Teresa Adragão¹, João M. Frazão²

¹ Nephrology Department, Hospital de Santa Cruz. Carnaxide, Portugal.

²Nephrology Research and Development Unit and School of Medicine, University of Porto; and Nephrology Department, Hospital S. João, Porto, Portugal.

correspondence to:

ABSTRACT

In chronic kidney disease patients there are three main stimuli for parathyroid hormone (PTH) secretion by the chief cell in the parathyroid glands: hypocalcaemia, low 1,25(OH)₂D₃ levels and hyperphosphataemia.

FGF23 is a regulator of phosphate and vitamin D metabolism. The discovery of FGF₂₃ actions enlightened our understanding of the development of secondary hyperparathyroidism in CKD patients. The main systemic factors that stimulate FGF₂₃ secretion by the osteocyte in the bone appear to be phosphate load and 1,25(OH)₂D₃. In the kidney, FGF₂₃ decreases the number of Na/Pi co-transporters IIa and IIc in the tubular cell and promotes phosphaturia. FGF23 also reduces 1,25(OH)₂D₃ levels by inhibiting, in the kidney, its production by 1-alpha-hydroxylase and stimulating its degradation by 24-hydroxylase. Increase in FGF₂₃ levels has been described in early 2 and 3 CKD stages preceding the decrease of 1,25(OH)₂D₃ levels and hyperphosphatemia. In this sequence of events, increase of FGF₂₃ in CKD patients seems to be a novel mechanism for the early decline of 1,25(OH)₂D₃ levels observed in these patients. It was hypothesised that klotho deficiency creates a tissue resistance to FGF₂₃ which is responsible for the increase of FGF₂₃ levels. Reduced renal expression of klotho has been demonstrated in CKD patients preceding FGF₂₃ increase. Chronic kidney disease may be considered a state of klotho deficiency with increase of FGF₂₃ levels. Klotho deficiency may be the initial alteration for the development of phosphate retention and secondary hyperparathyroidism in CKD patients. In this article we review the classic and new pathways involved in the development of secondary hyperparathyroidism in chronic kidney disease and the subsequent actions ensuing from this knowledge.

Key-Words: Bone-kidney-parathyroid endocrine axis; chronic kidney disease; FGF₂₃; Klotho; phosphate balance.

STIMULI FOR PARATHYROID HORMONE SYNTHESIS AND SECRETION WITH THE CONSEQUENT DEVELOPMENT OF SECONDARY HYPERPARATHYROIDISM IN CHRONIC KIDNEY DISEASE

In chronic kidney disease (CKD) patients there are three main stimuli for parathyroid hormone (PTH) secretion by the chief cell in the parathyroid glands: hypocalcaemia, low 1,25(OH)₂D₃ levels and hyperphosphataemia¹ (Fig.1). Low 1,25(OH)₂D₃ levels and low calcium levels directly stimulate the parathyroid cell through their action on specific receptors, the vitamin D receptor² in the nucleus and the calcium receptor³ in the cell membrane, respectively. A receptor for phosphate has not yet been identified in the parathyroid cell, but a direct effect of hyperphosphataemia on PTH secretion, independent of its effect on calcium and 1,25(OH)₂D₃, has already been demonstrated^4-6; 1,25(OH)₂D₃ decreases PTH gene transcription⁷ and calcium and phosphate regulate the PTH gene post-transcriptionally⁸.

Figure 1

Development of secondary hyperparathyroidism in CKD

In the normal parathyroid gland few cells proliferate. In secondary hyperparathyroidism there is an increase in parathyroid cell number, in PTH gene expression and secretion. Hypocalcaemia, hyperphosphataemia and uraemia lead to parathyroid cell proliferation⁹.

CALCIUM, PHOSPHATE AND 1,25(OH)2D3 LEVELS DURING CKD PROGRESSION

1.Hyperphosphataemia contributes to the development of secondary hyperparathyroidism

The trade-off hypothesis has conferred on phosphate a pivotal role in the development of secondary hyperparathyroidism¹⁰ and hyperphosphataemia has been considered the primordial stimulus for the development of this pathological condition¹¹. The observation that hyperphosphataemia is only present in late 4 and 5 CKD stages^12,13 has cast doubts on phosphate’s alleged role in stimulating PTH secretion in early CKD stages. However, this imaginative hypothesis holds true when applied to more advanced CKD stages. The mechanisms commonly considered as explaining the development of hyperparathyroidism in consequence of hyperphosphataemia are the phosphorus-induced decrease in 1,25(OH)₂D₃ levels, the phosphorus-induced hypocalcaemia and the direct independent effect of phosphorus on parathyroid cell function¹¹.

2. 1 ,25(OH)2D3 deficiency contributes to the development of secondary hyperparathyroidism

The hypothesis that vitamin D plays the primordial role in the progression of secondary hyperparathyroidism has also been raised¹⁴. This hypothesis has been strengthened by more recent studies demonstrating that reductions of 1,25(OH)₂D₃ levels appear in early CKD stages and precede the development of hyperphosphataemia^15,16.

3. H ypocalcaemia contributes to the development of secondary hyperparathyroidism

The development of hypocalcaemia is an event that occurs in late CKD stages^12,13 and has been explained by several factors, such as the lower renal tubular reabsorption from the failing kidney, the lower intestinal absorption of calcium in relation with low 1,25(OH)₂D₃ levels and the lower release of Ca from bone in relation to hyperphosphataemia¹⁷.

Inappropriate postprandial calciuria with episodic relative hypocalcaemia and increase in PTH levels in 3 and 4 CKD stages is a new proposed mechanism for the development of secondary hyperparathyroidism driven by hypocalcaemia in early CKD stages¹⁸.

Fibroblast growth factors family members are now defined as humoral factors which have in common a three-dimensional β-trefoil structure. To date, twenty-two human fibroblast growth factors have been identified (1 to 14 and 16 to 23) and grouped into seven subfamilies. Fibroblast growth factor (FGF) 23 was identified as the last member of the FGF superfamily and belongs to the FGF₁₉ subfamily.

FGFs execute their biological action by binding to an FGF receptor (FGFR) with an extracellular domain, a single-pass transmembrane domain and an intracellular domain responsible for a tyrosine kinase activity¹⁹. Contrary to the other FGFs which act in a paracrine way, FGF₁₉ subfamily members achieve their activities in an endocrine fashion. In paracrine FGFs, stable FGF-FGFR binding is regulated by heparin and heparan sulphate²⁰. In the FGF₁₉ subfamily heparin or heparan sulphate have a poor ability to promote binding to FGFR, and FGF₁₉ subfamily members require the presence of Klotho or beta-Klotho in their target tissues²¹. Membrane Klotho forms a complex with FGFR and functions as an obligate co-receptor for FGF₂₃²¹. The restricted tissular expression of Klotho proteins also contributes to the endocrine behavior of this subfamily by limiting the signalling of these ligands to the specific tissues²¹. Membrane Klotho has been identified in kidney, in choroid plexus in brain and in parathyroid glands.

The FGFs are now considered to play substantial roles in development, angiogenesis, haematopoiesis and tumorigenesis. FGF₁₉ subfamily members regulate diverse physiological processes uncommon to classical FGFs²¹, namely bile acid homeostasis (FGF₁₉), glucose and lipid metabolism (FGF₂₁) and phosphate and vitamin D homeostasis (FGF₂₃).

FGF23 AND THE BONE-KIDNEYPARATHYROID ENDOCRINE AXIS: A LINK BETWEEN PHOSPHATE LOAD AND LOW VITAMIN D LEVELS

FGF23 is a regulator of phosphate and vitamin D metabolism. It is a 32-kDa protein with 251 amino acids that is secreted mainly by osteocytes in bone²².

The discovery of FGF₂₃ actions enlightened our understanding of the development of secondary hyperparathyroidism in CKD patients. The main systemic factors that stimulate FGF₂₃ secretion by the osteocyte in the bone appear to be phosphate load²³ and 1,25(OH)₂D₃²⁴. In the kidney, FGF₂₃ decreases the number of Na/Pi co-transporters IIa and IIc in the tubular cell and promotes phosphaturia^25,26.

FGF23 also reduces 1,25(OH)₂D₃ levels by inhibiting, in the kidney, its production by 1-alpha-hydroxylase^25,26 and stimulating its degradation by 24-hydroxylase²⁶.

In parathyroid glands, FGF₂₃ suppresses production and secretion of PTH. Suppression of PTH contributes to the reduction of 1,25(OH)₂D₃ levels.

Klotho is much more abundant in distal convoluted tubules than in proximal tubules. It is not known whether FGF₂₃ acts directly or indirectly in the proximal tubule, promoting phosphaturia and inhibiting 1,25(OH)₂D₃²⁷.

In this sequence of events, increase of FGF₂₃ in CKD patients seems to be a novel mechanism for the early decline of 1,25(OH)₂D₃ levels observed in these patients³². Increased phosphate load stimulates the synthesis of FGF₂₃²⁵ and FGF₂₃ promotes phosphaturia and maintains phosphate levels between normal ranges. The price to maintain normal phosphate levels is the decrease in 1,25(OH)₂D₃ levels with the subsequent stimulation of PTH synthesis. In this new paradigm FGF₂₃ is a determinant player in the pathophysiology of secondary hyperparathyroidism in early CKD stages³².

23, PHOSPHATE LOAD AND PHOSPHATE RESTRICTION

Phosphate loading in mice increases FGF₂₃ levels²⁵, but the data in humans are conflicting. Hyperphosphataemia induced by intravenous phosphorus infusion was not associated with increase in FGF₂₃ levels³³. After an oral phosphate load, an increase in the fractional excretion of phosphate was observed in early CKD patients¹⁸ and healthy volunteers³⁴ but FGF₂₃ levels did not increase immediately after the oral phosphate load. However, 8 hours after phosphate ingestion, a 20% increase of FGF₂₃ levels was observed in healthy volunteers³⁴.

The mechanism by which phosphate regulates FGF₂₃ production is still unknown. A phosphate sensor that controls FGF₂₃ production has not been identified and extracellular phosphate has not been shown to regulate FGF₂₃ gene transcription in osteoblast cultures²⁴, raising the possibility that phosphate effects on FGF₂₃ production might be indirect³⁵.

In theory, a low phosphate diet and/or the administration of phosphate binders in CKD stages₃ and ₄, even with normophosphataemia, may prevent the development of mineral abnormalities associated with secondary hyperparathyroidism³⁶. Some of the beneficial effects of phosphate restriction in early CKD stages were described more than 25 years ago^37,38. It was found that a restriction in the dietary intake of phosphorus in patients with moderate renal insufficiency was associated with a decrease in fractional excretion of phosphate³⁷, increase in 1,25(OH)₂D₃ levels^37,38 and a decrease in iPTH levels^37,38.

These findings, due to the recent discovery of FGF₂₃ actions, may now be interpreted in a new light.

The effect of phosphate binders in preventing gastrointestinal phosphate absorption and phosphate load has been evaluated in two pilot studies in normophosphataemic CKD stages 3 and 4 patients^39,40. During a 6-wk period followed by a 2-wk washout period, calcium acetate and sevelamer treatment were associated with a decrease in PTH levels and urinary phosphate; in the sevelamer group but not in the calcium acetate group there was also a decrease in FGF₂₃ levels after the 4th week of treatment³⁹. This latter observation of a different effect of calcium acetate and sevelamer on FGF₂₃ levels still is not fully understandable in the light of present knowledge, but some authors suggest that might be the consequence of a direct effect of calcium load on osteocytes. This study raises the interesting possibility of controlling the mineral metabolism disturbances and secondary hyperparathyroidism with the early control of phosphate loading.

In a very short study with only a 2-wk duration⁴⁰, lanthanum carbonate and dietary phosphate restriction lowered urinary phosphate excretion without lowering FGF₂₃.

These interesting preliminary results need to be confirmed in appropriate clinical trials.

FGF23 AND CLINICAL OUTCOMES

FGF²³ is a more robust predictor of adverse outcomes in CKD patients than serum phosphate levels³¹.

Increased levels of FGF₂₃ have been associated with mortality in incident⁴¹ and prevalent⁴² haemodialysis patients and in patients with stable coronary disease, without end-stage renal disease⁴³. Increased risk of cardiovascular events has been also predicted by high FGF₂₃ levels in CKD patients not on dialysis⁴⁴.

FGF23 increase has been associated with left ventricular hypertrophy⁴⁵, left ventricular mass, severe vascular calcification⁴⁶ and with increased risk of CKD progression⁴⁷. However, all these observational studies can only demonstrate an association effect between high FGF₂₃ levels and adverse clinical outcomes, and another type of evidence, such as randomised clinical trials, is needed to demonstrate that high FGF₂₃ levels are the cause of these adverse outcomes.

Another intriguing aspect of the possible causal relationship between FGF₂₃ and cardiovascular events is the fact that although klotho is needed as a co-factor for FGF₂₃ klotho is not expressed in the cardiovascular system, and there is a klotho deficiency in CKD patients⁴⁸. It was hypothesised that very high FGF₂₃ levels, independent of klotho collaboration, may activate other FGF receptors³¹ but klotho deficiency also contributes directly to vascular calcification⁴⁸. A recent study has definitely demonstrated a direct contribution of FGF₂₃, independent of klotho, in the development of left ventricular hypertrophy in mice⁴⁹.

KLOTHO, PHOSPHATE AND FGF₂₃

Animal models lacking klotho or FGF₂₃ develop similar phenotypes with growth retardation, shortened life span, phosphate retention, osteopaenia and vascular and ectopic calcifications, among other alterations, revealing an unexpected link between phosphate and aging^50,51. These similar phenotypes of klotho and FGF₂₃ knockout mice have been explained by the discovery that FGF₂₃ requires klotho to bind with high affinity to the FGF receptor²¹.

However, in CKD patients, it is the increase of FGF₂₃ levels and not FGF₂₃ level decrease that is associated with mortality, higher risk of cardiovascular events and vascular calcifications^41-47. This discrepancy with the FGF₂₃ knockout phenotype may be explained by the finding that mice lacking klotho show, similarly, high levels of FGF₂₃⁵² (Table I). It was hypothesised that klotho deficiency creates a tissue resistance to FGF₂₃ which is responsible for the increase of FGF₂₃ levels⁵². Reduced renal expression of klotho has been demonstrated in CKD patients⁵³ preceding FGF₂₃ increase⁵⁴. Chronic kidney disease may be considered a state of klotho deficiency with increase of FGF₂₃ levels similar to what is observed in klotho-deficient mice. The rescue of klotho-deficient or FGF₂₃-deficient mice has been performed by correcting the hyperphosphataemia or hypervitaminosis D with dietary or genetic interventions.

CKD shares some manifestations of Klotho knockout and FGF₂₃ knockout Models

These mice do not develop vascular calcifications and show an increase in life span. All these interventions have in common the reduction of phosphate levels, with opposite effects on Ca and vitamin D levels, suggesting that phosphate is primarily responsible for these aging-like phenotypes⁵⁴. Klotho deficiency may be the initial alteration for the development of phosphate retention and secondary hyperparathyroidism in CKD patients⁵⁴.

PROPOSED ROLE OF KLOTHO AND FGF23 IN THE DEVELOPMENT OF SECONDARY HYPERPARATHYROIDISM IN CKD (Fig. 2)

Phosphate load in the diet transitorily stimulates FGF₂₃^23,25 with a consequent and adequate phosphaturic action^25,26, contributing to the maintenance of normal phosphate blood levels. In CKD patients, with reduction of renal mass, there is a decrease in the renal expression of klotho⁵³, contributing to the increased levels of FGF₂₃⁵². In initial CKD stages, this increase of FGF₂₃ levels maintains an efficient phosphate excretion and is associated with an increase of fractional excretion of phosphate and with normal phosphate levels. At the same time FGF₂₃ decreases 1,25(OH)₂D₃^25,26 by decreasing its synthesis and increasing its catabolism. The decrease of 1,25(OH)₂D₃ is a stimulus for the increase in the synthesis of PTH⁷.

Role of phosphate load, klotho and FGF₂₃ in the development of secondary hyperparathyroidism in CKD.

As the kidney insufficiency progresses there is a greater decrease of renal klotho expression to which 1,25(OH)₂D₃ also deficiency contributes. This decrease in klotho expression contributes to a further increase in FGF₂₃ levels. At this stage, with important reduction of renal mass, FGF₂₃ increase is no longer efficient, and reduced phosphaturia is responsible for the appearance of hyperphosphataemia.

In this proposed pathway for the development of secondary hyperparathyroidism two main mechanisms are recognised: an early mechanism resulting from the increase of FGF₂₃, associated with low 1,25(OH)₂D₃ levels³² and a late mechanism, corresponding to the classic trade-off hypothesis derived from hyperphosphataemia. The decrease in the renal expression of klotho precedes the increase of FGF₂₃ levels⁵⁴ and may be the initial alteration in CKD patients responsible for the development of secondary hyperparathyroidism⁵⁴.

CONCLUSIONS

FGF₂₃ is a regulator of phosphate and vitamin D metabolism. FGF₂₃ levels are increased in early CKD stages. Increase of FGF₂₃ seems to be a novel mechanism for the early decline of 1,25(OH)₂D₃ levels observed in CKD patients. Phosphate is one of the recogniaed stimuli for FGF₂₃ secretion. In this new updated model for secondary hyperparathyroidism, FGF₂₃ may act as a link between phosphate load and low vitamin D levels [Figs 1 and 2]. The discovery of klotho and FGF₂₃ actions has given back to phosphate a primordial role in the development of secondary hyperparathyroidism.

It is possible that in CKD stages₃ and ₄ an early therapeutic intervention on phosphate with a low phosphate diet and/or phosphate binders, even in the presence of normophosphataemia³⁶, might retard the development of secondary hyperparathyroidism.

References

^1. Silver J, Moallem E, Killav R, et al. New insights into the regulation of parathyroid hormone synthesis and secretion in chronic renal failure. Nephrol Dial Transplant 1996;11 (Suppl 3):2-5        [ Links ]

^2. Haussler MR, Norman AW. Chromosomal receptor for a vitamin D metabolite. Proc Natl Acad Sci USA 1969;62:155-62        [ Links ]

^3. Brown E, Gambia G, Riccardi D, et al. Cloning and characterization of an extracellular calcium sensing receptor from bovine parasthyroid. Nature 1993;366:575-580        [ Links ]

^4. Kilav R, Silver J, Naveh-Many T. Parathyroid hormone gene expression in hypophosphatemic rats. J Clin Invest 1995;96:327-33        [ Links ]

^5. Hernandez A, Concepcion MT, Rodriguez M, Salido E, Torres A. High phosphorus diet increases prepro PTHm RNA independent of calcium and calcitriol in normal rats. Kidney Int 1996;50:1872-8        [ Links ]

^6. Kates DM, Sherrard DJ, Andress DL. Evidence that serum phosphate is independently associated with serum PTH in patients with chronic renal failure. Am J Kidney Dis 1997;30:809-13        [ Links ]

^7. Silver J, Naveh-Many T, Mayer H, et al. Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat. J Clin Invest 1986;78:1296-301        [ Links ]

^8. Moallem E, Silver J, Kilav R, et al. RNA protein binding and post-transcriptional regulation of PTH gene expression by calcium and phosphate. J Biol Chem 1998; 273:5253-9        [ Links ]

^9. Navey-Many T, Rahamimov R, Livni N, et al. Parathyroid cell proliferation in normal and chronic renal failure rats. The effects of calcium, phosphate and vitamin D. J Clin Invest 1995;96:1786-93         [ Links ]

^10. Bricker NS: On the pathogenesis of the uremic state. An exposition of the “trade-off hypothesis”. N Engl J Med 1972;286:1093-9        [ Links ]

^11. Slatopolsky E, Delmez JA: Pathogenesis of secondary hyperparathyroidism. Nephrol Dial Transplant 1996;11 (Suppl 3):130-5        [ Links ]

^12. Levin A, Bakris GL, 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;71:31-8        [ Links ]

^13. Kestenbaum B, Sampson JN, Rudser KD, et al. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol 2005;16520-8        [ Links ]

^14. Llach F, Yudd M. Pathogenic, clinical, and therapeutic aspects of secondary hyperparathyroidism in chronic renal failure. Am J Kidney Dis 1998;32 2 Suppl 2):S3-S12        [ Links ]

^15. Llach F. Secondary hyperparathyroidism in renal failure: the trade-off hypothesis revisited. Am J Kidney Dis 1995;25:663-79        [ Links ]

^16. Llach F, Yudd M. Pathogenic, clinical, and therapeutic aspects of secondary hyperparathyroidism in chronic renal failure. Am J Kidney Dis 1998;32 (2 Suppl 2):S3-S12        [ Links ]

^17. Kaye M. Hypocalcemia after an acute phosphate load is secondary to reduced calcium efflux from bone: studies in patients with minimal renal function and varying parathyroid activity. J Am Soc Nephrol 1995;6:273-80        [ Links ]

^18. Isakova T, Gutierrez O, Shah A, et al. Postprandial mineral metabolism and secondary hyperparathyroidism in early CKD. J Am Soc Nephrol 2008;19:615-23        [ Links ]

^19. Mohammadi M, Olsen S.K, Ibrahimi O.A. Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Ver 2005;16:107-37        [ Links ]

^20. Ornitz DM, Itoh N. Fibroblast growth factors. Genome Biol 2001;2(3):reviews 3005        [ Links ]

^21. Kurosu H, Ogawa Y, Miyoshi M, et al. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 2006;281:6120-3        [ Links ]

^22. Liu S, Zhou J, Tang W et al. Pathogenic role of FGF 23 in Hyp mice. Am J Physiol Endocrinol Metab 2006;291:E38-49        [ Links ]

^23. Saito H, Maeda A, Ohtomo S, et al. Circulating FGF-23 is regulated by 1alpha,25-dihydroxyvitamin D3and phosphorus in vivo. J Biol Chem 2005;280:2543-9        [ Links ]

^24. Liu 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;17:1305-15        [ Links ]

^25. Saito H, Kusano K, Kinosaki M, et al. Human fibroblast growth factor-23 mutants suppress Na-dependent phosphate co-transport activity and 1alpha,25- dihydroxyvitamin D3 production. J Biol Chem 2003;278:2206-11        [ Links ]

^26. Shimada 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; 19:429-35        [ Links ]

^27. Kuro-o M. Klotho in chronic kidney disease – What’s new? Nephrol Dial Transplant 2009;24:1705-8        [ Links ]

^28. 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;64:2272-9        [ Links ]

^29. Gutierrez O, Isakova T, Rhee E, et al. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 2005;16:2205-15        [ Links ]

^30. Evenepoel P, Meijers B, Viaene L, et al. Fibroblast growth factor-23 in early chronic kidney disease: additional supporting favor of a phosphate-centric paradigm for the pathogenesis of secondary hyperparathyroidism. Clin J Am Soc Nephrol 2010;5:1268-76        [ Links ]

^31. Wolf M. Forging forward with 10 burning questions on FGF23 in kidney disease. J Am Soc Nephrol 2010;21:1427-35        [ Links ]

^32. Gutiérrez OM. Fibroblast growth factor 23 and disordered vitamin D metabolism in chronic kidney disease: updating the “trade-off” hypothesis. Clin J Am Soc Nephrol 2010:5:1710-6        [ Links ]

^33. Ito N, Fukumoto S, Takeuchi Y, et al. Effect of acute changes of serum phosphate on fibroblast growth factor (FGF)23 levels in humans. J Bone Miner Metab 2007; 25:419-22        [ Links ]

³⁴ 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;70:2141-7        [ Links ]

^35. Liu S, Quarles LD. How fibroblast growth factor 23 works. J Am Soc Nephrol 2007;18:1637-47        [ Links ]

^36. Moe SM, Zidehsarai MP, Chambers MA, et al.Vegetarian compared with meat dietary protein source and phosphorus homeostasis in chronic kidney disease. Clin J Am Soc Nephrol 2011;6:257-64        [ Links ]

^37.Portale AA, Booth BE, Halloran BP, et al. Effect of dietary phosphorus on circulating concentrations of 1,25-dihydroxyvitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency. J Clin Invest 1984; 73:1580-9        [ Links ]

^38. Llach F, Massry SG. On the mechanism of secondary hyperparathyroidism in moderate renal insufficiency. J Clin Endocrinol Metab 1985;61:601-6        [ Links ]

^39. Oliveira RB, Cancela AL, Graciolli FG, et al. Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy? Clin J Am Soc Nephrol 2010;5:286-91        [ Links ]

^40. Isakova T, Gutiérrez OM, Smith K, et al. Pilot study of dietary phosphorus restriction and phosphorus binders to target fibroblast growth factor 23 in patients with chronic kidney disease. Nephrol Dial Transplant 2011;26:584-91        [ Links ]

^41. Gutierrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 2008;359:584-92        [ Links ]

^42. Jean G, Terrat JC, Vanel T, et al. High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long hemodialysis patients. Nephrol Dial Transplant 2009;24:2792-6        [ Links ]

^43. Parker BD, Schurgers LJ, Brandenburg VM, et al. The associations of fibroblast growth factor 23 and uncarboxylated matrix Gla protein with mortality in coronary artery disease: the Heart and Soul Study. Ann Intern Med 2010;18;152:640-8        [ Links ]

^44.Seiler S, Reichart B, Roth D, et al. FGF-23 and future cardiovascular events in patients with chronic kidney disease before initiation of dialysis treatment. Nephrol Dial Transplant 2010 25:3983-9        [ Links ]

^45.Gutierrez OM, Januzzi JL, Isakova T, et al. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation 2009;119:2545-52        [ Links ]

^46. Jean G, Bresson E, Terrat JC, et al. Peripheral vascular calcification in long-hemodialysis patients: associated factors and survival consequences. Nephrol Dial Transplant 2009;24:948-55        [ Links ]

^47. Fliser D, Kollerits B, Neyer U, et al. Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: The Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol 2007;18:2600-8        [ Links ]

^48. Hu MC, Shi M, Zhang J, et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 2011:22:124-36        [ Links ]

^49. Faul C,AmaralAP,Oskouei B, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest 2011;121:4393-408        [ Links ]

^50. Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997;390:45-51        [ Links ]

^51. Shimada T, KakitaniM, Yamazaki Y, et al . Targeted ablation of FGF23 demonstrates as essential physiological role of FGF23 in phosphate and vitamin D metabolism. J ClinInvest 2004;113:561-8        [ Links ]

^52.Urakawa I Yamazaki Y, Shimada T, et al. Klothoconverts canonical FGF receptor into a specific receptor for FGF23. Nature 2006;444:770-4        [ Links ]

^53. Koh N, Fujimori T, Nishiguchi S et al. Severely reduced production of klothoin human chronic renal failure kidney. BiochemBiophys Res Commun2001;280:1015-20        [ Links ]

^54. Kuro-o M. Phosphate and Klotho. Kidney Int2011;79(Suppl121):S20-S23        [ Links ]

Correspondence to:

Dra. Teresa Adragão

Nephrology Department, Hospital de Santa Cruz

Carnaxide, Portugal

Email:tadragao@netcabo.pt

Conflict of interest statement. None declared

Received for publication: 26/10/2011

Accepted in revised form: 28/02/2012