Median Fibroblast Growth Factor 23 Research Articles

Serum fibroblast growth factor 23 concentration and the risk of mortality in patients undergoing peritoneal dialysis.

Fibroblast growth factor 23 (FGF23) is a phosphate-regulating hormone that is secreted in large amounts early in chronic kidney disease. In this cohort, we aimed to investigate the association between serum FGF23 concentration and mortality in patients undergoing peritoneal dialysis (PD). Serum FGF23 level was determined by enzyme-linked immunosorbent assay (ELISA) in a large 15-year prospective cohort study of PD patients with stored serum samples at baseline. Kaplan-Meier survival curves and Cox proportional hazards models were performed to characterise the relationship of FGF23 with mortality. A total of 737 incident PD patients were analysed. The baseline median FGF23 concentration was 683.2 (518.5-896.2) pg/mL. Age, serum phosphorus, high-density lipoprotein cholesterol and high-sensitivity C-reactive protein were independently correlated with serum FGF23 concentration. During a median follow-up of 66.7 (41.1-95.4) months, 171 of the 737 participants (23.2%) died, including 84 (49.1%) cardiovascular disease-related and 50 (29.2%) infection-related deaths. Multivariable Cox regression analysis showed that the adjusted hazard ratios of the highest tertile of serum FGF23 compared with those in the lowest tertile were 1.36 (95% confidence interval (CI): 0.89-2.07; p = 0.154), 0.75 (95% CI: 0.40-1.38; p = 0.353) and 2.66 (95% CI: 1.15-6.15; p = 0.022) for all-cause, cardiovascular disease-related and infection-related mortality, respectively. High serum FGF23 concentration is associated with a higher risk of infection-related death for incident PD patients.

Association of Fibroblast Growth Factor 23 with Blood Pressure in Primary Proteinuric Glomerulopathies

Introduction: Fibroblast growth factor 23 (FGF23) has direct effects on the vasculature and myocardium, and high levels of FGF23 are a risk factor for cardiovascular disease (CVD); however, the impact of FGF23 on CVD in primary proteinuric glomerulopathies has not been addressed. Methods: The associations of baseline plasma intact FGF23 levels with resting blood pressure (BP) and lipids over time among adults and children with proteinuric glomerulopathies enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) were analyzed using generalized estimating equation regression analyses. Models were adjusted for age, sex, glomerular diagnosis, follow-up time, estimated glomerular filtration rate, urine protein/creatinine ratio, obesity, and serum phosphorous levels. Results: Two hundred and four adults with median FGF23 77.5 (IQR 51.3–119.3) pg/mL and 93 children with median FGF23 62.3 (IQR 44.6–83.6) pg/mL were followed for a median of 42 (IQR 20.5–54) months. In adjusted models, each 1 µg/mL increase in FGF23 was associated with a 0.3 increase in systolic BP index at follow-up (p < 0.001). Greater baseline FGF23 was associated with greater odds of hypertensive BP (OR = 1.0003; 95% CI 1.001–1.006, p = 0.03) over time. Compared to tertile 1, tertile 2 (OR = 2.1; 95% CI 1.12–3.99, p = 0.02), and tertile 3 (OR = 3; 95% CI 1.08–8.08, p = 0.04), FGF23 levels were associated with greater odds of hypertensive BP over time. Tertile 2 was associated with greater triglycerides compared to tertile 1 (OR = 48.1; 95% CI 4.4–91.9, p = 0.03). Conclusion: Overall, higher baseline FGF23 was significantly associated with hypertensive BP over time in individuals with proteinuric glomerulopathies. Further study of FGF23 as a therapeutic target for reducing CVD in proteinuric glomerular disease is warranted.

Fibroblast growth factor 23 and calcium-phosphate metabolism in relation to cardiovascular risk factors in patients with type 1 diabetes.

Cardiovascular disease (CVD) is the major cause of mortality in type 1 diabetes (T1D). The objective of this study is to evaluate fibroblast growth factor 23 (FGF23) and calcium-phosphate metabolism in relation to cardiovascular risk factors in adults with and without T1D. A case-control study was conducted using data from patients with T1D and age- and sex matched controls without T1D from the Lifelines Cohort Study. We included 302 adults in the T1D group and 302 adults in the control group. Median age was 42 years. Median glycosylated hemoglobin (HbA1c) in the T1D group was 7.8%. FGF23 of all patients with T1D was not significantly different from controls. Females with T1D had significantly higher FGF23 than males with T1D (83.3 vs 69.3 U/mL, p = 0.002), this was not observed in controls. Serum phosphate, calcium, and alkaline phosphatase were higher and parathyroid hormone was lower in patients with T1D, compared to controls (all p < .001), all within normal range. In the T1D group, FGF23 was positively correlated with serum phosphate (p < .001), alkaline phosphatase (p = .01), and calcium (p = .030), these correlations were not observed in controls. Median FGF23 was significantly higher in current smokers than in nonsmokers with T1D (84.9 vs 73.5 U/mL, p < .05). Serum calcium, phosphate, and alkaline phosphatase were higher in patients with T1D than in controls and were positively correlated to FGF23 in patients with T1D. Current smokers with T1D had higher FGF23 than nonsmokers with T1D. These findings may contribute to the increased risk of CVD in patients with T1D.

1662-P: The Bidirectional Relationship of Fibroblast Growth Factor 23 and Glucose Homeostasis

Objective: To investigate potential cross-talk between the phosphate-regulating hormone fibroblast growth factor 23 (FGF23) and glucose homeostasis. Research Design and Methods: First, we investigated the effect of glucose loading on plasma FGF23 and its temporal relationship with changes in plasma phosphate (0-15-30-45-60-75-90-120-150-180-240-300-360-420-480 minutes) in 45 overweight (BMI 25-30) subjects using time-lag analyses. Second, we studied cross-sectional associations of plasma FGF23 with glucose homeostasis using multivariable linear regression in a population-based cohort. We also investigated associations of FGF23 with incident diabetes and obesity (BMI &amp;gt;30 kg/m2) in individuals without diabetes or obesity at baseline, respectively, using multivariable Cox regression analyses. Finally, we explored whether the association between FGF23 and diabetes depends on BMI. Results: After glucose loading, changes in FGF23 preceded changes in plasma phosphate (Ptime-lag=0.04). In the population-based cohort (N=5482; mean age 52 yrs, 52% women, median FGF23 69 RU/mL), FGF23 was associated with plasma glucose (est. β 0.13[0.03-0.23], P=0.01), insulin (est. β 0.10[0.03-0.17], P&amp;lt;0.001), and proinsulin (est. β 0.06[0.02-0.10], P=0.01) at baseline. Upon longitudinal analyses, a higher baseline FGF23 was independently associated with the development of diabetes (199 events (4%); fully adjusted HR 1.66[95% CI 1.06-2.60], P=0.03) and development of obesity (241 events (6%); fully adjusted HR 1.84[1.34-2.50], P&amp;lt;0.001). The association between FGF23 and incident diabetes lost significance after additional adjustment for BMI. Conclusions: Glucose loading has phosphate-independent effects on FGF23; vice versa, FGF23 is associated with glucose, insulin, proinsulin levels and obesity. These findings suggest deleterious cross-talk between FGF23 and glucose homeostasis, which may promote susceptibility to incident diabetes. Disclosure A.Van der vaart: None. C.Eelderink: None. A.Van beek: Advisory Panel; Novo Nordisk, Consultant; Novo Nordisk. S.J.Bakker: None. P.Van dijk: None. M.De borst: None.

Fibroblast growth factor 23, glucose homeostasis and incident diabetes: findings of two cohort studies.

The phosphate-regulating hormone fibroblast growth factor 23 (FGF23) has been linked to deregulations in glucose metabolism, but its role is insufficiently understood. This study investigates potential cross-talk between FGF23 and glucose homeostasis. First, we investigated the effect of glucose loading on plasma C-terminal FGF23 levels and its temporal relationship with changes in plasma phosphate in 45 overweight (BMI 25-30 kg/m2) subjects using time-lag analyses. Second, we studied cross-sectional associations of plasma C-terminal FGF23 levels with glucose homeostasis using multivariable linear regression in a population-based cohort. We also investigated associations of FGF23 with incident diabetes and obesity (BMI >30 kg/m2) in individuals without diabetes or obesity at baseline, respectively, using multivariable Cox regression analyses. Finally, we explored whether the association between FGF23 and diabetes depends on BMI. After glucose loading, changes in FGF23 preceded changes in plasma phosphate (Ptime-lag=0.04). In the population-based cohort (N=5482; mean age 52 yrs, 52% women, median FGF23 69 RU/mL), FGF23 was associated with plasma glucose (b 0.13[0.03-0.23], P=0.01), insulin (b 0.10[0.03-0.17], P<0.001), and proinsulin (b 0.06[0.02-0.10], P=0.01) at baseline. Upon longitudinal analyses, a higher baseline FGF23 was independently associated with development of diabetes (199 events (4%); fully adjusted HR 1.66[95% CI 1.06-2.60], P=0.03) and development of obesity (241 events (6%); fully adjusted HR 1.84[1.34-2.50], P<0.001). The association between FGF23 and incident diabetes lost significance after additional adjustment for BMI. Glucose loading has phosphate-independent effects on FGF23 and, vice versa, FGF23 is associated with glucose, insulin and proinsulin levels and obesity. These findings suggest cross-talk between FGF23 and glucose homeostasis, which may promote susceptibility to incident diabetes.

Fibroblast Growth Factor 23 Level and Cardiovascular Parameters in Children with Chronic Kidney Disease.

To find out the serum fibroblast growth factor 23 (FGF-23) levels in different grades of CKD, and the prevalence of abnormal left ventricular mass index (LVMI), carotid intima-medial thickness (cIMT), and central pulse wave velocity (cPWV) and the risk factors including FGF-23 for these abnormalities. Fifty-nine patients of CKD with G2 to G5, aged 2-18 y were included. The LVMI, cIMT, and cPWV were measured using standard techniques, and serum intact FGF-23 levels were estimated at enrollment. Median FGF-23 levels were significantly raised in all the grades of CKD than controls (p < 0.001), and also in G4 and G5 in comparison to G2&3 and in G5D than G5. Increased LVMI in 42 (71.2%), elevated cIMT in 30 (57.7%), and cPWV in 14 (26.9%) patients were found. The FGF-23 showed significant negative correlation with eGFRcr and positive with serum iPTH, phosphate and alkaline phosphatase levels, but had no correlations with LVMI, cIMT SDS, and cPWV SDS. Only systolic BP SDS (odds ratio 1.5, 95% CI 1.008-2.231, p = 0.046) was observed as a significant predictor for increased cIMT, while no variables had any association with abnormal LVMI and cPWV. Serum FGF-23 showed higher levels with increasing grades of CKD, but no significant association with cardiovascular parameters. Systolic BP SDS was found as a significant risk factor for increased cIMT in children with CKD.

Discharge FGF23 levels predicts one year outcome in patients admitted with acute heart failure

Abstract Background Patients with acute heart failure (AHF) show high levels of fibroblast growth factor-23 (FGF23) on admission. We examined if plasma FGF23 changes during an episode of AHF, and if FGF23 holds prognostic significance in this setting. Methods Consecutive AHF patients were enrolled. Blood samples were collected on admission and at discharge. Patients were then followed for all-cause death or HF hospitalization. Results Patients (n=125; median age 76 years [interquartile interval 71–83], 63% men, left ventricular ejection fraction 35% [25–56%]) had median admission FGF23 70 ng/L (47–100), N-terminal pro-B-type natriuretic peptide (NT-proBNP) 5,844 ng/L (2,503–10,468), high-sensitivity troponin T (hs-TnT) 40 ng/L (25–72), and soluble suppression of tumorigenesis-2 (sST2) 26 ng/mL (17–37). While other biomarkers decreased, FGF23 increased by 15% from admission to discharge (p=0.033), with a significant correlation with percent changes in estimated glomerular filtration rate (rho=0.306, p=0.001). Over a 12-month follow-up, 64 patients (51%) experienced the endpoint. They were more often men, older, with higher systolic pulmonary artery pressure (sPAP), higher NT-proBNP, hs-TnT and discharge FGF23. The best FGF23 cut-off at discharge from receiver operating characteristics analysis was 78 ng/L. Both discharge FGF23 and the 78 ng/L cut-off independently predicted outcome in models including gender, sPAP, age, and 1) admission NT-proBNP, 2) discharge NT-proBNP, 3) admission NT-proBNP and hs-TnT, 4) discharge NT-proBNP and hs-TnT. The 78 ng/L cut-off also refined risk reclassification. Conclusions During an AHF episode, FGF23 increases from admission to discharge, and patients with higher discharge FGF23 have a higher risk of worse outcome. Funding Acknowledgement Type of funding sources: None.

Discharge FGF23 level predicts one year outcome in patients admitted with acute heart failure

BackgroundPatients with acute heart failure (AHF) show high levels of fibroblast growth factor-23 (FGF23) on admission. We examined if plasma FGF23 changes during an episode of AHF, and if FGF23 holds prognostic significance in this setting. MethodsConsecutive AHF patients were enrolled. Blood samples were collected on admission and at discharge. Patients were then followed for all-cause death or HF hospitalization. ResultsPatients (n = 125; median age 76 years [interquartile interval 71–83], 63% men, left ventricular ejection fraction 35% [25%–56%]) had median admission FGF23 70 ng/L (47–100), N-terminal pro-B-type natriuretic peptide (NT-proBNP) 5844 ng/L (2,503-10,468), high-sensitivity troponin T (hs-TnT) 40 ng/L (25–72), and soluble suppression of tumorigenesis-2 (sST2) 26 ng/mL (17–37). While other biomarkers decreased, FGF23 increased by 15% from admission to discharge (p = 0.033), with a significant correlation with percent changes in estimated glomerular filtration rate (rho = 0.306, p = 0.001). Over a 12-month follow-up, 64 patients (51%) experienced the endpoint. They were more often men, older, with higher systolic pulmonary artery pressure (sPAP), higher NT-proBNP, hs-TnT and discharge FGF23. The best FGF23 cut-off at discharge from receiver operating characteristics analysis was 78 ng/L. Both discharge FGF23 and the 78 ng/L cut-off independently predicted outcome in models including gender, sPAP, age, and 1) admission NT-proBNP, 2) discharge NT-proBNP, 3) admission NT-proBNP and hs-TnT, 4) discharge NT-proBNP and hs-TnT. The 78 ng/L cut-off also refined risk reclassification. ConclusionsDuring an AHF episode, FGF23 increases from admission to discharge, and patients with higher discharge FGF23 have a higher risk of worse outcome.

Фактор роста фибробластов 23 (FGF-23) и хроническая болезнь почек у детей

Chronic kidney disease (CKD) in children is a complex medical and social problem in healthcare. One of the serious complications is mineral bone disorder (MBD), the pathogenesis of which is related to a new biomarker of bone origin - fibroblast growth factor 23 (FGF-23). The aim. To study the features of fibroblast growth factor 23 (FGF-23) in children with chronic kidney disease. Material and methods. A cross-sectional study was carried out on 73 children with CKD and 14 healthy children. Inclusion criteria: chronic kidney disease stage 1-5, written informed consent of the participants. The exclusion criteria: tubulopathy, infectious and inflammatory processes, oncological diseases, kidney transplant, condition after surgery, taking glucocorticosteroids, calcium and vitamin D drugs. We took fasting blood samples of participants and carried out an enzyme-linked immunosorbent assay in order determine the level of FGF-23 (Biomedica Medizinprodukte GmbH, Austria). The obtained data were analyzed using IBM SPSS, version 22 (New York, USA). Results and discussion. In healthy children, the median (Q1-Q3) level of FGF-23 in serum was 0.65 (0.22-0.98) pmol/l, in patients with stage 1 CKD it was 0.65 (0.22-1.08) pmol/l. At stage 2, the level of FGF-23 significantly increased in comparison with healthy individuals and with patients of stage 1, p≤0.05. Further, there is a gradual increase by stages, p≤0.05. Thus, in stage 3 patients, the median FGF-23 value was 1.9 (1.15-3.5) pmol/l, at stage 4 - 3.55 (2.48-6.35) pmol/l, at 5 stages - 14 (7.5-18.75) pmol/l. As a percentage, there were 7.1% of patients at the stage 1 with increased levels of phosphatonin, at stage 2 - 53.3%, at stage 3 - 69.2%, respectively. At stages 4 and 5, absolutely 100% of patients had high levels of FGF-23. At the same time, FGF-23 did not depend on gender, age, birth weight and type of renal replacement therapy at stage 5, p&gt;0.05. Conclusions. Thus, in our study, we determined the features of changes FGF-23 in serum in children at various stages of CKD. The obtained results allow us to consider FGF-23 as a predictor of the clinical course of CKD. Keywords: fibroblast growth factor 23, phosphatonin, pediatric nephrology, chronic kidney disease, mineral-bone disorder.

Fibroblast growth factor 23 and cognitive impairment: The health, aging, and body composition study.

BackgroundConcentrations of fibroblast growth factor 23 (FGF-23), a hormone that regulates phosphorus and vitamin D metabolism, increase as kidney function declines. Excess fibroblast growth factor 23 may impact brain function through promotion of vascular disease or through direct effects on neuronal tissue.MethodsIn the Healthy Aging and Body Composition Study, a longitudinal observational cohort of well-functioning older adults, intact serum FGF-23 was assayed in 2,738 individuals. Cognitive function was assessed at baseline and longitudinally at years 3, 5, and 8 by administration of the Modified Mini Mental State Examination (3MSE), a test of global cognitive function, and the Digit Symbol Substitution Test (DSST), a test primarily of executive function. The associations between FGF-23 and baseline cognitive function and incident cognitive impairment were evaluated using logistic and Poisson regression respectively, and were adjusted for demographics, baseline estimated glomerular filtration rate (eGFR), urine albumin/creatinine ratio, comorbidity, and other measures of mineral metabolism including soluble klotho.ResultsThe mean (SD) age was 74(3) years, with 51% female, and 39% black. The median (25th, 75th) FGF-23 concentration was 47 pg/mL (37, 60). Three hundred ninety-two individuals had prevalent cognitive impairment by the 3MSE and 461 by the DSST. There was no observed association between FGF-23 and baseline cognitive function for either cognitive test. There were 277 persons with incident cognitive impairment by 3MSE, and 333 persons with incident cognitive impairment by DSST. In fully adjusted models, each two-fold higher concentration of baseline FGF-23 was not associated with incident cognitive impairment by the 3MSE (IRR = 1.02[0.88, 1.19] fully adjusted model) or by the DSST (IRR = 0.98 [0.84, 1.15]. We saw no difference when analyses were stratified by eGFR greater than or less than 60 ml/min/1.73m2.ConclusionIntact FGF-23 was not associated with baseline cognitive function or incident cognitive impairment in this cohort well-functioning older adults.

The correlation between serum fibroblast growth factor-23 with urinary fractional excretion of phosphate in predialysis chronic kidney disease

Purpose: To investigate the correlation of serum fibroblast growth factor-23 (FGF-23) with urinary fractional excretion of phosphate (FEPi) in predialysis chronic kidney disease (CKD).Methods: This cross-sectional study involved 75 patients with CKD stage 2-4. Blood and 24-hour urine samples were taken from eligible participants to measure key variables using standard commercial assays. FGF-23 concentration was measured using enzyme-linked immunosorbent assay (ELISA). The correlation between FGF-23 serum level and urinary FEPi was analyzed using the Spearman correlation test.Results: Of 75 eligible subjects, the majority had the characteristics of male gender, CKD stage 3, with mean age and body mass index of 50±10.8 and 23.51±3.3, respectively. The median FGF-23 level was 108.7 (13.6-1226.2) RU/ml, while the median urinary FEPi was 24.3% (4.04%-65.9%). There was a moderate positive correlation between FGF-23 and FEPi (r = 0.44, p&lt;0.001). Conclusion: The result confirmed the correlation between serum FGF-23 level with urinary FEPi in predialysis CKD.

Fibroblast growth factor-23 and fetuin-A in black South African children with chronic kidney disease

Background. Both fibroblast growth factor-23 (FGF-23) and fetuin-A levels have been implicated in mineral and bone disorders associated with chronic kidney disease (CKD), and several single nucleotide polymorphisms (SNPs) of the fetuin-A gene have also been associated with fetuin-A levels. Objectives. This study aimed to determine the relationship between FGF-23 and fetuin-A and to determine the role of fetuin-A SNPs with respect to fetuin-A levels and markers of bone mineralisation in black South African children. Methods. Blood samples from 93 children (5 - 18 years) with various stages of CKD were assessed for C-reactive protein (CRP), calcium, phosphate, parathyroid hormone, 25-hydroxyvitamin D, FGF-23 and fetuin-A levels. Genomic DNA was extracted from whole blood and regions of the fetuin-A gene amplified by polymerase chain reaction. SNPs were genotyped by restriction fragment length polymorphism analysis or by direct sequencing. Results. The median FGF-23 and fetuin-A levels were 28.9 (11.7 - 147.1) pg/mL and 57.7 (37.7 - 71.8) mg/dL, respectively. A significant negative relationship between fetuin-A and FGF-23 was only observed in the CKD V group ( p =–0.60, p <0.001). Plasma FGF-23 levels correlated better with markers of bone mineralisation than fetuin-A. We found significant association of the fetuin-A SNPs rs4918-G and rs2070633-T alleles with log-transformed fetuin-A levels. Serum phosphate and parathyroid hormone levels were also associated with fetuin-A SNPs. Conclusion. Plasma FGF-23 levels increase with CKD progression while changes in fetuin-A levels are more likely to be observed in children with advanced CKD; and FGF-23 correlated better with markers of bone mineralisation than fetuin-A.

Fibroblast Growth Factor 23 and Mortality Among Prevalent Hemodialysis Patients in the Japan Dialysis Outcomes and Practice Patterns Study

IntroductionElevated fibroblast growth factor 23 (FGF23) levels have been strongly associated with mortality in the predialysis and incident hemodialysis populations, but few studies have examined this relationship in a large cohort of prevalent hemodialysis patients and in particular among persons with high dialysis vintage. To address this, we analyzed data from the Japan Dialysis Outcomes and Practice Patterns Study (J-DOPPS).MethodsWe included 1122 prevalent hemodialysis patients from the J-DOPPS phase 5 (2012–2015) who had FGF23 measurements. We evaluated the association of FGF23 levels with all-cause mortality and cardiovascular composite outcome using Cox regression adjusted for potential confounders.ResultsAt study enrollment, median dialysis vintage was 5.8 years (interquartile range, 2.7–12.4 years) and median FGF23 level was 2113 pg/ml (interquartile range, 583–6880 pg/ml). During 3-year follow-up, 154 of the 1122 participants died. In adjusted analyses, higher FGF23 was associated with a greater hazard of death (hazard ratio per doubling of FGF23, 1.12; 95% confidence interval, 1.03–1.21); however, the association became weaker as the dialysis vintage increased and finally disappeared in the highest tertile (>9.4 years). Similar patterns of effect modification by dialysis vintage were observed for cardiovascular composite outcome and in time-dependent models.ConclusionElevated FGF23 was associated with mortality and cardiovascular events in prevalent hemodialysis patients, but the association was attenuated at longer dialysis vintages. This novel finding suggests that long-term hemodialysis patients may be less susceptible to the detrimental effects of FGF23 or correlated biological processes, and additional studies are needed to gain understanding of these possibilities.

Fibroblast growth factor 23: a biomarker of fibrosis and prognosis in heart failure with preserved ejection fraction.

AimsBesides regulating calcium‐phosphate metabolism, fibroblast growth factor 23 (FGF‐23) has been associated with incident heart failure (HF) and left ventricular hypertrophy. However, data about FGF‐23 in HF and preserved ejection fraction (HFpEF) remain limited. The aim of this study was to assess the association between FGF‐23 levels, clinical and imaging characteristics, particularly diffuse myocardial fibrosis, and prognosis in HFpEF patients.Methods and resultsWe prospectively included 143 consecutive HFpEF patients (78 ± 8 years, 61% female patients) and 31 controls of similar age and gender (75 ± 6 years, 61% female patients). All subjects underwent a complete two‐dimensional echocardiography and cardiac magnetic resonance with extracellular volume (ECV) assessment by T1 mapping. FGF‐23 was measured at baseline. Among the patients, differences in clinical and imaging characteristics across tertiles of FGF‐23 levels were analysed with a trend test across the ordered groups. Patients were followed over time for a primary endpoint of all‐cause mortality and first HF hospitalization and a secondary endpoint of all‐cause mortality. Median FGF‐23 was significantly higher in HFpEF patients compared with controls of similar age and gender (247 [115; 548] RU/mL vs. 61 [51; 68] RU/mL, P < 0.001). Among HFpEF patients, higher FGF‐23 levels were associated with female sex, higher incidence of atrial fibrillation, lower haemoglobin, worse renal function, and higher N terminal pro brain natriuretic peptide levels (P for trend < 0.05 for all). Regarding imaging characteristics, patients with higher FGF‐23 levels had greater left atrial volumes, worse right ventricular systolic function, and more fibrosis estimated by ECV (P for trend < 0.05 for all). FGF‐23 was moderately correlated with ECV (r = 0.46, P < 0.001). Over a mean follow‐up of 30 ± 8 months, 43 patients (31%) died and 69 patients (49%) were hospitalized for HF. A total of 87 patients (62%) reached the primary composite endpoint of all‐cause mortality and/or first HF hospitalization. In multivariate Cox regression analysis for the primary endpoint, FGF‐23 (HR: 3.44 [2.01; 5.90], P < 0.001) and E wave velocities (HR: 1.01 [1.00; 1.02], P = 0.034) were independent predictors of the primary composite endpoint. In multivariate Cox regression analysis for the secondary endpoint, ferritin (HR: 1.02 [1.01; 1.03], P < 0.001), FGF‐23 (HR: 2.85 [1.26; 6.44], P = 0.012), and ECV (HR: 1.26 [1.03; 1.23], P = 0.008) were independent predictors of all‐cause mortality.ConclusionsFibroblast growth factor 23 (FGF‐23) levels were significantly higher in HFpEF patients compared with controls of similar age and gender. FGF‐23 was correlated with fibrosis evaluated by ECV. High levels of FGF‐23 were significantly associated with signs of disease severity such as worse renal function, larger left atrial volumes, and right ventricular dysfunction. Moreover, FGF‐23 was a strong predictor of poor outcome (mortality and first HF hospitalization).

P1304FIBROBLAST GROWTH FACTOR (FGF23) AND CARDIOVASCULAR MORTALITY IN DIALYSIS PATIENTS: A 10 YEAR PROSPECTIVE SINGLE CENTER STUDY

Abstract Background and Aims The aim of the study is to evaluate whether circulating fibroblast growth factor 23 (FGF23) predicts cardiovascular mortality in dialysis patients, independent of markers of calcium-phosphate metabolism and cardiovascular risk factors. Method A prospective observational study at Akdeniz University Medical Center including 51 peritoneal dialysis patients and 27 hemodialysis patients was undertaken from 01/2009 to 12/2019. Plasma C-terminal FGF23 concentrations in addition to other measures of mineral metabolism were performed at baseline. Patients were followed for all-cause mortality, cardiovascular mortality, non-fatal MI, non-fatal stroke, coronary revascularization, heart failure hospitalization and atrial fibrillation. Results The mean age of patients 48± 15 years. During a ten year follow up period, there were 47 deaths. The median plasma FGF23 level was 321 pg/ml (interquartile range 51-1784 pg/ml). Patients were stratified by their baseline FGF23 levels according to the tertiles. Cumulative survival analysis by tertiles of FGF23 were made with the Kaplan-Meier survival curve. Kaplan Meier analysis with log-rank did reveal a significant difference between the groups (p=0,048). Conclusion Higher FGF23 levels are associated with an increased incidence of cardiovascular mortality in dialysis patients, independent of other markers of calcium-phosphate metabolism and cardiovascular risk factors.

0002 Decreased Concentration of Klotho and Increased Concentration of FGF-23 in the Cerebrospinal Fluid of Patients with Narcolepsy

Abstract Introduction Narcolepsy is a disorder characterized by hypersomnolence, cataplexy, sleep paralysis, hallucinations and sleep fragmentation. Patients with type 1 narcolepsy have cataplexy and/or hypocretin-1 deficiency. Klotho is a protein expressed by kidneys and choroid plexus, with anti-aging properties. Fibroblast growth factor 23 (FGF-23) is a hormone secreted by osteocytes with actions on mineral metabolism. The purpose of study was to explore the status of concentration of klotho and FGF23 in the cerebrospinal fluids (CSF) of patients with narcolepsy. Methods 59 patients with narcolepsy and 17 individuals were enrolled. We used a radioimmunoassay technique, human klotho enzyme-linked immunosorbent assay (ELISA), human intact FGF23 ELISA and spectrophotometry to measure hypocretin-1, klotho, FGF-23 and phosphorus, respectively. T-Student Test was used to compare klotho and phosphate concentrations and Mann-Whitney U Test was used to compare FGF-23 levels between groups. ANOVA Test was used to compare klotho and phosphate CSF concentrations among narcolepsy patients with CSF hypocretin-1 &amp;lt;110pg/ml (HCRT-) and narcolepsy patients with CSF hypocretin-1 &amp;gt;110pg/ml (HCRT+) versus control subjects. Results Klotho and phosphorus CSF levels were lower in narcoleptic patients than in control (908.18 ± 405.51 versus 1265.78 ± 523.26 pg/ml; p=0.004 and 1.34 ± 0.25 versus 1.58 ± 0.23 mg/dl; p= 0.001, respectively). We found higher median FGF-23 levels in narcoleptic patients (5.51 versus 4.00 RU/ml; p= 0.001). Klotho and phosphorus CSF levels were lower in both HCRT-/HCRT+ than controls (892.63 ± 388.34/ 925.95 ± 430.76 versus 1265.78 ± 523.26 pg/ml; p=0.014 and 1.35 ± 0.28/ 1.33 ± 0.22 versus 1.58 ± 0.23 mg/dl; p= 0.004). Moreover, we found higher median FGF-23 levels in both HCRT-/HCRT+ groups versus controls (5.51/ 6.02 versus 4.00 RU/ml in controls), p= 0.009. Conclusion Patients with narcolepsy have decreased CSF concentration of klotho and increased CSF levels of FGF-23. These findings may play a role in understanding the pathogenesis of narcolepsy. Support

Changes in Fibroblast Growth Factor 23 and Soluble Klotho Levels After Hemodialysis Initiation

Rationale & ObjectivePatients with chronic kidney failure have markedly elevated fibroblast growth factor 23 (FGF-23) levels and decreased soluble Klotho levels. However, no studies have examined the effects of hemodialysis initiation on the levels of these hormones and other parameters of mineral metabolism.Study DesignProspective single-arm study.Setting & Participants20 individuals with incident kidney failure initiating hemodialysis.ExposureInitiation of hemodialysis. Dose adjustments of phosphate binders and vitamin D receptor activators and use of calcimimetics, erythropoiesis-stimulating agents, and intravenous iron were prohibited.OutcomesChanges in serum levels of FGF-23, soluble Klotho, and other biochemical parameters of mineral metabolism, measured before and after each hemodialysis session, for a total of 4 sessions over 5 days.Analytical ApproachRepeated-measures analysis of variance.ResultsAt baseline, participants had 18-fold higher median FGF-23 levels and 1.6-fold lower mean soluble Klotho levels compared with age- and sex-matched healthy individuals. Initiation of hemodialysis led to progressive reductions in serum phosphorus, intact parathyroid hormone, and FGF-23 levels, with dialysis-related fluctuations. No reductions were observed in levels of α1-microglobulin, which has molecular weight comparable to FGF-23. The magnitude of the FGF-23 level reductions was strongly associated with concomitant changes in serum phosphorus levels but not with the changes in intact parathyroid hormone levels. Soluble Klotho levels did not change after the initiation of hemodialysis.LimitationsSingle-arm design, small sample size, short follow-up period.ConclusionsInitiation of hemodialysis in patients with chronic kidney failure led to progressive reductions in FGF-23 levels in association with reductions in serum phosphorus levels. These results suggest that phosphorus is a strong inducer of FGF-23 production and that regulation of FGF-23 production is a rapid process.

The role of vitamin D replacement therapy in serum FGF23 concentration in children with myelomeningocele compared with healthy children - a preliminary study.

Background Fibroblast growth factor 23 (FGF23) is a recently discovered bone-derived regulator of vitamin D metabolism and phosphate homeostasis. It inhibits phosphate reabsorption and calcitriol production by the kidney. Myelomeningocele (MMC) remains the most severe form of neural tube defects involving serious locomotor disability, osteoporosis and pathologic fractures. We aimed to investigate the influence of vitamin D replacement therapy on serum FGF23 concentration in children with MMC and compare the results with healthy participants. Methods This prospective analysis was conducted on 16 children with MMC and 20 healthy children. Serum FGF23 levels were measured; for the studied group, before and after vitamin D replacement therapy with cholecalciferol (vitamin D3). The children's medical charts were analyzed to determine age, sex, anthropometric measurements, calcium and phosphate, cholecalciferol and renal function parameters. Results There were significant differences in vitamin D and FGF23 serum concentrations between the studied groups. The median vitamin D levels in the MMC group increased during replacement therapy (7 vs. 18.5 ng/mL, p = 0.29) in comparison to the median of 25.5 ng/mL in the control group. In MMC children we found a significant decrease in median serum FGF23 after vitamin D replacement therapy (from 42.1 to 0 RU/mL, p < 0.001). FGF23 correlated positively with albumin, serum and urine phosphate levels and negatively with alkaline phosphatase. Conclusions 1. Serum concentration of FGF-23 is increased in MMC children in comparison to a healthy control group. 2. Vitamin D replacement therapy decreases FGF23 concentrations in MMC children, although further studies are still warranted to gain detailed insight on the FGF23 in the MMC population. 3. Children with MMC present vitamin D deficiency. Nutrition supplemented with low doses of cholecalciferol (vitamin D3) (intakes reaching recommended daily allowances) was insufficient to correct 25(OH)-D level in that population of patients.

Effects of Nicotinamide and Lanthanum Carbonate on Serum Phosphate and Fibroblast Growth Factor-23 in CKD: The COMBINE Trial

Higher serum phosphate and fibroblast growth factor-23 (FGF23) levels may be modifiable to prevent cardiovascular disease in CKD. Short-term studies have reported modest efficacy in phosphate and FGF23 reduction with intestinal phosphate binders in CKD. To investigate effects of lanthanum carbonate (LC; a phosphate binder) and/or nicotinamide (NAM; an inhibitor of active intestinal phosphate transport) on serum phosphate and FGF23 in stage 3b/4 CKD, we conducted a randomized trial among individuals with eGFR 20-45 ml/min per 1.73 m2 to NAM (750 mg twice daily) plus LC (1000 mg thrice daily), NAM plus LC placebo, LC plus NAM placebo, or double placebo for 12 months. Dual primary end points were change from baseline in serum phosphate and intact FGF23 concentrations. Mean eGFR for the 205 participants was 32ml/min per 1.73 m2. At baseline, serum phosphate was 3.7 mg/dl and median FGF23 was 99 pg/ml (10th, 90th percentiles: 59, 205). Mean rates of change in phosphate increased slightly over 12 months in all groups and did not differ significantly across arms. Similarly, percent changes in FGF23 per 12 months increased for all arms except LC plus placebo, and did not differ significantly across arms. Gastrointestinal symptoms limited adherence. Adverse events rates were similar across arms. LC and/or NAM treatment did not significantly lower serum phosphate or FGF23 in stage 3b/4 CKD over 12 months. Although these agents appeared safe, intestinal symptoms limited adherence. Reducing phosphate and FGF23 in nondialysis CKD will require new approaches.

Evaluation of serum fibroblast growth factor-23 in patients with axial spondyloarthritis and its association with sclerostin, inflammation, and spinal damage.

The mechanisms underlying new bone formation in individuals with axial spondyloarthritis (axSpA) remain unclear; however, low levels of sclerostin (SOST) may be associated with development of syndesmophytes in those with ankylosing spondylitis (AS). Expression of fibroblast growth factor-23 (FGF-23), another osteocyte factor, is high in those with osteoporosis and chronic renal failure, but levels in those with axSpA are unknown. To evaluate serum FGF-23 and SOST levels in axSpA patients, and to assess their relationship with inflammation and structural damage. In total, 109 axSpA patients (55 with AS and 54 with non-radiographic axSpA) and 57 healthy control (HC) subjects were included in the analysis. Serum concentrations of FGF-23 and SOST were measured and correlation analysis was performed. The presence of syndesmophytes and the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) were used to assess structural damage. Levels of serum FGF-23 in axSpA patients were significantly higher than those in HCs [median (interquartile range-IQR) FGF-23 level, pg/ml; AxSpA = 144 (82.3-253.2), HC = 107 (63.3-192.8), p = 0.010]; however, there was no difference in SOST levels. FGF-23 levels correlated with the erythrocyte sedimentation rate (ESR) (r = 0.265, p = 0.006) and serum C-reactive protein (CRP) level (r = 0.229, p = 0.010). In the axSpA, SOST levels correlated negatively with mSASSS (r = - 0.283, p = 0.007), whereas those in the AS group correlated negatively with CRP (r = - 0.426, p = 0.001). Serum FGF-23 levels were high in axSpA patients. Increased FGF-23 was associated with inflammation, but not with SOST levels or disease activity. SOST correlated negatively with both inflammation and structural damage.