Fibroblast Growth Factor-23 in Early Chronic Kidney Disease

Evenepoel, Pieter; Meijers, Björn; Viaene, Liesbeth; Bammens, Bert; Claes, Kathleen; Kuypers, Dirk; Vanderschueren, Dirk; Vanrenterghem, Yves

doi:10.2215/cjn.08241109

Cited by 103 publications

(100 citation statements)

References 57 publications

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“…FGF23 controls phosphate and vitamin D metabolism, and it is a primary regulator of renal phosphate excretion (10,26). It is inversely associated with GFR (9); this mechanism is fundamental to maintain serum phosphate at constant levels as renal function worsens.…”

Section: Discussionmentioning

confidence: 99%

Acute Effects of Very-Low-Protein Diet on FGF23 Levels

Iorio¹,

Micco²,

Torraca³

et al. 2012

Clinical Journal of the American Society of Nephrology

102

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SummaryBackground and objectives High levels of fibroblast growth factor 23 are associated with mortality, CKD progression, and calcification in CKD patients. The aim of this pilot study is to assess whether a very-low-protein diet (0.3 g/kg per day) with a consequent low intake of phosphorus would reduce fibroblast growth factor 23 compared with a low-protein diet (0.6 g/kg per day) in CKD patients not yet on dialysis.Design, setting, participants, & measurements A prospective, randomized, controlled crossover study was performed in which 32 patients were randomized into two groups. Group A (16 patients) received a very-lowprotein diet (0.3 g/kg body wt per day) supplemented with ketoanalogues during the first week and a lowprotein diet during the second week, and group B (16 patients) received a low-protein diet during the first week and a very-low-protein diet during the second week. Fibroblast growth factor 23, seric, and urinary phosphate levels were measured at baseline and the end of each study period.Results After only 1 week of the very-low-protein diet, reductions in fibroblast growth factor 23 levels (33.5%), serum phosphate (12%), and urinary phosphate (34%) with the very-low-protein diet compared with the lowprotein diet were observed. Serum and urinary phosphate levels and protein intake were significant determinants of fibroblast growth factor 23 (95% confidence interval=1.04-1.19, 1.12-1.37, and 1.51-2.23, respectively).Conclusions A very-low-protein diet supplemented with ketoanalogues reduced fibroblast growth factor 23 levels in CKD patients not yet on dialysis.

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Section: Discussionmentioning

confidence: 99%

Acute Effects of Very-Low-Protein Diet on FGF23 Levels

Iorio¹,

Micco²,

Torraca³

et al. 2012

Clinical Journal of the American Society of Nephrology

102

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“…In patients with cardiac failure [16,17], acute renal failure [18], chronic kidney disease [7,17,19], diabetic nephropathy [20] and hepatic failure [21], plasma FGF23 concentrations are high and associated with accelerated disease progression, morbidity and/or mortality. Mechanisms up-regulating FGF23 in those disorders are still ill-defined.…”

Section: Introductionmentioning

confidence: 99%

NFκB-sensitive Orai1 expression in the regulation of FGF23 release

et al. 2015

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Fibroblast growth factor (FGF23) plasma levels are elevated in cardiac and renal failure and correlate with poor clinical prognosis of those disorders. Both disorders are associated with inflammation and activation of the inflammatory transcription factor NFB. An excessive FGF23 level is further observed in Klotho-deficient mice. The present study explored a putative sensitivity of FGF23 expression to transcription factor NFB, which is known to upregulate Orai1, the Ca(2+) channel accomplishing storeoperated Ca(2+) entry (SOCE). In osteoblastic cells (UMR106) and immortalized primary periosteal (IPO) cells, protein abundance was determined by Western blotting, and in UMR106 cells, transcript levels were quantified by RT-PCR, cytosolic Ca(2+) activity utilizing Fura-2-fluorescence, and SOCE from Ca(2+) entry following store depletion by thapsigargin. As a result, UMR106 and IPO cells expressed Ca(2+) channel Orai1. SOCE was lowered by NFB inhibitor wogonin as well as by Orai1 inhibitors 2-APB and YM58483. UMR106 cell Fgf23 transcripts were increased by stimulation of SOCE and Ca(2+) ionophore ionomycin and decreased by Orai inhibitors 2-APB, YM58483 and SKF96365, by Orai1 silencing, as well as by NFB inhibitors wogonin, withaferin A, and CAS 545380-34-5. In conclusion, Fgf23 expression is upregulated by stimulation of NFB-sensitive, store-operated Ca(2+) entry. KEY MES-SAGES Osteoblast UMR106 and IPO cells express Ca(2+) channel Orai1. Osteoblast store-operated Ca(2+) entry is accomplished by NFB-sensitive Orai1. Osteoblast Fgf23 transcription is upregulated by increase in the cytosolic Ca(2+) activity.

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“…Early increases in FGF23 secretion play a key role in the initiation and progression of disordered bone and mineral metabolism in CKD (2,3). Studies have also shown that increased FGF23 is independently linked with cardiovascular disease events and mortality in individuals across a broad range of kidney function (4)(5)(6)(7)(8), establishing excess FGF23 as a novel risk factor for adverse clinical outcomes.…”

Section: Introductionmentioning

confidence: 99%

(1-34) Parathyroid Hormone Infusion Acutely Lowers Fibroblast Growth Factor 23 Concentrations in Adult Volunteers

Gutiérrez

Smith

Barchi-Chung

et al. 2012

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Fibroblast growth factor 23 (FGF23) regulates phosphorus and vitamin D metabolism. Parathyroid hormone (PTH) infusion for 24 hours stimulated FGF23 secretion in healthy volunteers. The extent to which this was due to a direct stimulatory effect of PTH versus an indirect effect of increasing 1,25-dihydroxyvitamin D [1,25(OH) 2 D] levels was unclear.Design, setting, participants, & measurements Changes in FGF23 in 26 adults undergoing 6-hour (1-34) PTH infusion were examined, focusing particularly on the effects of PTH on FGF23 in the early period of infusion before sustained increases in 1,25(OH) 2 D.Results FGF23 levels declined in parallel with serum phosphate during infusion (P,0.05 for both), with both analytes decreasing within the first hour and reaching their respective nadirs at 6 hours. These changes were observed despite no change in 1,25(OH) 2 D levels during the first hour and a significant increase in 1,25(OH) 2 D from baseline after 6 hours (P,0.001). There were no differences in these responses by race. However, modest racial differences in the phosphaturic response to (1-34) PTH were observed (P=0.04 for interaction), with a higher rate of increase in fractional phosphate excretion in blacks than in whites.Conclusions During short-term (1-34) PTH infusion, FGF23 levels decreased in parallel with serum phosphate levels and despite significant increases in 1,25(OH) 2 D. When coupled with the results of prior longer-term infusion studies, these findings suggest that acute increases in PTH initially act to suppress FGF23 secretion, perhaps to mitigate urinary phosphate losses, before the stimulatory effect of 1,25(OH) 2 D on FGF23 eventually begins to predominate.

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Fibroblast Growth Factor-23 in Early Chronic Kidney Disease

Abstract: Conclusions: Our data are in favor of the new paradigm for the pathogenesis of secondary hyperparathyroidism according to which a reduced phosphate excretion capacity is the principal abnormality that initiates secondary hyperparathyroidism.

Cited by 103 publications

References 57 publications

Acute Effects of Very-Low-Protein Diet on FGF23 Levels

Acute Effects of Very-Low-Protein Diet on FGF23 Levels

NFκB-sensitive Orai1 expression in the regulation of FGF23 release

(1-34) Parathyroid Hormone Infusion Acutely Lowers Fibroblast Growth Factor 23 Concentrations in Adult Volunteers

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