The role of fibroblast growth factor 23 in renal disease
Kenneth B. Jonsson
Department of Surgical Sciences, Unit of Orthopedic Surgery, Uppsala University, Uppsala, Sweden
Correspondence and offprint requests to: Kenneth B. Jonsson, Department of Surgical Sciences, Unit of Orthopedic Surgery, Uppsala University, SE-751 85 Uppsala, Sweden. E-mail: Kenneth.jonsson{at}surgsci.uu.se
Keywords: CKD; ESRD; FGF23; hyperparathyroidism; hyperphosphataemia; phosphate; renal failure; vitamin D
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FGF23 is a phosphate regulator in physiology and pathology
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Activating mutations in the fibroblast growth factor 23 (FGF23) gene were identified as the cause of autosomal dominant hypophosphataemic rickets (ADHR) [1]. This secreted protein was later shown to play a role in both physiological and pathological phosphate handling.
FGF23 may be the key pathogenetic molecule in three different diseases with hypophosphataemia and inappropriate regulation of vitamin D metabolism. In ADHR, the mutations stabilize the FGF23 protein, which leads to increased circulating levels [2]. In X-linked hypophosphataemia (XLH), a disease caused by inactivating mutations of the PHEX gene, the loss of a membrane-bound protease results in increased circulating levels of FGF23 [3]. Also, in the paraneoplastic syndrome of tumour-induced osteomalacia (TIO), tumours secrete large amounts of FGF23 [35]. Thus, in three disorders of inorganic phosphate (Pi) wasting, FGF23 circulates in increased amounts, suggesting a pathological role for the molecule.
Evidence for a physiological role for FGF23 in Pi handling comes from animal models of altered FGF23 expression. Fgf23 null mice have hyperphosphataemia and increased 1,25(OH)2D3 levels [6], and normal mice treated with Fgf23-blocking antibodies respond by a significant elevation in Pi and 1,25(OH)2D3 levels [7]. Transgenic mice that overexpress FGF23 show a phenotype in concordance with XLH, ADHR and TIO [810]. Thus, these animals have reduced serum Pi and 1,25(OH)2D3 levels. Furthermore, FGF23 levels change in response to changes in dietary Pi intake in both rodents and humans [1113], suggesting a physiological regulation of FGF23 production in response to Pi availability.
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Phosphate homeostasis and vitamin D metabolism in renal disease
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Normal levels of Pi in plasma are maintained within a relatively narrow range (0.81.3 mmol/l). Processes that regulate intestinal absorption and renal excretion of Pi balance this level. In fact, the renal reabsorption of Pi is the single most important mechanism for maintaining Pi levels within this range. The activity of the NPT2 transporter located in the proximal tubules of the kidney is responsible for
70% of the overall Pi reabsorption, and several known hormonal mechanisms, most notably that of parathyroid hormone (PTH), affect its activity [14]. In renal disease, the ability of the kidney to filter Pi decreases with the loss of functional nephrons, whereas intestinal absorption is unaffected. Therefore, in the early stages of chronic kidney disease (CKD), hyperparathyroidism develops as a compensatory mechanism to control serum levels of Ca, Pi and 1,25(OH)2D3, but as the glomerular filtration rate (GFR) falls bellow 25 ml/min, a rise in serum Pi levels will occur. Indeed, hyperphosphataemia is a hallmark of end-stage renal disease (ESRD) [15].
The increase in Pi levels is coupled to the development of complications such as hyperparathyroidism and vascular calcifications, and studies have shown a clear rise in mortality in ESRD patients with uncontrolled hyperphosphataemia [16]. High circulating levels of PTH induce the metabolic bone diseases osteitis fibrosa cystica and mixed renal osteodystophy and contribute to cardiovascular complications that increase morbidity and mortality.
As CKD progresses, the renal ability to activate vitamin D decreases. This also contributes to the generation and maintenance of parathyroid hyperplasia and increased synthesis and secretion of PTH. These two problems, hyperphosphataemia and low vitamin D activity, are the rationale for traditional therapy of a Pi-restricted diet in combination with intestinal Pi binders and vitamin D substitution. The question then arises, will our novel understanding of FGF23 actions on Pi handling and vitamin D metabolism affect future care of patients with renal disease?
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The role of FGF23 in the dysregluation of phosphate/calcium/vitamin D homeostasis in CKD
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FGF23 levels are increased in renal disease
With the development of immunoassays for the measurement of FGF23 in human serum or plasma, it became possible to study its role in disorders of Pi homeostasis [3,17]. The first studies focused on patients with hypophosphataemia, but we also reported that patients with renal failure have elevated levels of FGF23 [3]. There are currently three commercially available FGF23 assays. Immutopics, Inc. (www.immutopics.com) provides the original C-terminal assay and a newly developed intact assay. The C-terminal assay detects full-length protein and, in addition, the C-terminal fragments that are the result of proteolytical cleavage at the R179 site of the intact protein. Kainos Laboratories, Inc. (www.kainos.co.jp) provides an assay that uses epitopes on either site of the cleavage site which results in measurements of full-length FGF23 levels. Several studies, using both the Immutopics C-terminal and Kainos full-length assay, have corroborated the initial findings and it is now clear that immunoreactive FGF23 is highly elevated in both CKD and ESRD (
1000-fold) patients. After a successful renal transplant, the levels drop to near normal [1821].
One potential reason for the high circulating FGF23 levels could be a decreased renal clearance of FGF23 in the diseased kidney. Some evidence for this exists since C-terminal FGF23 immunoreactivity is present in urine in both healthy individuals and in ESRD patients with residual urine production [20]. A more intriguing reason could be that FGF23 synthesis is stimulated by the hyperphosphataemia per se. As mentioned above, several observations suggest that FGF23 production is stimulated by hyperphosphataemia. Rodents and humans given high Pi diets increase their FGF23 production, and patients with hyperphosphataemia due to hypoparathyroidism also have increased levels [1113,22]. Also, immunoprecipitation of FGF23 in serum from ESRD patients detects increased full-length immunoreactivity [19,20]. Together, this suggests that the elevation is, at least partially, due to increased production of FGF23.
In simple regression models, FGF23 levels have been found to correlate strongly with parameters of renal function in different populations of CKD patients. Other correlations include serum Pi, [Ca x Pi] and PTH. It is also of interest that in patients with normal or slightly depressed GFR, inverse correlations with serum 1,25(OH)2D3 appear to be very strong, which is in line with the known potent inhibitory actions of FGF23 on renal 25-hydroxyvitamin D-1
-hydroxylase (1
-hydroxylase) [18,23].
So its up, does it matter?
Several models of systemic overexpression of FGF23 have demonstrated that high levels of circulating FGF23 will result in basically four important changes: (i) hypophosphataemia due to decreased renal Pi reabsorption; (ii) decreased 1,25(OH)2D3 levels due to inhibiton of the 1
-hydroxylase and stimulation of the 25-hydroxyvitamin D-24-hydroxylase activity; (iii) development of parathyroid hyperplasia; and (iv) osteomalacia or rickets. All of these effects may be relevant to CKD.
Two important but hitherto unpublished studies highlight this hypothesis [24,25]. In experimentally induced renal failure in the rat, FGF23 levels started to rise 10 days after injection of a nephritis-inducing antibody which coincided with the rise of serum creatinine. At day 20, serum PTH and 1,25(OH)2D3 levels were significantly changed from baseline and, only later, at day 30, did Pi levels significantly increase. Before the rise in serum Pi levels, FGF23 levels correlated significantly with increased fractional excretion of Pi, suggesting that, in early CKD, FGF23 maintains its phosphaturic actions. Concomitantly, FGF23 inhibits 1
-hydroxylase activity, thereby lowering the 1,25(OH)2D3 levels. This results in a relative hypocalcaemia which drives PTH secretion. 1,25(OH)2D3 also has direct effects on the parathyroid, inhibiting PTH gene transcription and parathyroid hyperplasia by suppressing the expression of autocrine growth signals [26]. In the same model, one injection of neutralizing antibodies against FGF23 improved the deranged renal phosphate excretion and serum 1,25(OH)2D3 levels [25], thus suggesting that FGF23 may be a major culprit in the development of secondary hyperparathyroidism in CKD. As GFR further declines, daily excretion of Pi declines in the face of a rise in the phosphaturic hormones PTH and FGF23. This further aggravates parathyroid dysfunction since increased Pi levels themselves stimulate the parathyroid cell [15].
Medical therapies including active vitamin D agents are effective in most cases of early secondary hyperparathyroidism. However, resistance to medical therapy occurs in cases with developed hyperparathyroidism through changes in the biological properties of parathyroid cells. It is possible that the hyperparathyroidism itself contributes to the increased FGF23 activity since one study showed a significant drop in FGF23 levels after parathyroidectomy [27]. However, this occurred with a concomitant drop in [Ca x P] and Pi levels. Therefore, the results could be explained by changes in the systemic Ca/Pi balance.
Are FGF23 measurements clinically useful in CKD patients?
So far, very few data are available to answer this question. Nakanishi et al. investigated 103 patients with early stages of CKD and found that patients with increased levels of FGF23 were more likely to develop severe secondary hyperparathyroidism [28]. Also, dialysis patients with the highest levels of FGF23 were the least likely to respond to vitamin D therapy, suggesting that FGF23 measurements may help in the management of these patients [29].
In conclusion, it is plausible that increased FGF23 levels are, at least partially, responsible for the reduction of 1,25(OH)2D3 levels in the early phase of renal insufficiency and that this contributes to the development of secondary hyperparathyroidism in chronic and end-stage kidney disease. Future development of anti-FGF23 therapy may be potentially beneficial for patients with early CKD, and measurements of FGF23 levels in this group of patients may help in deciding on an optimal treatment strategy.
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Acknowledgments
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The work was supported by the Swedish Research Council, the Novo Nordisk Foundation and the Swedish Society of Medicine.
Conflict of interest statement. None declared.
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