Clinical relevance of FGF-23 in chronic kidney disease
2009; Elsevier BV; Volume: 76; Linguagem: Inglês
10.1038/ki.2009.405
ISSN1523-1755
AutoresSarah Seiler, Gunnar H. Heine, Danilo Fliser,
Tópico(s)Pancreatitis Pathology and Treatment
ResumoFibroblast growth factor (FGF)-23 is a recently discovered regulator of calcium–phosphate metabolism. Whereas other known FGFs mainly act in a paracrine manner, FGF-23 has significant systemic effects. Together with its cofactor Klotho, FGF-23 enhances renal phosphate excretion in order to maintain serum phosphate levels within the normal range. In patients with chronic kidney disease (CKD), FGF-23 levels rise in parallel with declining renal function long before a significant increase in serum phosphate concentration can be detected. However, in cross-sectional studies increased FGF-23 levels in patients with CKD were found to be associated not only with therapy-resistant secondary hyperparathyroidism but were also independently related to myocardial hypertrophy and endothelial dysfunction after adjustment for traditional markers of calcium–phosphate metabolism. Finally, in prospective studies high serum FGF-23 concentrations predicted faster disease progression in CKD patients not on dialysis, and increased mortality in patients receiving maintenance hemodialysis. FGF-23 may therefore prove to be an important therapeutic target in the management of CKD. Fibroblast growth factor (FGF)-23 is a recently discovered regulator of calcium–phosphate metabolism. Whereas other known FGFs mainly act in a paracrine manner, FGF-23 has significant systemic effects. Together with its cofactor Klotho, FGF-23 enhances renal phosphate excretion in order to maintain serum phosphate levels within the normal range. In patients with chronic kidney disease (CKD), FGF-23 levels rise in parallel with declining renal function long before a significant increase in serum phosphate concentration can be detected. However, in cross-sectional studies increased FGF-23 levels in patients with CKD were found to be associated not only with therapy-resistant secondary hyperparathyroidism but were also independently related to myocardial hypertrophy and endothelial dysfunction after adjustment for traditional markers of calcium–phosphate metabolism. Finally, in prospective studies high serum FGF-23 concentrations predicted faster disease progression in CKD patients not on dialysis, and increased mortality in patients receiving maintenance hemodialysis. FGF-23 may therefore prove to be an important therapeutic target in the management of CKD. Patients with chronic kidney disease (CKD) stage 5 who receive hemodialysis therapy have a more than 10-fold increased risk for cardiovascular events compared with individuals with normal kidney function.1Foley R.N. Parfrey P.S. Sarnak M.J. Clinical epidemiology of cardiovascular disease in chronic renal disease.Am J Kidney Dis. 1998; 32: S112-S119Abstract Full Text PDF PubMed Scopus (2973) Google Scholar In addition to classic cardiovascular risk factors (e.g., arterial hypertension, smoking, dyslipidemia, family history), disturbances in calcium–phosphate metabolism contribute to vascular calcification and higher cardiovascular mortality in CKD patients.2Blacher J. Safar M.E. Guerin A.P. et al.Aortic pulse wave velocity index and mortality in end-stage renal disease.Kidney Int. 2003; 63: 1852-1860Abstract Full Text Full Text PDF PubMed Scopus (454) Google Scholar,3London G.M. Guérin A.P. Marchais S.J. et al.Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality.Nephrol Dial Transplant. 2003; 18: 1731-1740Crossref PubMed Scopus (1517) Google Scholar Disturbed calcium–phosphate metabolism was traditionally characterized by low-to-normal serum calcium, high serum phosphate, low serum 1,25-(OH)2-vitamin D3 (calcitriol), and high serum parathyroid hormone (PTH) levels.4Levin A. Bakris G.L. Molitch M. et al.Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease.Kidney Int. 2007; 71: 31-38Abstract Full Text Full Text PDF PubMed Scopus (1156) Google Scholar Elevated serum phosphate, low calcitriol, and high PTH levels are each independently associated with future cardiovascular events and mortality in large epidemiological trials of patients with CKD stage 5.5Tentori F. Blayney M.J. Albert J.M. 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: 519-530Abstract Full Text Full Text PDF PubMed Scopus (813) Google Scholar,6Wald R. Sarnak M.J. 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: 531-540Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar Recent in vitro studies have illuminated possible mechanisms by which these factors may actively contribute to vessel damage and subsequent cardiovascular events.7Giachelli C.M. The emerging role of phosphate in vascular calcification.Kidney Int. 2009; 75: 890-897Abstract Full Text Full Text PDF PubMed Scopus (355) Google Scholar It is therefore not surprising that preliminary data from clinical trials suggest that therapeutic interventions such as vitamin D therapy,8Naves-Díaz M. Alvarez-Hernández D. Passlick-Deetjen J. et al.Oral active vitamin D is associated with improved survival in hemodialysis patients.Kidney Int. 2008; 74: 1070-1078Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar, 9Shoben A.B. Rudser K.D. de Boer I.H. et al.Association of oral calcitriol with improved survival in nondialyzed CKD.J Am Soc Nephrol. 2008; 19: 1613-1619Crossref PubMed Scopus (247) Google Scholar, 10Teng M. Wolf M. Ofsthun M.N. et al.Activated injectable vitamin D and hemodialysis survival: a historical cohort study.J Am Soc Nephrol. 2005; 16: 1115-1125Crossref PubMed Scopus (756) Google Scholar phosphate lowering with phosphate binders,11Isakova T. Gutiérrez O.M. Chang Y. et al.Phosphorus binders and survival on hemodialysis.J Am Soc Nephrol. 2009; 20: 388-396Crossref PubMed Scopus (309) Google Scholar and treatment of secondary hyperparathyroidism (sHPT) with cinacalcet12Kawata T. Nagano N. Obi M. et al.Cinacalcet suppresses calcification of the aorta and heart in uremic rats.Kidney Int. 2008; 74: 1270-1277Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar may be vasculoprotective, even though outcome data from large randomized clinical trials are still pending. However, the above traditional pathophysiological concept of a deranged calcium–phosphate metabolism in CKD has been challenged by the recent discovery of the phosphaturic hormone, fibroblast growth factor (FGF)-23. In this article, we review available evidence on the (patho)physiological role of FGF-23 and discuss its potential clinical impact in CKD. FGFs comprise a family of polypeptides that share a common core region containing approximately 120 highly conserved amino-acid residues, with variable flanking N- and C-terminal residues. The core region contains a β-trefoil structure composed of folded β-strands and loops. On the basis of phylogenetic analysis, seven known subfamilies of human FGFs have been defined.13Goetz R. Beenken A. Ibrahimi O.A. et al.Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members.Mol Cell Biol. 2007; 27: 3417-3428Crossref PubMed Scopus (428) Google Scholar,14Yamashita T. Structural and biochemical properties of fibroblast growth factor 23.Ther Apher Dial. 2005; 9: 313-318Crossref PubMed Scopus (42) Google Scholar The FGF-19 subfamily is composed of three proteins—FGF-19, FGF-21, and FGF-23—which exert diverse physiological functions. FGF-23 is a central regulator of phosphate homeostasis and calcitriol blood levels, whereas FGF-19 inhibits the expression of enzyme cholesterol-7-α-hydroxylase (CYP7A1), which is the first and rate-limiting step in bile acid synthesis.15Crestani M. Sadeghpour A. Stroup D. et al.Transcriptional activation of the cholesterol 7α-hydroxylase gene (CYP7A) by nuclear hormone receptors.J Lipid Res. 1998; 39: 2192-2200Abstract Full Text Full Text PDF PubMed Google Scholar FGF-21 stimulates insulin-independent glucose uptake in adipocytes and lowers triglycerides.16Kharitonenkov A. Shiyanova T.L. Koester A. et al.FGF-21 as a novel metabolic regulator.J Clin Invest. 2005; 115: 1627-1635Crossref PubMed Scopus (1626) Google Scholar Interestingly, FGF-19, FGF-21, and FGF-23 contain a disulfide bond that is absent in most other subfamilies. This disulfide bond may stabilize their unique atypical β-trefoil structure, which differs from the common fundamental β-trefoil structure of the core homology region of other FGF subfamilies. Such a conformational change may explain why FGF-19 and FGF-23 have a low affinity for heparin,13Goetz R. Beenken A. Ibrahimi O.A. et al.Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members.Mol Cell Biol. 2007; 27: 3417-3428Crossref PubMed Scopus (428) Google Scholar and can therefore be distributed in the bloodstream throughout the body to mediate their systemic functions. In contrast, members of other FGF subfamilies bind to heparin sulfate present on the cell surface of producing cells, resulting in their capture and explaining their paracrine function.14Yamashita T. Structural and biochemical properties of fibroblast growth factor 23.Ther Apher Dial. 2005; 9: 313-318Crossref PubMed Scopus (42) Google Scholar FGF-23 is a 251-amino-acid protein (MW 26 kDa) synthesized and secreted by bone cells, mainly osteoblasts.17Riminucci M. Collins M.T. Fedarko N.S. et al.FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting.J Clin Invest. 2003; 112: 683-692Crossref PubMed Scopus (543) Google Scholar It is composed of an amino-terminal signal peptide (residues 1–24), followed by an 'FGF-like sequence' (residues 25–180) and a carboxyl-terminal extended sequence (residues 181–251) that is unique compared with other members of the FGF family.14Yamashita T. Structural and biochemical properties of fibroblast growth factor 23.Ther Apher Dial. 2005; 9: 313-318Crossref PubMed Scopus (42) Google Scholar The biologically active protein can be cleaved at its RXXR motif by a subtilisin-type proprotein convertase.18Benet-Pagès A. Lorenz-Depiereux B. Zischka H. et al.FGF23 is processed by proprotein convertases but not by PHEX.Bone. 2004; 35: 455-462Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 19Nakayama K. Furin: a mammalian subtilisin/Kex2p-like endoprotease involved in processing of a wide variety of precursor proteins.Biochem J. 1997; 327: 625-635Crossref PubMed Scopus (702) Google Scholar, 20Shimada T. Muto T. Urakawa I. et al.Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo.Endocrinology. 2002; 143: 3179-3182Crossref PubMed Scopus (384) Google Scholar The half-life of intact FGF-23 in the circulation of healthy individuals has been estimated to be 58 min.21Khosravi A. Cutler C.M. Kelly M.H. et al.Determination of the elimination half-life of fibroblast growth factor-23.J Clin Endocrinol Metab. 2007; 92: 2374-2377Crossref PubMed Scopus (124) Google Scholar Two assays for measurement of human FGF-23 are commercially available. Full-length FGF-23 levels can be determined with a sandwich enzyme-linked immunosorbent assay, in which two kinds of monoclonal antibodies detect the simultaneous presence of both the N-terminal and C-terminal portions of FGF-23. In contrast, the C-terminal assay recognizes both full-length and processed (presumably inactive) C-terminal fragments of FGF-23 (Figure 1). For the C-terminal FGF-23 assay, intra-assay variability is 5% at 52.7 and 140.0 RU/ml, whereas interassay variability is 5% at 50.9 RU/ml and 7.3% at 153.0 RU/ml, with a lower detection limit of 3.0 RU/ml. For the intact FGF-23 assay, intra-assay variability is 4.4% at 14.6 pg/ml and 2.6% at 148.0 pg/ml, whereas interassay variability is 6.1% at 15.6 pg/ml and 6.5% at 166.0 pg/ml, with a lower detection limit of 1.0 pg/ml (according to the manufacturer's specifications). Klotho is a 130-kDa transmembrane β-glucuronidase capable of hydrolyzing steroid β-glucoronides. This protein was discovered in 1997 by Kuro-o et al.22Kuro-o M. Matsumura Y. Aizawa H. et al.Mutation of the mouse klotho gene leads to a syndrome resembling ageing.Nature. 1997; 390: 45-51Crossref PubMed Scopus (2804) Google Scholar It was named after Klotho, one of the Moirae (The Fates) in Greek mythology who spun the thread of life from her distaff onto her spindle, as Klotho-deficient mice manifest a syndrome resembling accelerated human aging and extensive atherosclerosis. Because FGF-23-/- mice show similar phenotypes to klotho-/- mice,23Nakatani T. Sarraj B. Ohnishi M. et al.In vivo genetic evidence for klotho-dependent, fibroblast growth factor 23 (Fgf23)-mediated regulation of systemic phosphate homeostasis.FASEB J. 2009; 23: 433-441Crossref PubMed Scopus (211) Google Scholar,24Razzaque M.S. Sitara D. Taguchi T. et al.Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process.FASEB J. 2006; 20: 720-722Crossref PubMed Scopus (299) Google Scholar a common signaling pathway has been postulated. Indeed, FGF-23 exerts its biological effects through activation of FGF receptors (FGF-Rs) in a Klotho-dependent manner, as a Klotho/FGF-R complex binds to FGF-23 with higher affinity than does FGF-R or Klotho alone.25Kurosu H. Ogawa Y. Miyoshi M. et al.Regulation of fibroblast growth factor-23 signaling by klotho.J Biol Chem. 2006; 281: 6120-6123Crossref PubMed Scopus (1069) Google Scholar Klotho gene expression was detected in cells of the renal tubule, parathyroid, and choroid plexus,26Tohyama O. Imura A. Iwano A. et al.Klotho is a novel β-glucuronidase capable of hydrolyzing steroid β-glucuronides.J Biol Chem. 2004; 279: 9777-9784Crossref PubMed Scopus (189) Google Scholar conferring FGF-23 tissue selectivity, despite the ubiquitous expression of FGF-R. Currently, it is unclear why Klotho is expressed only at these sites. FGF-Rs consist of an extracellular domain with two or three immunoglobulin (Ig)-like ligand-binding domains, and one intracellular domain mediating tyrosine kinase activity. Four receptor tyrosine kinases are designated as high-affinity FGF-Rs (FGF-R 1–4). Alternative RNA splicing generates multiple FGF-R isoforms. In particular, this can occur in the third Ig-like domain of FGF-R 1–3, giving rise to epithelial-lineage specific 'b' and mesenchymal-lineage specific 'c' isoforms.27Eswarakumar V.P. Lax I. Schlessinger J. Cellular signaling by fibroblast growth factor receptors.Cytokine Growth Factor Rev. 2005; 16: 139-149Abstract Full Text Full Text PDF PubMed Scopus (1501) Google Scholar, 28Mohammadi M. Olsen S.K. Ibrahimi O.A. Structural basis for fibroblast growth factor receptor activation.Cytokine Growth Factor Rev. 2005; 16: 107-137Abstract Full Text Full Text PDF PubMed Scopus (560) Google Scholar, 29Ornitz D.M. Itoh N. Fibroblast growth factors.Genome Biol. 2001; 2 (REVIEWS3005)Crossref PubMed Google Scholar Klotho has a high binding affinity for FGF-R 1–4, with a preference for the c-isoforms of FGF-Rs.25Kurosu H. Ogawa Y. Miyoshi M. et al.Regulation of fibroblast growth factor-23 signaling by klotho.J Biol Chem. 2006; 281: 6120-6123Crossref PubMed Scopus (1069) Google Scholar In the presence of Klotho, FGF-23 induces the phosphorylation and subsequent activation of the extracellular signal-regulated kinase (ERK), which regulates an important intracellular signal-transduction pathway.30Urakawa I. Yamazaki Y. Shimada T. et al.Klotho converts canonical FGF receptor into a specific receptor for FGF23.Nature. 2006; 444: 770-774Crossref PubMed Scopus (1457) Google Scholar Renal phosphate excretion is physiologically regulated mainly by proximal tubular cells, which express Na/Pi Type II cotransporters at their apical membrane that control phosphate reclamation.31Miyamoto K. Segawa H. Ito M. et al.Physiological regulation of renal sodium-dependent phosphate cotransporters.Jpn J Physiol. 2004; 54: 93-102Crossref PubMed Scopus (58) Google Scholar Renal phosphate reabsorption is mediated primarily through the Na/Pi IIa cotransporter,32Beck L. Karaplis A.C. Amizuka N. et al.Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities.Proc Natl Acad Sci USA. 1998; 95: 5372-5377Crossref PubMed Scopus (521) Google Scholar whereas approximately one-third of phosphate ions are reabsorbed through the Na/Pi IIc cotransporter.33Tenenhouse H.S. Martel J. Gauthier C. et al.Differential effects of Npt2a gene ablation and X-linked Hyp mutation on renal expression of Npt2c.Am J Physiol Renal Physiol. 2003; 285: F1271-F1278Crossref PubMed Scopus (93) Google Scholar FGF-23 mediates its phosphaturic effect by reducing the abundance of the Na/Pi IIa cotransporter34Baum M. Schiavi S. Dwarakanath V. et al.Effect of fibroblast growth factor-23 on phosphate transport in proximal tubules.Kidney Int. 2005; 68: 1148-1153Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar (and possibly also Na/Pi IIc) in proximal tubular cells. In animal studies, transgenic mice overexpressing human or mouse FGF-23 have severe renal phosphate wasting because of suppression of renal Na/Pi cotransporter activity,35Bai X. Miao D. Li J. et al.Transgenic mice overexpressing human fibroblast growth factor 23 (R176Q) delineate a putative role for parathyroid hormone in renal phosphate wasting disorders.Endocrinology. 2004; 145: 5269-5279Crossref PubMed Scopus (301) Google Scholar, 36Larsson T. Marsell R. 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Nonetheless, PTH is not indispensable for FGF-23 activity, as the phosphaturic effects of FGF-23 are maintained in animals after parathyroidectomy.37Shimada T. Hasegawa H. Yamazaki Y. et al.FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.J Bone Miner Res. 2004; 19: 429-435Crossref PubMed Scopus (1419) Google Scholar The precise relationship between FGF-23 and PTH regulation is still under investigation. FGF-R and Klotho are expressed in parathyroid glands, suggesting that FGF-23 might regulate PTH secretion. In support of this hypothesis, in vitro data suggest that FGF-23 decreases PTH mRNA transcription and protein secretion in a dose-dependent manner.41Krajisnik T. Björklund P. Marsell R. et al.Fibroblast growth factor-23 regulates parathyroid hormone and 1α-hydroxylase expression in cultured bovine parathyroid cells.J Endocrinol. 2007; 195: 125-131Crossref PubMed Scopus (397) Google Scholar Conversely, PTH may stimulate FGF-23 secretion by osteoblasts, as FGF-23 levels are increased in rodents with primary HPT, which may be reversed by parathyroidectomy.42Kawata T. Imanishi Y. Kobayashi K. et al.Parathyroid hormone regulates fibroblast growth factor-23 in a mouse model of primary hyperparathyroidism.J Am Soc Nephrol. 2007; 18: 2683-2688Crossref PubMed Scopus (168) Google Scholar Interestingly, significantly less FGF-23 is needed to reduce calcitriol levels than that required to reduce serum phosphate levels, and calcitriol levels decrease before phosphaturia occurs.37Shimada T. Hasegawa H. Yamazaki Y. et al.FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.J Bone Miner Res. 2004; 19: 429-435Crossref PubMed Scopus (1419) Google Scholar In rodents, injection of recombinant FGF-23 reduces calcitriol levels within hours by decreasing renal expression of 1α-hydroxylase (CYP27B1)—the rate-limiting step in the generation of calcitriol—and increasing the expression of 24-hydroxylase (CYP24A1), which controls calcitriol degradation.37Shimada T. Hasegawa H. Yamazaki Y. et al.FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.J Bone Miner Res. 2004; 19: 429-435Crossref PubMed Scopus (1419) Google Scholar Consistent with this observation, marked increases in serum calcitriol levels have been reported in FGF-23-deficient mice. Hypervitaminosis D has been implicated in extensive vascular and soft tissue calcification and increased mortality in these FGF-23-/- mice.24Razzaque M.S. Sitara D. Taguchi T. et al.Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process.FASEB J. 2006; 20: 720-722Crossref PubMed Scopus (299) Google Scholar,38Shimada 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: 561-568Crossref PubMed Scopus (1270) Google Scholar However, recent evidence suggests that hyperphosphatemia, rather than elevated calcitriol, may be the major culprit, as normalization of serum phosphate levels prevented vascular and soft-tissue calcification in FGF-23-/- mice, whereas normalization of calcitriol levels failed to do so.39Stubbs J.R. Liu S. Tang W. et al.Role of hyperphosphatemia and 1,25-dihydroxyvitamin D in vascular calcification and mortality in fibroblastic growth factor 23 null mice.J Am Soc Nephrol. 2007; 18: 2116-2124Crossref PubMed Scopus (241) Google Scholar Conversely, although FGF-23 reduces calcitriol levels, calcitriol itself stimulates FGF-23 generation by binding to a vitamin D response region in the FGF-23 gene promoter.43Liu S. Tang W. Zhou J. et al.Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D.J Am Soc Nephrol. 2006; 17: 1305-1315Crossref PubMed Scopus (541) Google Scholar In humans, the clinical relevance of FGF-23 was first discovered in the context of hereditary diseases of phosphate metabolism, which provided further insight into the major pathways regulating serum phosphate balance. In 2000, Yamashita et al.44Yamashita T. Yoshioka M. Itoh N. Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain.Biochem Biophys Res Commun. 2000; 277: 494-498Crossref PubMed Scopus (447) Google Scholar discovered the twenty-third FGF using homology-based PCR. FGF-23 cDNA was cloned from tumor tissue obtained from patients with tumor-induced osteomalacia.45Shimada 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: 6500-6505Crossref PubMed Scopus (1223) Google Scholar This condition is characterized by inappropriately increased FGF-23 levels (i.e., a FGF-23 concentration that is too high for the concomitant level of serum phosphate) with hypophosphatemia, elevated alkaline phosphatase, severe muscular weakness, and bone pain. Tumor resection normalizes FGF-23 levels within 1 h, followed by normalization of serum phosphate levels within 6 h.21Khosravi A. 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Urakawa I. et al.Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo.Endocrinology. 2002; 143: 3179-3182Crossref PubMed Scopus (384) Google Scholar, 47ADHR Consortium Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23.Nat Genet. 2000; 26: 345-348Crossref PubMed Scopus (1280) Google Scholar, 48Liu S. Zhou J. Tang W. et al.Pathogenic role of Fgf23 in Dmp1-null mice.Am J Physiol Endocrinol Metab. 2008; 295: E254-E261Crossref PubMed Scopus (119) Google Scholar, 49White K.E. Carn G. Lorenz-Depiereux B. et al.Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23.Kidney Int. 2001; 60: 2079-2086Abstract Full Text Full Text PDF PubMed Scopus (440) Google Scholar In contrast, hyperphosphatemia and extraosseous calcification result from inactivating mutations in the FGF-23 gene in patients with hyperphosphatemic tumoral calcinosis,50Araya K. 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Phosphate loading generally resulted in increased renal phosphate excretion,54Antoniucci D.M. Yamashita T. Portale A.A. Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men.J Clin Endocrinol Metab. 2006; 91: 3144-3149Crossref PubMed Scopus (355) Google Scholar, 55Burnett S.M. Gunawardene S.C. Bringhurst F.R. et al.Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women.J Bone Miner Res. 2006; 21: 1187-1196Crossref PubMed Scopus (392) Google Scholar, 56Ferrari S.L. Bonjour J.P. Rizzoli R. Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men.J Clin Endocrinol Metab. 2005; 90: 1519-1524Crossref PubMed Scopus (449) Google Scholar, 57Isakova T. Gutierrez O. Shah A. et al.Postprandial mineral metabolism and secondary hyperparathyroidism in early CKD.J Am Soc Nephrol. 2008; 19: 615-623Crossref PubMed Scopus (137) Google Scholar, 58Larsson T. Nisbeth U. 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