16:397-402.
32.
Reichel H, Koeffler HP, Norman AW: The role of the vitamin D endocrine system in health and disease. N Engl J Med 1989;320:980-991.
33.
Inaba M, Yukioka K, Furumitsu Y, Murano M, Goto H, Nishizawa Y, Morii H: Positive correlation between levels of IL-1 or IL-2 and 1,25(OH)2D/25-OH-D ratio in synovial fluid of patients with rheumatoid arthritis. Life Sci 1997;61:977-985.
34.
Razzaque MS, Sitara D, Taguchi T, St-Arnaud R, Lanske B: Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process. FASEB J 2006;20:720-722.
35.
Carpenter TO, Insogna KL, Zhang JH, Ellis B, Nieman S, Simpson C, Olear E, Gundberg CM: 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.
36.
Bosworth CR, Levin G, Robinson-Cohen C, Hoofnagle AN, Ruzinski J, Young B, Schwartz SM, Himmelfarb J, Kestenbaum B, de Boer IH: The serum 24,25-dihydroxyvitamin D concentration, a marker of vitamin D catabolism, is reduced in chronic kidney disease. Kidney Int 2012;82:693-700.
37.
Dai B, David V, Alshayeb HM, Showkat A, Gyamlani G, Horst RL, Wall BM, Quarles LD: Assessment of 24,25(OH)2D levels does not support GFG23-mediated catabolism of vitamin D metabolites. Kidney Int 2012;82:1061-1070.
38.
Alshayeb H, Showkat A, Wall BM, Gyamlani GG, David V, Quarles LD: Activation of FGF-23 mediated vitamin D degradative pathways by cholecalciferol. J Clin Endocrinol Metab 2014;99:E1830-E1837.
39.
de Boer IH, Sachs MC, Chonchol M, Himmelfarb J, Hoofnagle AN, Ix JH, Kremsdorf RA, Lin YS, Mehrotra R, Robinson-Cohen C, Siscovick DS, Steffes MW, Thummel KE, Tracy RP, Wang Z, Kestenbaum B: Estimated GFR and circulating 24,25-dihydroxyvitamin D3 concentration: a participant-level analysis of 5 cohort studies and clinical trials. Am J Kidney Dis 2014;64:187-197.
40.
Portale AA, Wolf M, Jüppner H, Messinger S, Kumar J, Wesseling-Perry K, Schwartz GJ, Furth SL, Warady BA, Salusky IB: Disordered FGF23 and mineral metabolism in children with CKD. Clin J Am Soc Nephrol 2014;9:344-353.
41.
Tsujikawa H, Kurotaki Y, Fujimori T, Fukuda K, Nabeshima Y: Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Mol Endocrinol 2003;17:2393-2403.
42.
Shimada T, Urakawa I, Yamazaki Y, Hasegawa H, Hino R, Yoneya T, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T: FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem Biophys Res Commun 2004;314:409-414.
43.
Sitara D, Razzaque MS, Hesse M, Yoganathan S, Taguchi T, Erben RG, Jüppner H, Lanske B: Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol 2004;23:421-432.
44.
Razzaque MS, St-Arnaud R, Taguchi T, Lanske B: FGF-23, vitamin D and calcification: the unholy triad. Nephrol Dial Transplant 2005;20:2032-2035.
45.
Jones G, Byford V, West S, Masuda S, Ibrahim G, Kaufmann M, Knutson JC, Strugnell S, Mehta R: Hepatic activation and inactivation of clinically-relevant vitamin D analogs and prodrugs. Anticancer Res 2006;26:2589-2595.
46.
Jones G, Horst R, Carter G, Makin H: Contemporary diagnosis and treatment of vitamin D-related disorders. J Bone Miner Res 2007;22(suppl 2):V11-V15.
47.
Marsell R, Grundberg E, Krajisnik T, Mallmin H, Karlsson M, Mellström D, Orwoll E, Ohlsson C, Jonsson KB, Ljunggren O, Larsson TE: Fibroblast growth factor-23 is associated with parathyroid hormone and renal function in a population-based cohort of elderly men. Eur J Endocrinol 2008;158:125-129.
48.
Westerberg PA, Linde T, Wikström B, Ljunggren O, Stridsberg M, Larsson TE: Regulation of fibroblast growth factor-23 in chronic kidney disease. Nephrol Dial Transplant 2007;22:3202-3207.
49.
Tenenhouse HS: Phosphate transport: molecular basis, regulation and pathophysiology. J Steroid Biochem Mol Biol 2007;103:572-577.
50.
Berndt T, Kumar R: Phosphatonins and the regulation of phosphate homeostasis. Annu Rev Physiol 2007;69:341-359.
51.
Miyamoto K, Haito-Sugino S, Kuwahara S, Ohi A, Nomura K, Ito M, Kuwahata M, Kido S, Tatsumi S, Kaneko I, Segawa H: Sodium-dependent phosphate cotransporters: lessons from gene knockout and mutation studies. J Pharm Sci 2011;100:3719-3730.
52.
Segawa H, Kaneko I, Yamanaka S, Ito M, Kuwahata M, Inoue Y, Kato S, Miyamoto K: Intestinal NA-P(i) cotransporter adaptation to dietary P(i) content in vitamin D receptor null mice. Am J Physiol Renal Physiol 2004;287:F39-F47.
53.
Xu H, Bai L, Collins JF, Ghishan FK: Age-dependent regulation of rat intestinal type IIb sodium-phosphate cotransporter by 1,25-(OH)(2) vitamin D(3). Am J Physiol Cell Physiol 2002;282:C487-C493.
54.
Okazaki R, Sugimoto T, Kaji H, Fujii Y, Shiraki M, Inoue D, Endo I, Okano T, Hirota T, Kurahashi I, Matsumoto T: Vitamin D insufficiency defined by serum 25-hydroxyvitamin D and parathyroid hormone before and after oral vitamin D3 load in Japanese subjects. J Bone Miner Metab 2011;29:103-110.
55.
Abdel-Wareth L, Haq A, Turner A, Khan S, Salem A, Mustafa F, Hussein N, Pallinalakam F, Grundy L, Patras G, Rajah J: Total vitamin D assay comparison of the roche diagnostics ‘vitamin D total' electrochemiluminescence protein binding assay with the chromsystems HPLC method in a population with both D2 and D3 forms of vitamin D. Nutrients 2013;5:971-980.
56.
Granado-Lorencio F, Olmedilla-Alonso B, Herrero-Barbudo C, Blanco-Navarro I, Pérez-Sacristán B: Seasonal variation of serum alpha- and beta-cryptoxanthin and 25-OH-vitamin D(3) in women with osteoporosis. Osteoporos Int 2008;19:717-720.
57.
Lensmeyer GL, Wiebe DA, Binkley N, Drezner MK: HPLC method for 25-hydroxyvitamin D measurement: comparison with contemporary assays. Clin Chem 2006;52:1120-1126.
58.
Mawer EB, Jones G, Davies M, Still PE, Byford V, Schroeder NJ, Makin HL, Bishop CW, Knutson JC: Unique 24-hydroxylated metabolites represent a significant pathway of metabolism of vitamin D2 in humans: 24-hydroxyvitamin D2 and 1,24-dihydroxyvitamin D2 detectable in human serum. J Clin Endocrinol Metab 1998;83:2156-2166.
© 2015 S. Karger AG, Basel
2015
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.