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The effect of GH treatment on serum FGF23 and Klotho in GH-deficient children.
Efthymiadou, A, Kritikou, D, Mantagos, S, Chrysis, D
European journal of endocrinology. 2016;(4):473-9
Abstract
BACKGROUND Normal phosphate homeostasis is essential for normal linear growth. The phosphaturic fibroblast growth factor 23 (FGF23)/Klotho axis is a major regulator of phosphate homeostasis; therefore, an intact FGF23/Klotho axis is important for normal linear growth. On the other hand, GH/IGF1 axis has opposing effects on phosphate homeostasis, but the underline mechanisms remain unclear. AIM: The main objective of this study was to investigate the possible interactions of FGF23 and its co-receptor Klotho, with growth hormone (GH)/IGF1 axis in the regulation of phosphate metabolism in GH-deficient children under GH treatment. METHODS We studied 23 GH-deficient children, before and 3 months after the onset of GH treatment. Anthropometry and assessment of biochemical parameters were performed, as well as measurement of FGF23 (intact FGF23/iFGF23 and C-terminal FGF23/cFGF23) and soluble α-Klotho (sKlotho) levels. RESULTS After 3 months on GH treatment, the elevation of serum phosphate and TmPO4/GFR (P<0.0001 and P<0.01 respectively) was accompanied by a significant increase in cFGF23 (P<0.01), iFGF23 (P<0.0001), sKlotho (P<0.0001) and IGF1 (P<0.0001). Serum phosphate and TmPO4/GFR were positively associated with iFGF23 (P<0.01 and P<0.05) and IGF1 (P<0.05 and P<0.05). iFGF23 levels were positively correlated with sKlotho (P<0.001), IGF1 (P<0.0001) and height SDS (P<0.0001), whereas sKlotho was positively associated with IGF1 (P<0.0001) and height SDS (P<0.001). CONCLUSION The increase in serum phosphate, which we found in GH-deficient children under GH treatment, is not associated with suppression but rather than with upregulation of the phosphaturic FGF23/Klotho axis.
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Decreased conversion of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3 following cholecalciferol therapy in patients with CKD.
Stubbs, JR, Zhang, S, Friedman, PA, Nolin, TD
Clinical journal of the American Society of Nephrology : CJASN. 2014;(11):1965-73
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Abstract
BACKGROUND AND OBJECTIVES Elevated concentrations of fibroblast growth factor 23 (FGF23) are postulated to promote 25-hydroxyvitamin D (25[OH]D) insufficiency in CKD by stimulating 24-hydroxylation of this metabolite, leading to its subsequent degradation; however, prospective human studies testing this relationship are lacking. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS An open-label prospective study was conducted from October 2010 through July 2012 to compare the effect of 8 weeks of oral cholecalciferol therapy (50,000 IU twice weekly) on the production of 24,25(OH)2D3 in vitamin D-insufficient patients with CKD (n=15) and controls with normal kidney function (n=15). Vitamin D metabolites were comprehensively profiled at baseline and after treatment, along with FGF23 and other mineral metabolism parameters. RESULTS Vitamin D3 and 25(OH)D3 concentrations increased equivalently in the CKD and control groups following cholecalciferol treatment (median D3 change, 8.6 ng/ml [interquartile range, 3.9-25.6 ng/ml] for controls versus 12.6 ng/ml [6.9-41.2 ng/ml] for CKD [P=0.15]; 25(OH)D3 change, 39.2 ng/ml [30.9-47.2 ng/ml] for controls versus 39.9 ng/ml [31.5-44.1 ng/ml] for CKD [P=0.58]). Likewise, the absolute increase in 1α,25(OH)2D3 was similar between CKD participants and controls (change, 111.2 pg/ml [64.3-141.6 pg/ml] for controls versus 101.1 pg/ml [74.2-123.1 pg/ml] for CKD; P=0.38). Baseline and post-treatment 24,25(OH)2D3 concentrations were lower in the CKD group; moreover, the absolute increase in 24,25(OH)2D3 after therapy was markedly smaller in patients with CKD (change, 2.8 ng/ml [2.3-3.5 ng/ml] for controls versus 1.2 ng/ml [0.6-1.9 ng/ml] for patients with CKD; P<0.001). Furthermore, higher baseline FGF23 concentrations were associated with smaller increments in 24,25(OH)2D3 for individuals with CKD; this association was negated after adjustment for eGFR by multivariate analysis. CONCLUSIONS Patients with CKD exhibit an altered ability to increase serum 24,25(OH)2D3 after cholecalciferol therapy, suggesting decreased 24-hydroxylase activity in CKD. The observed relationship between baseline FGF23 and increments in 24,25(OH)2D3 further refutes the idea that FGF23 directly contributes to 25(OH)D insufficiency in CKD through stimulation of 24-hydroxylase activity.
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Diabetes modifies effect of high-phosphate diet on fibroblast growth factor-23 in chronic kidney disease.
Muras, K, Masajtis-Zagajewska, A, Nowicki, M
The Journal of clinical endocrinology and metabolism. 2013;(12):E1901-8
Abstract
CONTEXT The pathophysiology of calcium-phosphate disturbances in diabetic (DM) kidney disease differs from that in non-DM chronic kidney disease (CKD). OBJECTIVE We compared the effect of a 6-day high-phosphate diet on serum fibroblast growth factor-23 (FGF-23) and other parameters of calcium-phosphate metabolism in DM and non-DM CKD patients. DESIGN AND SETTING This was a prospective interventional study in a research center setting. PARTICIPANTS, INTERVENTION, AND MEASURES Twenty-six nondialysis patients with stages 3-5 CKD and albuminuria less than 300 mg/g creatinine were recruited from February 2011 to November 2012 (15 DM, 11 non-DM). All patients received a high-phosphate diet (1800 mg/d) for 6 days. At baseline, day 3, and day 7 serum FGF-23, PTH, Ca, P, 25-hydroxyvitamin D, 1,25 dihydroxyvitamin D, monocyte chemoattractant protein-1, and calcium and phosphate urine excretion were measured. RESULTS In DM CKD patients, serum calcium was lower on days 3 and 7 vs baseline (P < .01, respectively), and in non-DM patients, it was unchanged. Serum phosphorus increased significantly only in non-DM patients on days 3 and 7 vs baseline (P < 0.01, respectively). Serum PTH was higher in the DM group on day 7 vs baseline (P = .04). Plasma 25-hydroxyvitamin D, 1,25 dihydroxyvitamin D, and serum monocyte chemoattractant protein-1 were unchanged in both groups. Serum FGF-23 increased in DM patients, from baseline to day 3 (58.1 ± 52.7 and 91.6 ± 71.1 pg/mL, P = .001) but later tended to decrease. In non-DM patients, there was a steady increase of FGF-23 between baseline and day 7 (75 ± 84.3 to 176 ± 197 pg/mL, P = .04). Urine phosphate excretion was significantly higher on day 7 in DM patients only (P < .05). CONCLUSIONS PTH seems to play the major role in the regulation of phosphate excretion in DM CKD. The role of FGF-23 in phosphate disposal in DM CKD remains debatable.
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Changes in plasma FGF23 in growth hormone deficient children during rhGH therapy.
Gardner, J, Ashraf, A, You, Z, McCormick, K
Journal of pediatric endocrinology & metabolism : JPEM. 2011;(9-10):645-50
Abstract
BACKGROUND Children with growth hormone deficiency (GHD) have increased renal phosphorus reabsorption during rhGH therapy, Fibroblast growth factor 23 (FGF23) is a known regulator of serum phosphorus and may be responsible for this effect. METHODS Prospective study in GHD children investigating changes in plasma C-terminal FGF23 (C-FGF23), markers of mineral metabolism, and insulin-like growth factor (IGF-1) in the first year of rhGH therapy. Normal stature children served as baseline controls. RESULTS The two groups at baseline were similar, except GHD patients had lower baseline TmP/GFR vs. controls (p < 0.05). C-FGF23 in GHD patients trended upward at follow-up 1 (p = 0.058) and significantly increased at follow-up 2 (p = 0.0005) compared to baseline. TmP/GFR also rose at follow-up 1 (p = 0.002) and follow-up 2 (p = 0.027). The C-FGF23 rise persisted after adjusting for age, gender, sex, total calcium, and phosphorus (p < 0.01) but attenuated after adjusting for TmP/GFR or IGF-1. CONCLUSIONS C-FGF23 rises during rhGH therapy in spite of increased Tmp/GFR, an unanticipated observation given the role of FGF23 as a phosphaturic factor. The C-FGF23 rise may be a secondary response during rhGH therapy.
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Effects of rosiglitazone on fasting plasma fibroblast growth factor-21 levels in patients with type 2 diabetes mellitus.
Li, K, Li, L, Yang, M, Zong, H, Liu, H, Yang, G
European journal of endocrinology. 2009;(3):391-5
Abstract
OBJECTIVE Fibroblast growth factor-21 (FGF-21) has recently been characterized as a potent metabolic regulator, but its pathophysiologic roles in humans remain unknown. This study aimed to investigate the effects of rosiglitazone on plasma FGF-21 levels in patients with type 2 diabetes mellitus (T2DM). DESIGN AND METHODS Thirty patients with new-onset T2DM (nT2DM), 34 type 2 diabetic patients with poor glycemic control (pT2DM) after the treatment with single hypoglycemic agent metformin, and 30 sex- and age-matched normal glycaemic controls (NGT) participated in the study. The pT2DM group was treated with rosiglitazone for 12 weeks. Plasma FGF-21 levels were measured with a RIA. The relationship between plasma FGF-21 levels and metabolic parameters was also analyzed. RESULTS Fasting plasma FGF-21 levels were higher in nT2DM and pT2DM groups than in the control (1.81+/-0.64 vs 1.87+/-0.63 vs 1.52+/-0.61 microg/l, P<0.05), but there was no difference between nT2DM and pT2DM groups. Fasting plasma FGF-21 levels were decreased significantly in pT2DM group after the treatment with rosiglitazone compared with pre-treatment (1.59+/-0.63 vs 1.87+/-0.64 micro/l, P<0.05). In all diabetic patients, multiple regression analysis showed that HbA1c, fasting insulin, and homeostasis model assessment-insulin resistance index were independently associated with plasma FGF-21 levels. CONCLUSIONS In pT2DM patients, plasma FGF-21 levels are increased, but significantly decreased after the treatment with rosiglitazone on top of ongoing metformin therapy. These data suggest that rosiglitazone may play a role in lowering FGF-21 levels in T2DM patients.