Fibroblast Growth Factor 23 Concentrations Research Articles

Serum fibroblast growth factor-23 concentrations in young and mature adult cats with chronic kidney disease.

The aim of this study was to investigate serum fibroblast growth factor (FGF)-23 concentrations in young and mature adult cats with chronic kidney disease (CKD). The present study retrospectively investigated the serum samples and medical records of 1-8-year-old clinically healthy cats (control group, n = 7) and cats with CKD (n = 54). Cats with CKD were divided into four stages based on serum creatinine concentrations, according to the International Renal Interest Society (IRIS) CKD guidelines. Serum FGF-23 concentrations were compared between cats in the control group, IRIS stages 1, 2 and 3-4 CKD. Continuous variables were analysed using correlations and multiple linear regression. Serum FGF-23 concentrations were significantly higher in cats with IRIS stages 1, 2 and 3-4 CKD, compared with those in the control group (P = 0.02, P = 0.002 and P = 0.002, respectively). Additionally, serum FGF-23 concentrations in cats with IRIS stages 3-4 CKD had higher serum FGF-23 concentrations than those with IRIS stages 1 and 2 CKD (P = 0.04 and P = 0.02, respectively). In the multiple linear regression analysis, serum urea nitrogen concentration, serum phosphorus concentration and blood ionised calcium concentration were independent variables predicting serum FGF-23 concentration. Serum FGF-23 concentrations in younger cats with CKD increased in early-stage CKD and were associated with mineral metabolic markers, as also occurs in geriatric cats.

Влияние эмпаглифлозина на фосфорно-кальциевый метаболизм у больных сахарным диабетом 2 типа с сохранной функцией почек

Background : Sodium glucose co-transporter type 2 inhibitors (iSGLT2) are antihyperglycemic drugs approved for the treatment of type 2 diabetes mellitus (T2DM). Clinical trials with these drugs have shown evidence of an increased risk of fractures and an effect on phosphorus, vitamin D and parathyroid hormone (PTH) levels. Aim : The aim of this study was to investigate the effect of the most selective iSGLT2 empagliflozin on the calcium and phosphorus metabolism in patients with T2DM and preserved kidney function. Materials and methods : Thirty-nine T2DM patients were received empagliflozin 10 mg in addition to their antihyperglycemic drugs for 12 weeks. Before starting treatment, a dual-energy X-ray absorptiometry (DXA) with an assessment of the trabecular bone score (TBS) was performed. The concentration of phosphorus (P), total (tCa) and ionized calcium (Ca ++ ), fibroblast growth factor 23 (FGF-23), 25(OH)D and PTH were assessed. Results : According to the DXA results, only 2 patients had osteoporosis, 10 (25.6%) patients had bone mineral density (BMD) values below 1.35 g /cm 2 on the TCI scale. Treatment with empagliflozin for 12 weeks was lead to significant increase in FGF-23. Compared to the baseline level, there were no statistically significant differences in the concentrations of P, oCa, Ca ++ , PTH and 25(OH)D after 12 weeks of treatment. The level of FGF-23 did not correlate with the level of glomerular filtration rate either before or after treatment (r = 0.31, p = 0.27 and r = 0.39, p = 0.55, respectively). In addition, baseline BMD adjusted for TBS and baseline 25(OH)D did not correlate with Ca, F, FGF-23, and PTH concentrations (p>0.05). Conclusion : Thus, empagliflozin has increased the level of FGF-23 without significant changes in the concentration of phosphorus, calcium, 25 (OH) D, and PTH after 12 weeks of treatment in patients with T2DM and preserved renal function. The obtained data confirmed the necessity to assess the TBS in patients with T2DM, because it’s provide additional information on the quality of bone tissue.

High Fibroblast Growth Factor 23 as a Biomarker for Severe Cardiac Impairment in Children with Chronic Kidney Disease: A Single Tertiary Center Study.

IntroductionLeft ventricular hypertrophy (LVH) is the most common cardiac abnormality in chronic kidney disease (CKD). Changes in cardiac geometry and functions may occur in an early stage and worsen as CKD progresses. Recently, the role of fibroblast growth factor 23 (FGF23) is being highlighted and investigated in CKD-related cardiomyopathy. However, only a few studies have reviewed the utilization of FGF23 as a diagnostic biomarker in the pediatric CKD population.PurposeThis study aimed to identify the role of FGF23 as a biomarker in assessing cardiac changes in children with CKD.Patients and MethodsWe conducted a cross-sectional study that involved children aged 2 to 18 years old with CKD stages 2 to 5D in Dr. Sardjito General Hospital, Yogyakarta, Indonesia. The level of FGF23 was measured using an immunometric enzyme-linked immunosorbent assay. LVMI, RWT, and left ventricular ejection fraction (LVEF) were assessed with echocardiography. Receiver-operating characteristic (ROC) analyses were conducted to assess the diagnostic performance of FGF23 in detecting LVH with impaired contractility.ResultsA total of 43 children with CKD stages 2 to 5D were included, among whom the prevalence of LVH diagnosis was 95.35%. The area under the curve (AUC) of FGF23 to assess LVH and systolic dysfunction was 0.82 (95% CI 0.62–1.0), and the optimal cutoff point was 1413 RU/mL (sensitivity 80%, specificity 78.95%). The median concentration of FGF23 increased with the decreasing eGFR and the increasing LVMI although the systolic and diastolic functions were preserved.ConclusionFGF23 might be used as an early biomarker to detect cardiac changes in pediatric CKD patients, particularly for LVH and impaired systolic function among children with CKD stage 2 and higher.

MO480FGF-23 AND LOW BIRTH WEIGHT: IS THERE ANY ASSOCIATION?

Abstract Background and Aims According to Barker’s theory and Brenner’s hypothesis, persons were born with low birth weight (LBW) have a higher risk of CKD due to low nephron number. Also, it is well known that mineral-bone disorder (MBD) is one of the most serious complications of CKD. Views on the pathogenesis of CKD-MBD have changed considerably since Fibroblast growth factor 23 (FGF-23) was discovered. It is thought that FGF-23 increases as the nephron mass reduces. Therefore, we aimed to determine if there is an association between LBW and FGF-23. Method We conducted a cross-sectional study on 56 children with CKD stages 1-4. There were approximately equal numbers of participants in each stage. The mean age was 8.9 ±4.9 years old. We measured the concentration of FGF-23 (C-terminal) in serum by a sandwich enzyme-linked immunosorbent assay (ELISA) kit (Biomedica Medizinprodukte GmbH, Austria). The exclusion criteria: tubulopathy, active inflammatory, infectious, oncological and bone diseases, renal transplant, as well as taking steroids, calcium, and vitamin D. The informed consent was obtained from the parents. The study was conducted in accordance with the Declaration of Helsinki and approved by the Local Ethical Committee. FGF-23 concentration more than 1.5 pmol/l was considered as abnormal. Statistical analysis was performed using GraphPad Prism 9.0.0 (San Diego, USA) Results Mineral-bone disorder was diagnosed as CKD complication in 20 (35.7%) children. LBW was revealed in 14 (25%) patients. The median (IQR) eGFR among patients with normal birth weight was 65.23 (31.23-84.73) ml/min/1.73m2, among LBW – 68.93 (24.59-98.9) ml/min/1.73m2, so there were no differences in kidney function between the two groups (p=0.64). The median (IQR) level of serum FGF-23 in patients with normal birth weight was 1.75 (0.68- 2.5) pmol/l, in LBW children was 1.85 (0.78 -3.1) pmol/l. Analysis of serum level of FGF-23 in relation to weight at birth revealed no statistical differences in patients with LBW and those with normal birth weight (p=0.719), and the Spearman rank correlation was insignificant as well (r=-0.08, p=0.560). Conclusion FGF-23 is an important biomarker of CKD-MBD. FGF-23 does not depend on the birth weight although LBW is considered as a risk factor for CKD. However, further investigations and studies in this area are needed to make the right conclusions regarding the association between this bone biomarker and birth weight.

MO453SERUM AND VASCULAR FIBROBLAST GROWTH FACTOR 23 (FGF23) ARE ASSOCIATED WITH VASCULAR CALCIFICATION

Abstract Background and Aims Mineral metabolism imbalances and inflammation are related to the development of vascular calcification (VC). Fibroblast growth factor-23 (FGF23) is the main regulator of phosphate homeostasis and various studies have shown the existence of an association between elevated levels of FGF23 and the appearance of cardiovascular disease (CVD). We conducted a case-control study to test the hypothesis that serum and vascular levels of FGF23 are associated with the presence of VC. In addition, we determined the influence of inflammation in these levels. Method One hundred and thirty-three patients diagnosed with clinical atherosclerotic disease undergoing elective vascular surgery, and 20 cadaveric organ donors with no medical history of CVD, were included in this study. Serum levels of intact FGF23 (iFGF23), together with tumor necrosis factor-alpha (TNFα), interleukin (IL)10, were determined by ELISA. Vascular fragments of aorta, carotid and femoral arteries were obtained for assaying the gene expression of FGF23, TNF, IL10 and RUNX2 by qPCR. Immunohistochemical procedures were employed to determine vascular protein levels of FGF23, TNFα and IL10. VC was diagnosed by imaging techniques and confirmed by histological procedures including von Kossa staining. Results Case group presented a higher prevalence of hypertension, hypercholesterolemia and reduced estimated glomerular filtration rate, with no differences regarding other parameters. Serum iFGF23 and TNFα/IL10 ratio were higher in the case group (P<0.01 and P<0.001, respectively). Vascular expression of FGF23 was detected in 58.6% of CVD patients vs 35% of donors, with mean expression levels significantly higher in the first group (P<0.01). Vascular expression of TNF/IL10 was also increased (P<0.001) in CVD patients. FGF23 immunoreactivity was detected in 84% of CVD patients and only in 35% of controls. Immunoreactivity for FGF23 and TNFα/IL10 ratio were significantly higher in CVD patients (P<0.001 and P<0.0001, respectively). Stratified analysis according to serum iFGF23 levels showed a higher prevalence of VC in the upper tertiles. Patients with VC presented increased levels of all the FGF23 variables including serum [1.5 (1.2-1.6) vs. 1.4 (0.9-1.5) pg/mL, P<0.01], vascular mRNA [26.1 (14.3-67.4) vs. 18.8 (8.8-312.9) log AU, P<0.01] and vascular immunoreactivity [4.6 (3.8-4.9) vs. 3.7 (3.1-4.1) log µm2, P<0.05]. Moreover, FGF23 immunoreactivity was detected in 92.3% of fragments with VC and only in 53.6% of those without VC. Serum TNFα/IL10 and RUNX2 mRNA levels were also higher in this group (P<0.01 for both). Correlation analysis showed associations of serum iFGF23 with serum TNFα (r=0.375, P<0.001), neutrophil/lymphocyte (r=0.142, P<0.05), vascular RUNX2 mRNA (r=0.55, P<0.05), and vascular FGF23 immunoreactivity (r=0.281, P<0.05) in the CVD group. Vascular FGF23 expression correlated with RUNX2 mRNA (r=0.315, P<0.05) and FGF23 immunoreactivity (r=0.254, P<0.05). Multiple regression analysis showed that iFGF23 levels were determined by UAE, HDL, FGe, calcium and TNFα levels (adjusted R2= 0.473, P<0.0001) and that vascular FGF23 mRNA expression was determined by TNFα, PCR, glucose and age (adjusted R2= 0.795, P<0.0001). Multivariate logistic regression, with VC as dependent variable, showed that both iFGF23 and vascular mRNA constitute independent risk factors for the existence of VC [OR (95% CI): 1.05 and 1.12, P<0.05 for both]. Conclusion Patients with atherosclerosis and VC present significantly higher serum concentrations of FGF23, as well as higher immunoreactivity and gene expression levels in the vascular wall compared to patients without VC. Moreover, both serum and vascular mRNA levels of FGF23 are associated with the inflammatory status. Whether the increase in systemic and vascular FGF23 can directly promote or favor the calcifying process in the vascular bed is currently an issue under discussion.

Calcium and phosphate homeostasis in dogs with newly diagnosed naturally occurring hypercortisolism

BackgroundHypercortisolism affects calcium and phosphate metabolism in dogs; however, the exact mechanisms are not completely understood.ObjectivesTo evaluate circulating concentrations of whole parathormone (wPTH), 25‐hydroxyvitamin D (25‐(OH)D), calcitriol, and fibroblast growth factor‐23 (FGF‐23) in dogs with naturally occurring hypercortisolism (NOHC) and healthy dogs, and their association with calcium and phosphate homeostasis.AnimalsTwenty‐three client‐owned dogs with NOHC, and 12 client or staff‐owned healthy dogs.MethodsProspective cross‐sectional study. The circulating concentrations of total calcium, ionized calcium (iCa), phosphate, wPTH, 25‐(OH)D, calcitriol and FGF‐23, and the urinary fractional excretion of phosphate (FEP) and calcium (FECa) were compared between dogs with NOHC before treatment and healthy dogs.ResultsDogs with NOHC had higher mean serum phosphate concentrations (4.81 mg/dL, SD ± 0.71 vs 3.86 mg/dL, SD ± 0.60; P < .001), median FECa (0.43%, range, 0.03‐2.44 vs 0.15%, range, 0.06‐0.35; P = .005), and median serum wPTH concentrations (54.6 pg/mL, range, 23.7‐490 vs 24.6 pg/mL, range, 5.5‐56.4; P = .003) as compared to the controls. Circulating concentrations of total calcium, iCa, and calcitriol and the FEP did not differ between groups, whereas the serum 25‐(OH)D concentrations were lower in dogs with NOHC as compared to the controls (70.2 pg/mL, SD ± 42.3 vs 106.3 pg/mL, SD ± 35.3; P = .02). The dogs with NOHC had lower plasma FGF‐23 concentrations than controls (316.6 pg/mL, range, 120.8‐575.6 vs 448.7 pg/mL, range, 244.8‐753; P = .03).Conclusions and Clinical ImportanceUrine loss of calcium and hyperphosphatemia could contribute to the adrenal secondary hyperparathyroidism.

The effect of vitamin D supplementation on fibroblast growth factor-23 in patients with chronic kidney disease: A systematic review and meta-analysis.

This is a meta-analysis of randomized controlled trials (RCTs) investigating the effects of oral vitamin D supplementation on serum fibroblast growth factor-23 (FGF23) concentrations in patients with chronic kidney disease (CKD). Manuscripts were extracted from PubMed/MEDLINE, Scopus, and ISI Web of Science through February 2020. Subgroup analyses, sensitivity analysis, and meta-regression assessments were performed. A total of eight clinical trials with nine treatment arms were included in the final analysis. The pooled results showed no significant changes in circulating FGF23 following vitamin D supplementation compared to the control group (Standardized mean difference (SMD): 0.24; 95% confidence intervals (CIs): -0.03 to 0.50, p > 0.05). Subgroup analyses found that studies which had participants with a body mass index (BMI) higher than 25 kg/m2 , with an intervention duration shorter than 15 weeks, using phosphate binder medications, and trials that were on both patients with CKD undergoing hemodialysis and patients without hemodialysis treatment produced significant increases in FGF23 when concentration compared with the control group. This meta-analysis provides evidence that vitamin D supplementation does not have a significant effect on plasma FGF23 levels. However, further high-quality trials are required to identify the influence of oral vitamin D supplementation on FGF23 levels in patients with CKD.

Serum fibroblast growth factor 23 (FGF-23): associations with hyperphosphatemia and clinical staging of feline chronic kidney disease

Fibroblast growth factor 23 (FGF-23) is an independent monitor of the progression of chronic kidney disease (CKD) in human medicine, and FGF-23 may have value as a biomarker in feline CKD. We evaluated the relationship between serum FGF-23 and CKD stages, and the effect of age on FGF-23 in normal cats. We measured FGF-23 and intact parathyroid hormone (iPTH) concentrations by ELISA, with intra- and inter-assay CVs ≤ 15%. The percentage recovery of FGF-23 and iPTH remained stable for up to 7 d in samples stored at -20°C and -80°C. We measured FGF-23 in 304 cats, among which 196 were diagnosed with CKD. The 108 clinically healthy cats were divided into 5 subgroups based on growth stage (0-2 y, 3-6 y, 7-10 y, 11-14 y, ≥ 15 y). No statistical difference was found in FGF-23 among age groups (p = 0.15) or by sex in healthy subjects. Using the International Renal Interest Society guideline, 34 cats were defined as CKD stage 1, 74 stage 2, 51 stage 3, and 37 stage 4. FGF-23 was higher in cats in all CKD stages than in controls. Higher serum phosphorus was observed in stage 3 (p = 0.04) and 4 (p < 0.01) compared to controls. iPTH increased as CKD progressed. Pearson analysis indicated a positive linear relationship between FGF-23 and iPTH (control: r = 0.70, p < 0.01; CKD: r = 0.46, p = 0.02). FGF-23 may be a useful biomarker of feline CKD and may precede hyperphosphatemia in advanced feline CKD.

Quantification of fibroblast growth factor 23 and N-terminal pro-B-type natriuretic peptide to identify patients with atrial fibrillation using a high-throughput platform: A validation study.

Large-scale screening for atrial fibrillation (AF) requires reliable methods to identify at-risk populations. Using an experimental semi-quantitative biomarker assay, B-type natriuretic peptide (BNP) and fibroblast growth factor 23 (FGF23) were recently identified as the most suitable biomarkers for detecting AF in combination with simple morphometric parameters (age, sex, and body mass index [BMI]). In this study, we validated the AF model using standardised, high-throughput, high-sensitivity biomarker assays. For this study, 1,625 consecutive patients with either (1) diagnosed AF or (2) sinus rhythm with CHA2DS2-VASc score of 2 or more were recruited from a large teaching hospital in Birmingham, West Midlands, UK, between September 2014 and February 2018. Seven-day ambulatory ECG monitoring excluded silent AF. Patients with tachyarrhythmias apart from AF and incomplete cases were excluded. AF was diagnosed according to current clinical guidelines and confirmed by ECG. We developed a high-throughput, high-sensitivity assay for FGF23, quantified plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) and FGF23, and compared results to the previously used multibiomarker research assay. Data were fitted to the previously derived model, adjusting for differences in measurement platforms and known confounders (heart failure and chronic kidney disease). In 1,084 patients (46% with AF; median [Q1, Q3] age 70 [60, 78] years, median [Q1, Q3] BMI 28.8 [25.1, 32.8] kg/m2, 59% males), patients with AF had higher concentrations of NT-proBNP (median [Q1, Q3] per 100 pg/ml: with AF 12.00 [4.19, 30.15], without AF 4.25 [1.17, 15.70]; p < 0.001) and FGF23 (median [Q1, Q3] per 100 pg/ml: with AF 1.93 [1.30, 4.16], without AF 1.55 [1.04, 2.62]; p < 0.001). Univariate associations remained after adjusting for heart failure and estimated glomerular filtration rate, known confounders of NT-proBNP and FGF23. The fitted model yielded a C-statistic of 0.688 (95% CI 0.656, 0.719), almost identical to that of the derived model (C-statistic 0.691; 95% CI 0.638, 0.744). The key limitation is that this validation was performed in a cohort that is very similar demographically to the one used in model development, calling for further external validation. Age, sex, and BMI combined with elevated NT-proBNP and elevated FGF23, quantified on a high-throughput platform, reliably identify patients with AF. Registry IRAS ID 97753 Health Research Authority (HRA), United Kingdom.

Glucocorticoids dexamethasone and prednisolone suppress fibroblast growth factor 23 (FGF23)

Fibroblast growth factor 23 (FGF23) is a hormone mainly secreted by bone cells. Its most prominent effects are the regulation of renal phosphate reabsorption and calcitriol (active vitamin D, 1,25(OH)2D3) formation, effects dependent on its co-receptor αKlotho. Besides these actions, further paracrine and endocrine effects exist. The production of FGF23 is regulated by 1,25(OH)2D3, parathyroid hormone, dietary phosphate intake, iron status, as well as inflammation. Glucocorticoids are hormones with anti-inflammatory properties and are, therefore, widely used for acute and chronic inflammatory diseases, autoimmune disorders, and malignancies. The present study explored whether glucocorticoids influence the production of FGF23 in vitro as well as in mice. Fgf23 transcription was analyzed by semi-quantitative real-time PCR. Serum concentrations of FGF23 and 1,25(OH)2D3 were measured by ELISA. Urinary phosphate and Ca2+ excretion were determined in metabolic cages. As a result, in UMR106 rat osteoblast-like cells and in MC3T3-E1 cells, both, dexamethasone and prednisolone, downregulated Fgf23 transcription and FGF23 protein synthesis. Dexamethasone increased Dmp1 and Phex (encoding FGF23-regulating genes) as well as Nfkbia (encoding NFκB inhibitor IκBα) transcription in UMR106 cells. In mice, a single injection of dexamethasone or prednisolone was followed by a significant decrease of serum C-terminal and intact FGF23 concentration and bone Fgf23 mRNA expression within 12 h. These effects were paralleled by increased renal phosphate excretion and enhanced 1,25(OH)2D3 formation. We conclude that a single glucocorticoid treatment strongly downregulates the FGF23 plasma concentration.Key messagesGlucocorticoids dexamethasone and prednisolone suppress the formation of bone-derived hormone fibroblast growth factor 23 (FGF23) in vitro.The effect is accompanied by an upregulation of Dmp1, Phex, and IκBα, negative regulators of FGF23, in UMR106 osteoblast-like cells.Glucocorticoid receptor antagonist RU-486 attenuates the effect of dexamethasone on FGF23, Dmp1, and Phex.In mice, a single glucocorticoid dose suppresses FGF23 and enhances 1,25(OH)2D3 (active vitamin D).

Decreased concentration of klotho and increased concentration of FGF23 in the cerebrospinal fluid of patients with narcolepsy

Objectiveto explore the status of concentration of klotho and fibroblast growth factor 23 (FGF23) in cerebrospinal fluid (CSF) of patients with narcolepsy. Patients/methods59 patients with narcolepsy and 17 control individuals were enrolled. We used radioimmunoassay, 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, Mann–Whitney U Test were 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 <110 pg/ml (HCRT-) and narcolepsy patients with CSF hypocretin-1 >110 pg/ml (HCRT+) versus control subjects. ResultsKlotho 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 FGF-23 levels in narcoleptic patients (5.51 versus 4.00 pg/mL; p = 0.001). Klotho and phosphorus CSF levels were lower in both HCRT- and HCRT+ than controls. Moreover, there were higher FGF-23 levels in both HCRT-/HCRT+ groups versus controls. However, we did not find differences comparing HCRT- and HCRT+ groups, analyzing CSF klotho, FGF-23 or phosphorus levels. ConclusionsPatients 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.

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.

Effects of calcifediol supplementation on markers of chronic kidney disease-mineral and bone disorder in dogs with chronic kidney disease.

BackgroundChronic kidney disease‐mineral and bone disorder (CKD‐MBD) in dogs is associated with hypovitaminosis D, increased parathyroid hormone (PTH), and increased fibroblast growth factor‐23 (FGF‐23) concentrations. Best practice for vitamin D metabolite supplementation in CKD‐MBD remains unknown.ObjectiveTo provide an extended‐release calcifediol supplement to dogs with CKD and to measure its effects on variables indicative of CKD‐MBD.AnimalsTen dogs with International Renal Interest Society stages 2 and 3 CKD.MethodsIn a prospective study, dogs received a calcifediol supplement for 84 days. Serum 25‐hydroxyvitamin D (25[OH]D), 1,25‐dihydroxyvitamin D (1,25[OH]2D), 24,25‐dihydroxyvitamin D (24,25[OH]2D), creatinine, calcium, phosphorus, PTH, plasma FGF‐23 concentrations, and urine profiles were measured monthly during supplementation. Urine calcium to creatinine (UCa/Cr) ratios and fractional excretion of calcium, phosphorus, and sodium were determined.ResultsAll serum vitamin D metabolite concentrations increased significantly by day 84 (P < .001): [25(OH)D (median 249.9 ng/mL; range, 149.7‐469.9 ng/mL) compared to baseline (median 50.2 ng/mL; range, 31.3‐66.0 ng/mL); 1,25(OH)2D (median 66.1 pg/mL; range, 56.9‐88.1 pg/mL) compared to baseline (median 37.3 pg/mL; range, 29.3‐56.7 pg/mL); 24,25(OH)2D (median 81.4 ng/mL; range, 22.1‐151.7 ng/mL) compared to baseline (median 15.4 ng/mL; range, 6.9‐40.6 ng/mL)]. There were no significant differences in calcium, phosphorus, PTH concentrations, UCa/Cr or fractional excretion of calcium. No dog developed ionized hypercalcemia. Plasma FGF‐23 concentrations increased by day 84 (median 1219 pg/mL; range, 229‐8824 pg/mL) compared to baseline (median 798 pg/mL; range, 103‐4.145 pg/mL) (P < .01).Conclusions and Clinical ImportanceCalcifediol supplementation for 84 days was well‐tolerated in dogs with IRIS stages 2 and 3 CKD. It remains to be determined how long‐term supplementation would affect CKD progression and QOL.

Interactions of Anemia, FGF-23, and Bone in Healthy Adults-Results From the Study of Health in Pomerania (SHIP).

Osteoporosis and anemia are among the most common diseases in the aging population with an increasing prevalence worldwide. As the bone-derived hormone fibroblast growth factor 23 (FGF-23) was recently reported to regulate erythropoiesis, we examined age-related associations between hemoglobin levels and bone quality, bone turnover, and FGF-23 concentrations. We used data from more than 5000 adult subjects who participated in the population-based cohorts of the Study of Health in Pomerania (SHIP and SHIP-Trend). Bone quality was assessed by quantitative ultrasound at the heel, bone turnover by measurement of carboxy-terminal telopeptide of type I collagen (CTX), and intact amino-terminal propeptide of type I procollagen (P1NP) serum concentrations, respectively. Anemia was defined as hemoglobin <13 g/dL in men and <12 g/dL in women. Carboxy-terminal FGF-23 levels were measured in plasma in a subset of 852 subjects. Anemic subjects had poorer bone quality, higher fracture risk, and lower serum levels of P1NP than nonanemic individuals. Linear regression models revealed positive associations between hemoglobin and bone quality in subjects aged 40 or above and inverse associations with CTX in subjects aged 60 or above. Hemoglobin and FGF-23 concentrations were inversely associated, while FGF-23 was not related to bone quality or turnover. Our data corroborate a close link between FGF-23 and anemia, which is related to poor bone quality in elderly people. We observed no direct association of FGF-23 with bone parameters. Further studies are needed clarifying the role of FGF-23 on bone and red blood cell production.

Fibroblast growth factor-23 as an early marker of CKD-mineral bone disorder in dogs: preliminary investigation.

To examine the relationship between fibroblast growth factor-23 levels, chronic kidney disease severity and mineral metabolic disorders associated to chronic kidney disease in dogs. Fifteen control and 75 chronic kidney disease dogs were retrospectively included. Serum fibroblast growth factor-23 concentration and other phosphate metabolite parameters were compared between controls and each International Renal Interest Society stage. Multiple regression analysis was performed to determine the predictors of fibroblast growth factor-23. Serum fibroblast growth factor-23 concentrations were significantly higher in dogs with IRIS stages 2, 3 and 4 chronic kidney disease than those in dogs in control group and with stage 1 and increased along with the severity of chronic kidney disease. Compared with control dogs, serum intact parathyroid hormone significantly increased from stage 2 and serum phosphorus concentrations increased in dogs with stage 4. In dogs with stage 2, fibroblast growth factor-23 levels significantly increased in those with hyperphosphatemia compared with those with normophosphatemia. While eight of 26 (30.8%) dogs with stage 2 developed hyperparathyroidism (intact parathyroid hormone>8.5ng/L), 19 (73.1%) dogs with stage 2 had elevated fibroblast growth factor-23 levels above the reference range (>528 pg/mL). Log creatinine, log intact parathyroid hormone and log product of total calcium and phosphorus were independent predictors of log fibroblast growth factor-23. This preliminary study suggests that canine fibroblast growth factor-23 might be involved in mineral metabolic disorders associated to chronic kidney disease in dogs, and this factor could be potentially used as an early marker for this condition.

Relationship between GFR, intact PTH, oxidized PTH, non‐oxidized PTH as well as FGF23 in patients with CKD

Fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) are regulators of renal phosphate excretion and vitamin D metabolism. In chronic kidney disease (CKD), circulating FGF23 and PTH concentrations progressively increase as renal function declines. Oxidation of PTH at two methionine residues (positions 8 and 18) causes a loss of function. The impact of n-oxPTH and oxPTH on FGF23 synthesis, however, and how n-oxPTH and oxPTH concentrations are affected by CKD, is yet unknown. The effects of oxidized and non-oxidized PTH 1-34 on Fgf23 gene expression were analyzed in UMR106 osteoblast-like cells. Furthermore, we investigated the relationship between n-oxPTH and oxPTH, respectively, with FGF23 in two independent patients' cohorts (620 children with CKD and 600 kidney transplant recipients). While n-oxPTH stimulated Fgf23 mRNA synthesis in vitro, oxidation of PTH in particular at Met8 led to a markedly weaker stimulation of Fgf23. The effect was even stronger when both Met8 and Met18 were oxidized. In both clinical cohorts, n-oxPTH-but not oxPTH-was significantly associated with FGF23 concentrations, independent of known confounding factors. Moreover, with progressive deterioration of kidney function, intact PTH (iPTH) and oxPTH increased substantially, whereas n-oxPTH increased only moderately. In conclusion, n-oxPTH, but not oxPTH, stimulates Fgf23 gene expression. The increase in PTH with decreasing GFR is mainly due to an increase in oxPTH in more advanced stages of CKD.

Intact and C-Terminal FGF23 Assays-Do Kidney Function, Inflammation, and Low Iron Influence Relationships With Outcomes?

Higher fibroblast growth factor-23 (FGF23) concentrations are associated with heart failure and mortality in diverse populations, but the strengths of associations differ markedly depending up on which assay is used. We sought to evaluate whether iron deficiency, inflammation, or kidney function account for differences in the strengths of associations between these 2 FGF23 assays with clinical outcomes. Case cohort study from the Cardiovascular Health Study. A total of 844 community-dwelling individuals aged 65 years or older with and without chronic kidney disease were followed for 10 years. Outcomes included death, incident heart failure (HF), and incident myocardial infarction (MI). Exposure was baseline intact and C-terminal FGF23. Using modified Cox models, adjusting sequentially we tested whether observed associations of each assay with outcomes were attenuated by iron status, inflammation, kidney function, or their combinations. FGF23 measured by either assay was associated with mortality in unadjusted analysis (intact FGF23 hazard ratio [HR] per 2-fold higher 1.45; 95% CI, 1.25-1.68; C-terminal FGF23 HR 1.38; 95% CI, 1.26-1.50). Adjustment for kidney function completely attenuated associations of intact FGF23 with mortality (HR 1.00; 95% CI, 0.85-1.17), but had much less influence on the association of C-terminal FGF23, for which results remained significant after adjustment (HR 1.15; 95% CI, 1.04-1.28). Attenuation was much less with adjustment for iron status or inflammation. Results were similar for the HF end point. Neither C-terminal or intact FGF23 was associated with MI risk. The relationship of FGF23 with clinical end points is markedly different depending on the type of FGF23 assay used. The associations of biologically active FGF23 with clinical end points may be confounded by kidney disease, and thus much weaker than previously thought.

Fibroblast growth factor 23 concentrations and modifying factors in children from age 12 to 24months.

Fibroblast growth factor 23 (FGF23) participates in phosphate, calcium and vitamin D metabolism. In children these interactions and modifying factors are largely unknown. This study evaluates temporal changes and modifiers of FGF23 concentrations from 12 to 24months, in healthy children, participating in a randomized vitamin D intervention (VIDI). Participants received vitamin D3 of 10 or 30μg/day from age 2weeks to 24months. At 12 and 24months, growth measurements and venous blood samples were obtained for analyses of intact (iFGF23) and C-terminal FGF23 (cFGF23), 25-hydroxyvitamin D (25-OHD), calcium, phosphate, parathyroid hormone, iron and ferritin. Changes in FGF23 and modifying factors were examined by linear mixed models. The study included 594 infants. Girls had higher iFGF23 than boys (p<0.001 for both 12 and 24months), cFGF23 did not differ between the sexes. Adjusted mean iFGF23 decreased from 41.4 to 38.1pg/mL in boys (p<0.001) and from 45.2 to 42.5pg/mL in girls (p=0.002). Adjusted mean cFGF23 decreased from 2.89 to 2.00pmol/L in boys (p<0.001) and from 2.92 to 1.93pmol/L in girls (p<0.001). Iron modified FGF23 in both sexes, associating positively with iFGF23 and inversely with cFGF23. In girls, 25-OHD modified iFGF23. In boys, season modified FGF23, possibly through seasonal differences in 25-OHD. Vitamin D intervention dose did not affect FGF23. FGF23 decreases from 12 to 24months. Girls have higher iFGF23 than boys, at both time points. Iron modifies FGF23 in both sexes.

Supplemental Nicotinamide Dose-Dependently Regulates Body Phosphorus Excretion via Altering Type II Sodium-Phosphate Co-Transporter Expressions in Laying Hens

Dietary supplemental nicotinamide is used to treat hyperphosphatemia in humans. However, the mechanisms of its impact on body phosphorus homeostasis remain unclear. This study was to determine effects and molecular mechanisms of 3 dietary nicotinamide concentrations on body phosphorus homeostasis in laying hens. Hy-Line Brown layers (total=21; 40 wk old; body weight: 1,876±24g) were individually housed (n=7) and fed a corn-soybean meal-based diet supplemented with nicotinamide at 20 (N20), 140 (N140), and 1000 (N1000) mg/kg for 21 d. Serum phosphorus and fibroblast growth factor 23 (FGF23) concentrations, phosphorus and calcium excretion, and mRNA and/or protein of type II sodium-phosphate co-transporters (NPt2a, NPt2ab) and FGF23 and FGF23 receptors were measured in the intestines, calvaria, kidney, and liver. Hens in the N1000 group had a 16% lower serum phosphorus concentration and 22% greater phosphorus excretion than those in the N20 or N140 group (P≤0.05). Compared with hens in the N20 group, hens in the N140 and N1000 groups, which did not differ, had 15-21% lower serum FGF23 concentrations, 19-22% greater calcium excretion, 43-56% lower ileum NPT2b protein production, and 1.5- to 1.6-fold greater kidney NPT2a protein production, respectively (all differences at P≤0.05). Supplementing high concentrations of nicotinamide in diets for laying hens led to accelerated phosphorus and calcium excretions and decreased serum phosphorus and FGF23 concentrations, which were associated with downregulated intestinal NPt2b protein production. Our findings exclude kidney NPt2a protein production as a primary mechanism for the nicotinamide-induced body phosphorus loss.