With or without the kidney: the role of FGF23 in CKD
Masafumi Fukagawa1 and
Junichiro J. Kazama2
1 Division of Nephrology and Dialysis Center, Kobe University School of Medicine, Kobe and 2 Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medicine and Dental Sciences, Niigata, Japan
Correspondence and offprint requests to: Masafumi Fukagawa, MD, PhD, FJSIM, FASN, Division of Nephrology and Dialysis Center, Kobe University School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan. Email: fukagawa{at}med.kobe-u.ac.jp
Keywords: chronic kidney disease (CKD); FGF23; kidney; parathyroid hormone (PTH); phosphate; vitamin D
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Introduction
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The systemic balance of phosphate is maintained mainly by three organs, i.e. the intestine, kidney and bone. Several factors including parathyroid hormone (PTH) and vitamin D play a critical role in this system. Fibroblast growth factor 23 (FGF23) is a recently identified phosphatonin which also is implicated [1,2].
It has been demonstrated in several diseases that excessive activity of FGF23 resulted in hypophosphataemia, low plasma 1,25-dihydroxyvitamin D (1,25D) levels and osteomalacia [35]. In animals, the administration of recombinant FGF23 led to the same results [6]. Furthermore, overexpression of FGF23 led to phosphate wasting [7] and rickets, while ablation of this gene led to hyperphosphatemia and high circulating 1,25D levels [8].
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Physiological role of FGF23 with a normal kidney
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What are the physiological stimuli for FGF23 secretion? In normal rats, a dietary phosphate load leads to hyperphosphataemia and increased serum FGF23 levels [9]. Such an observation has also been confirmed recently in humans. It is of note that phosphate load rather than serum phosphate concentration may be most important [10].
FGF23 levels increase in response to phosphate load by as yet unknown mechanisms, which promote phosphaturia and suppresses renal 1,25D production. Thus, a significant role for FGF23 in phosphate homeostasis is suspected in physiological conditions, with the intact kidney as the target organ.
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Role of FGF23 with a failing kidney
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Then, what is the role of FGF23 in chronic kidney disease (CKD), when phosphate balance is often deranged? In rats made uraemic by anti-glomerular basement membrane antibody, serum FGF23 levels increased as the renal function declined, along with an increase of phosphate levels and a decrease of 1,25D levels, together with a significant increase of PTH secretion [11]. High serum FGF23 levels were also associated with a high fractional excretion of phosphate. The effects of FGF23 on 1,25D levels and fractional excretion of phosphate were abolished by treating the rats with a specific neutralizing antibody against FGF23. Enhanced PTH secretion was also suppressed by this antibody treatment. Since the increase of FGF23 preceded the decrease of 1,25D, it seems that FGF23 plays an important role in the development of secondary hyperparathyroidism in CKD.
Several papers have already been published on the serum levels of FGF23 in CKD patients [1214]. In pre-dialysis patients, FGF23 levels were high and correlated with those of phosphate and creatinine. Nevertheless, the assay performed in these previous studies used antibodies that also detect C-terminal fragments. A new assay was developed to detect a full-length human FGF23 using two kinds of monoclonal antibodies, thus eliminating the detection of accumulating C-terminal fragments [15].
By this intact assay, serum FGF23 levels increased along with the fall of glomerular filtration rate (GFR) [16]. As expected, serum 1,25D levels correlated negatively with serum FGF23 levels. Furthermore, maximal tubular reabsorption of phosphate (TmP/GFR) correlated negatively with serum FGF23 levels, consistent with the physiological action of FGF23 that inhibits phosphate reabsorption in the proximal tubule. In contrast, patients with advanced renal failure exhibited impaired urinary phosphate excretion, despite significantly higher FGF23 levels.
With normal renal function, FGF23, when secreted in response to phosphate load, suppresses 1
-hydroxylase activity. In turn, decreased 1,25D levels activate parathyroid function. FGF23 promotes phosphate excretion by the kidney, which returns the serum phosphate level to normal. Since decreased serum phosphate, in turn, suppresses parathyroid function, the suppressive action on 1
-hydroxylase activity is antagonized.
In contrast, the number of viable nephrons decreases in patients with CKD. Therefore, despite high FGF23 levels, the amount of net phosphate excretion does not increase sufficiently, and serum phosphate levels remain high. Thus, high phosphate and decreased 1,25D levels further stimulate PTH secretion, leading to the development of secondary hyperparathyroidism in advanced stages of CKD.
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Role of FGF23 in the absence of a functioning kidney
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As reported recently, serum concentrations of FGF23 are extremely high in the majority of dialysis patients, even using the new intact assay. What is the role of FGF23 under these circumstances, i.e. in the absence of the major target organ, the kidney?
In our recent analysis of dialysis patients without hyperparathyroidism, FGF23 showed a weak but significant positive correlation with intact PTH. To our surprise, FGF23 levels showed an even better correlation with intact PTH levels 2 years after the measurement of FGF23. Further analysis using receiver operated characteristic curves revealed that the measurement of initial serum FGF23 level was a better screening test than intact PTH or calcium to discriminate patients in whom uncontrollable secondary hyperparathyroidism would develop within the subsequent 2 years [17]. In another study in dialysis patients with marked hyperparathyroidism, the pre-treatment FGF23 and intact PTH levels both significantly predicted the response to intravenous calcitriol therapy [18].
Then, what is the role of very high FGF23 levels in the development of refractory hyperparathyroidism, and where do these high levels of FGF23 come from? The first possibility is that they come from enlarged parathyroid glands. A recent report by Larsson and his associates demonstrated the development of parathyroid hyperplasia in response to FGF23 overexpression [19]. In contrast, no FGF23 mRNA expression was found in surgically removed enlarged parathyroid glands from patients with severe hyperparathyroidism [17]. In dialysis patients, serum FGF23 levels decreased slowly after surgical parathyroidectomy [20], although they did not return to normal levels. In addition, the majority of patients with primary hyperparathyroidism showed normal serum FGF23 levels, especially those with normal renal function [21]. Thus, parathyroid glands do not seem to be the origin of the very high FGF23 observed in dialysis patients. Although FGF23 expression was found in bone [17,22], other organs need to be screened as a potential source of FGF23 in renal failure.
On the other hand, the increase of FGF23 levels induced by a high phosphorus diet was abolished by parathyroidectomy in normal and in uraemic rats [23]. When PTH was injected into sham-operated and parathyroidectomized rats, serum FGF23 levels increased only in sham-operated rats. Thus, although FGF23 was not produced in parathyroid glands themselves, parathyroid hyperplasia is needed to maintain high FGF23 levels in dialysis patients.
In a recent study by our group, intravenous calcitriol therapy further increased serum FGF23 levels despite suppression of PTH levels. The serum FGF23 levels at 6 months significantly correlated with the cumulative 6 month doses of calcitriol [24]. The delta increase of serum FGF23 levels during the 6 months also showed a significant positive correlation with the cumulative dose of calcitriol. In keeping with this observation, it has been reported by others that 1,25D administration increased FGF23 levels in vivo [9] and in vitro [25].
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Closed or open loop in the FGF23 system: with or without the kidney
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The regulatory system for phosphate balance involving FGF23 can be summarized as shown in Figure 1. With normal renal function, i.e. in the closed loop mode, FGF23 acts on the kidney to promote urinary phosphate excretion and to suppress 1,25D production. Serum FGF23 levels return to normal after normalization of serum phosphate levels or phosphate balance in this regulatory system. When the kidney becomes unable to excrete the phosphate load appropriately in response to FGF23, PTH secretion is progressively stimulated by low serum 1,25D as well as by high serum phosphate levels.

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Fig. 1. Regulatory system of phosphate balance implicating FGF23 with (A) or without (B) the kidney. (A) In the presence of a functioning kidney, the loop of the system involving FGF23 is closed. In advanced stages of CKD, this system may no longer work properly even in the presence of high FGF23 levels. High phosphate levels together with low 1,25D levels subsequently stimulate PTH secretion. (B) In the absence of a functioning kidney, the loop is open. Despite several stimuli for FGF23 production, the negative feedback system is interrupted. Thus, serum FGF levels remain very high in dialysis patients. Closed arrowheads denote stimulatory effects and open arrowheads denote suppressive effects.
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In contrast, the loop of the regulatory system for phosphate balance is open in the absence of the main target organ of FGF23, the kidney. In dialysis patients, FGF23 production in the bone is continuously stimulated by phosphate load, vitamin D treatment and possibly by high PTH, while the normal negative feedback loop is no longer active with respect to FGF23. This results in very high levels of serum FGF23.
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Conclusion
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Circulating FGF23 is a physiological regulator of phosphate balance. Although mechanisms of increased FGF23 levels remain to be fully elucidated, this factor turns into a potential uraemic toxin, or, in other words, a new player in the trade-off hypothesis proposed by Slatopolsky et al. more than 30 years ago to explain the pathogenesis of secondary hyperparathyroidism in CKD patients [26]. In dialysis patients, the measurement of serum FGF23 may become a promising laboratory test to predict the development of secondary hyperparathyroidism and the response to calcitriol therapy. Further studies are needed to clarify more precisely the mechanism of the action and regulation of FGF23 under normal conditions and in CKD. In particular, the initial step of the regulatory system, i.e. sensing of phosphate load, needs to be elucidated in the near future.
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Acknowledgments
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This work was partly supported by a grant-in-aid from the Japanese Ministry of Health, Labor and Welfare to M.F. (#16590787).
Conflict of interest statement. None declared.
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References
|
---|
- Schiavi SC, Kumar R. The phosphatonin pathway: new insights in phosphate homeostasis. Kidney Int 2004; 65: 114[CrossRef][ISI][Medline]
- Shimada T, Mizutani S, Muto T et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci USA 2001; 98: 65006505[Abstract/Free Full Text]
- Brame LA, White KE, Econs MJ. Renal phosphate wasting disorders: clinical features and pathogenesis. Semin Nephrol 2004; 24: 3947[CrossRef][ISI][Medline]
- White KE, Evans WE, O'Riordran JLH et al. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. The ADHR Consortium. Nat Genet 2000; 26: 345348[CrossRef][ISI][Medline]
- Jonsson KB, Zahradnik R, Larsson T et al. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med 2003; 348: 16561663[Abstract/Free Full Text]
- Shimada T, Hasegawa H, Yamazaki Y et al. FGF-23 is a potent regulator of the vitamin D metabolism and phosphate homeostasis. J Bone Mineral Res 2004; 19: 429435[ISI][Medline]
- Shimada T, Urakawa I, Yamazaki Y et al. FGF-23 transgenic mice demonstrate hypophostemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem Biophys Res Commun 2004: 314: 409414[CrossRef][ISI][Medline]
- Shimada T, Kakitani M, Yamazaki Y et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 2004; 113: 561568[Abstract/Free Full Text]
- Saito H, Maeda A, Ohtomo S et al. Circulating FGF23 is regulated by 1 alpha, 25-dihydroxyvitamin D3 and phosphate in vivo. J Biol Chem 2005; 280: 25432549[Abstract/Free Full Text]
- Ferrari SL, Bonjour JP, Rizzoli R. Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men. J Clin Endocrinol Metab 2005; 90: 15191524[Abstract/Free Full Text]
- Hasegawa H, Iijima K, Shimada T et al. FGF-23 plays a critical role in the development of reduced serum 1,25-dihydroxyvitamin D (1,25D) levels associated with renal insufficiency [abstract]. J Am Soc Nephrol 2003; 14: 40A
- 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: 22722279[CrossRef][ISI][Medline]
- Weber TJ, Liu S, Indridason OS, Quarles LD. Serum FGF23 levels in normal and disordered phosphorus homeostasis. J Bone Miner Res 2003; 18:12271234[ISI][Medline]
- Imanishi Y, Inaba M, Nakatsuka K et al. FGF-23 in patients with end-stage renal disease on hemodialysis. Kidney Int 2004; 65: 19431046[CrossRef][ISI][Medline]
- Yamazaki Y, Okazaki R, Shibata M et al. Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J Clin Endocrinol Metab 2002; 87: 49574560[Abstract/Free Full Text]
- Shigematsu T, Kazama JJ, Yamashita T et al. Possible involvement of circulating fibroblast growth factor-23 in the development of secondary hyperparathyroidism associated with renal insufficiency. Am J Kidney Dis 2004; 44: 250256[ISI][Medline]
- Nakanishi S, Kazama JJ, Nii-Kono T et al. Serum fibroblast growth factor-23 levels predict the future refractory hyperparathyroidism in dialysis patients. Kidney Int 2005; 67: 11711178[CrossRef][ISI][Medline]
- Kazama JJ, Sato F, Omori K et al. Pretreatment serum FGF-23 levels predict the efficacy of calcitriol therapy in dialysis patients. Kidney Int 2005; 67: 11201125[CrossRef][ISI][Medline]
- Larsson T, Marsell R, Schipani E et al. Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha (I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis. Endocrinology 2004; 145: 30873094.[Abstract/Free Full Text]
- Sato T, Tominaga Y, Ueki T et al. Total parathyroidectomy reduces elevated circulating fibroblast growth factor 23 in advanced secondary hyperparathyroidism. Am J Kidney Dis 2004; 44: 481487[ISI][Medline]
- Yamashita H, Yamashita T, Miyamoto M et al. Fibroblast growth factor (FGF)-23 in patients with primary hyperparathyroidism. Eur J Endocrinol 2004; 151: 5560[Abstract/Free Full Text]
- Mirams M, Robinson BG, Mason, Nelson AE. Bone as a source of FGF23: regulation by phosphate? Bone 2004; 35: 11921199[CrossRef][ISI][Medline]
- Hasegawa H, Shimada T, Yamazaki Y et al. Parathyroid-dependent and -independent mechanism to elevate serum concentration of FGF-23 [abstract]. J Am Soc Nephrol 2004; 15: 267A
- Nishi H, Nii-Kono T, Nakanishi S et al. Intravenous calcitriol therapy increases serum concentrations of fibroblast growth factor-23 in dialysis patients with secondary hyperparathyroidism. Nephron Clin Pract 2005; in press.
- Ito M, Sakai Y, Furumoto M et al. Vitamin D and phosphate regulate fibroblast growth factor-23 in K562 cells. Am J Physiol Endocrinol Metab 2005; in press
- Slatopolsky E, Caglar S, Pennell JP et al. On the pathogenesis of hyperparathyroidism in chronic experimental renal insufficiency in the dog. J Clin Invest 1971; 50: 492499[ISI][Medline]