Fibroblast growth factor 23 is associated with the development of gestational diabetes mellitus.

BACKGROUND: Besides its established impact on bone and mineral metabolism, it was suggested that fibroblast growth factor 23 (FGF23) might play an important role in the pathogenesis of type 2 diabetes. The impact of FGF23 on gestational diabetes mellitus (GDM), however, is not well understood. iFGF23 ELISAs measure the intact FGF23 molecule, whereas cFGF23 assays measure intact FGF23 as well as degradation products of FGF23. OBJECTIVES: The aim of this study is to compare the association of maternal and foetal cFGF23 and iFGF23 with GDM in a German birth cohort. METHODS: cFGF23 and iFGF23 were analysed in 826 random mother/child pairs from the Berlin Birth Cohort. RESULTS: Mothers who developed GDM had higher concentrations of iFGF-23 compared to mothers who did not suffer from GDM (19.73 vs. 13.23 pg/mL, p < 0.0001), but not higher concentrations of cFGF-23. Multivariant regression analyses showed that gestational diabetes is associated with iFGF23 independently of confounding factors such as age, BMI, ethnic background, family history of diabetes, smoking during pregnancy, and recurrent pregnancy loss. This, however, was only seen when using an iFGF23 ELISA measuring just the full length FGF23 and not in addition FGF23 fragments. No differences in both iFGF23 and cFGF23 concentrations between the GDM and non-GDM groups were detected in cord blood samples of the offspring. CONCLUSIONS: This study of a representative German birth cohort showed that maternal but not foetal iFGF23 is independently associated with GDM.

Longitudinal change in c-terminal fibroblast growth factor 23 and outcomes in patients with advanced chronic kidney disease.

BACKGROUND: Fibroblast growth factor23 (FGF23) is elevated in CKD and has been associated with outcomes such as death, cardiovascular (CV) events and progression to Renal Replacement therapy (RRT). The majority of studies have been unable to account for change in FGF23 over time and those which have demonstrate conflicting results. We performed a survival analysis looking at change in c-terminal FGF23 (cFGF23) over time to assess the relative contribution of cFGF23 to these outcomes. METHODS: We measured cFGF23 on plasma samples from 388 patients with CKD 3-5 who had serial measurements of cFGF23, with a mean of 4.2 samples per individual. We used linear regression analysis to assess the annual rate of change in cFGF23 and assessed the relationship between time-varying cFGF23 and the outcomes in a cox-regression analysis. RESULTS: Across our population, median baseline eGFR was 32.3mls/min/1.73m2, median baseline cFGF23 was 162 relative units/ml (RU/ml) (IQR 101-244 RU/mL). Over 70 months (IQR 53-97) median follow-up, 76 (19.6%) patients progressed to RRT, 86 (22.2%) died, and 52 (13.4%) suffered a major non-fatal CV event. On multivariate analysis, longitudinal change in cFGF23 was significantly associated with risk for death and progression to RRT but not non-fatal cardiovascular events. CONCLUSION: In our study, increasing cFGF23 was significantly associated with risk for death and RRT.

Short-Term Effects of Cholecalciferol Supplementation on cFGF23 Levels in Children with Chronic Kidney Disease and Vitamin D Insufficiency.

Data on the effect of vitamin D supplementation on fibroblast growth factor 23 (FGF23), in chronic kidney disease (CKD) are scarce. In a prospective interventional study, the effect of vitamin D supplementation on cFGF23 (C-terminal FGF23) levels in children with CKD stages 2-4 was examined. Forty-one children with CKD and vitamin D insufficiency were administered 600,000 units of cholecalciferol over 3 d; 88% of patients achieved sufficiency at 8 wk. Significant increase in serum cFGF23 and phosphate levels was observed in CKD stage 2 after supplementation, but not in CKD stages 3 and 4. There was no correlation of the change in cFGF23 level with baseline or change in bone health parameters (calcium, phosphate, parathormone or alkaline phosphatase) or with change in flow-mediated dilatation (FMD) of the brachial artery. It is concluded that cholecalciferol supplementation increases serum calcium and reduces PTH, but does not adversely affect FGF23 levels in CKD.

Perioperative changes of FGF23 in patients undergoing surgery for primary hyperparathyroidism.

Background: Fibroblast growth factor 23 (FGF23) is a key regulator of urine phosphate excretion. The aim of the study was to investigate the perioperative (intraoperative and postoperative) changes of plasma intact and C-terminal FGF23 (iFGF23, cFGF23) concentrations in patients with primary hyperparathyroidism (pHPT) submitted to surgery. Materials and methods: The study involved 38 adult patients with pHPT caused by adenoma. Parathyroid hormone (PTH) levels were investigated intraoperatively (just before the incision and 10 min after adenoma excision). cFGF23, iFGF23, phosphate, estimated glomerular filtration rate (eGFR), and procollagen type 1 N-terminal propetide (P1NP) were measured intraoperatively and postoperatively (next day after the surgery). Results: PTH levels decreased intraoperatively (13.10 pmol/L vs 4.17 pmol/L, P< 0.0001). FGF23 levels measured intraoperatively were at the upper level of reference interval. cFGF23 decreased postoperatively compared with the values measured just before the incision (cFGF23: 89.17 RU/mL vs 22.23 RU/mL, P< 0.0001). iFGF23 decreased as well, but the postoperative values were low. Postoperative inorganic phosphate values increased (1.03 mmol/L vs 0.8 mmol/L, P= 0.0025). We proved significant negative correlation of perioperative FGF23 with inorganic phosphate (cFGF23: Spearman's r = -0.253, P= 0.0065; iFGF23: Spearman's r = -0.245, P= 0.0085). We also found that FGF23 values just before incision correlated with eGFR (cystatin C) (cFGF23: Spearman's r = -0.499, P= 0.0014; iFGF23: Spearman's r = -0.413, P= 0.01). Conclusion: Intraoperative iFGF23 and cFGF23 did not change despite PTH decreased significantly. cFGF23 and iFGF23 significantly decreased 1 day after parathyroidectomy and are associated with increase of inorganic phosphate in pHPT patients. cFGF23 and iFGF23 just before incision correlated with eGFR (cystatin C). Similar results found in both iFGF23 and cFGF23 suggest that each could substitute the other.

Serum levels of C-terminal FGF23 (cFGF23) are associated with 1-year-mortality in patients undergoing transcatheter aortic valve replacement (TAVR).

INTRODUCTION: Serum levels of FGF23 have been associated with adverse outcomes in cardiovascular diseases in patients with and without impaired renal function. Hence, this study aimed to explore the prognostic relevance of intact FGF23 (iFGF23) and its derivate C-terminal FGF23 (cFGF23) in patients undergoing transcatheter aortic valve replacement (TAVR) with regard to renal function. METHODS: A total of 274 patients undergoing transfemoral TAVR were enrolled in this study. Blood samples were obtained preinterventionally and analyzed for iFGF23 and cFGF23 by means of enzyme linked immunosorbent assay (ELISA). Follow-up was obtained for 12 months. RESULTS: Serum levels of cFGF23 and iFGF23 both correlated positively with serum creatinine and inversely with estimated glomerular filtration rate (eGFR). Cox regression analysis revealed a significant association of cFGF23 with 1-year-mortality in patients with eGFR ≥45ml/min/1.73m², but not in patients with an eGFR <45ml/min/1.73m². A cut-off was calculated for cFGF23 (6.82 pmol/l) and patients with eGFR ≥45ml/min/1.73m² were retrospectively divided into two groups (above/below cut-off). Patients above the cut-off had a significantly worse 1-year-mortality than patients below the cut-off (33.3% vs. 19.6%; OR 2.05 (95%CI 1.03-4.07), p= 0.038). The association of cFGF23 with 1-year-mortality in patients with eGFR ≥45ml/min/1.73m² remained statistically significant even after correction for possible confounders in a multivariate Cox regression analysis. CONCLUSION: cFGF23 could be an individual risk factor for mortality in patients undergoing TAVR with an eGFR ≥45ml/min/1.73m².

Relationship between cFGF23/Klotho ratio and phosphate levels in patients with chronic kidney disease.

PURPOSE: To characterize the relationship between the cFGF23/Klotho ratio and phosphate level in patients with chronic kidney disease (CKD). METHODS: A total of 152 patients with CKD stage 3-5 (CKD stage 3: n = 74; CKD stage 4: n = 60; CKD stage 5: n = 18) were included in the study. Thirty healthy volunteers served as controls. Intact-FGF23, cFGF23, Klotho, serum calcium, serum phosphate, and serum creatinine were measured, and estimated glomerular filtration rate (eGFR) was calculated. The Kruskal-Wallis H test was used for comparison between groups, and the Spearman test was used for correlation analysis. RESULTS: In CKD stage 3-5, creatinine and iFGF23 levels, as well as the cFGF23/Klotho ratio, were higher (P < 0.01), phosphate levels were higher (P < 0.05), and Klotho levels were lower (P < 0.01), compared with controls. C-terminal-FGF23 levels were higher in CKD phase 4-5 (P < 0.05). In CKD stage 4-5, creatinine, iFGF23, and phosphate levels, as well as the cFGF23/Klotho ratio, were higher (P < 0.01), cFGF23 levels were higher (P < 0.05), and Klotho levels were lower (P < 0.05), compared with CKD stage 3. In CKD stage 5, creatinine and cFGF23 levels, as well as the cFGF23/Klotho ratio, were higher (P < 0.01), phosphate and iFGF23 levels were higher (P < 0.05), and Klotho levels were lower (P < 0.01), compared with CKD stage 4. Phosphate was positively correlated with the cFGF23/Klotho ratio (r = 0.235, P < 0.01). CONCLUSIONS: EGFR reduction was associated with an increased cFGF23/Klotho ratio, and the cFGF23/Klotho ratio was positively correlated with phosphate. This suggests that the phosphate level can be controlled by modifying the cFGF23/Klotho ratio.

Plasma fibroblast growth factor 23 concentration and iron status. Does the relationship exist in the elderly population?

OBJECTIVE: Fibroblast growth factor 23 (FGF23) is a phosphaturic agent involved in calcium-phosphate homeostasis. Recent findings show that iron deficiency and inflammation regulate FGF23 release and/or biodegradation. Iron deficiency is frequently observed in the elderly, therefore the aim of this study was to find out if iron deficiency is independent from low grade inflammatory factors affecting both forms of FGF23 that are detectable in circulation in a large population-based study of elderly subjects. DESIGN AND METHODS: The analysis included 3780 elderly (1798 females) PolSenior study participants and assessed levels of phosphorus, calcium, iron, ferritin, interleukin 6, C-reactive protein (hs-CRP), intact (iFGF23), and c-terminal FGF (cFGF23). The analysis was performed for all subjects and terciles of serum iron levels in relation to hs-CRP were calculated. RESULTS: The highest plasma cFGF23 and iFGF23 concentrations were found in subjects with the lowest serum iron levels (p<0.001). The effect of low grade inflammation was markedly weaker and affected only iFGF23 levels. The adjusted serum levels of hs-CRP, iPTH, phosphorus, and 25-(OH)-D3 analysis revealed that plasma iFGF23 and cFGF23 levels were almost unchanged up to a serum iron level of 59.3 ng/mL and 57.3 ng/mL respectively and then were nearly linearly increasing by 0.285 pg/mL and 3.742 RU/mL for each unit of serum iron increase. CONCLUSIONS: Low iron levels are associated with increased levels of both cFGF23 and iFGF23, independent of low grade inflammation. A similar analysis of cFGF23 and iFGF23 does not suggest enhanced biodegradation of iFGF23 induced by iron deficiency.