Serum Fibroblast Growth Factor 23 Concentrations Research Articles

FGF23 in kidney transplant: the strange case of Doctor Jekyll and Mister Hyde.

During the last decade, a new view into the molecular mechanisms of chronic kidney disease-mineral bone disorder (CKD-MBD) has been proposed, with fibroblast growth factor 23 (FGF23) as a novel player in the field. Enhanced serum FGF23 levels cause a reduction in serum phosphate, together with calcitriol suppression and consequent hyperparathyroidism (HPT). In contrast, reduced serum FGF23 levels are associated with hyperphosphatemia, higher calcitriol levels and parathyroid hormone (PTH) suppression. In addition, serum FGF23 levels are greatly increased and positively correlated with serum phosphate levels in CKD patients. In this population, high serum FGF23 concentration seems to predict the occurrence of refractory secondary HPT and to be associated with higher mortality risk in incident haemodialysis patients. In living-donor kidney transplant recipients, a faster normalization of FGF23 and phosphate levels with a lower prevalence of HPT, may be considered a major pathway to investigate.

Phosphate Binding Therapy to Lower Serum Fibroblast-Growth-Factor-23 Concentrations in Chronic Kidney Disease: Rationale and Study Design of the Sevelamer on FGF23 Trial (SoFT)

Background: Increased levels of phosphate and fibroblast growth factor-23 (FGF23) are strong predictors of cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). Preliminary data suggest that interventions lowering gastro-intestinal phosphate uptake lowers serum FGF23 concentrations and improves cardiovascular risk and subsequently survival. However, data are lacking about the magnitude of effects, the effect in different stages of CKD and whether there is a dose-effect relationship. Methods: Therefore, the Sevelamer on FGF23 Trial (SoFT) is designed as an open-label, single-arm, clinical pilot study aiming to demonstrate the feasibility of a phosphate-restricted diet in combination with the phosphate binder sevelamer to induce an effective, predictable and sustained decrease in FGF23 level in patients with an estimated glomerular filtration rate (eGFR) of 15-90 or >90 ml/min/1.73 m² with proteinuria >1.0 g in 24 h urine collection, despite optimally dosed RAAS blockade, without inducing hypophosphatemia using a forced uptitration treatment regimen aimed at restricting phosphate uptake.

Fibroblast Growth Factor-23 and Frailty in Elderly Community-Dwelling Individuals: The Cardiovascular Health Study.

To evaluate whether fibroblast growth factor 23 (FGF-23) is related to frailty and to characterize the nature of their joint association with mortality. Cross-sectional analysis for frailty and longitudinal cohort analysis for mortality. Cardiovascular Health Study. Community-dwelling individuals (N = 2,977; mean age 77.9 ± 4.7, 40% male, 83% white). The predictor was serum FGF-23 concentration (C-terminal enzyme-linked immunosorbent assay), and the outcomes were frailty status (determined according to frailty phenotype criteria of weight loss, weakness, exhaustion, slowness, and low physical activity) and mortality. Multinomial logistic regression was used to assess the cross-sectional association between FGF-23 and frailty and prefrailty, adjusting for demographic characteristics, cardiovascular disease and risk factors, and kidney markers. Proportional hazards Cox proportional hazards regression was used to assess the association between FGF-23, frailty, and all-cause mortality. Mean estimated glomerular filtration rate (eGFR) was 64 ± 17 mL/min per 1.73 m(2) . Median FGF-23 was 70.3 RU/mL (interquartile range 53.4-99.2); 52% were prefrail, and 13% were frail. After multivariate adjustment, each doubling in FGF-23 concentration was associated with 38% (95% confidence interval (CI) = 17-62%) higher odds of frailty than of nonfrailty and 16% (95% CI = 3-30%) higher odds of prefrailty. FGF-23 (hazard ratio (HR) = 1.16, 95% CI = 1.10-1.23) and frailty (HR = 1.82, 95% CI = 1.57-2.12) were independently associated with mortality, but neither association was meaningfully attenuated when adjusted for the other. In a large cohort of older adults, higher FGF-23 was independently associated with prevalent frailty and prefrailty. FGF-23 and frailty were independent and additive risk factors for mortality. FGF-23 may be a marker for functional outcomes.

Fibroblast growth factor-23 and phosphorus related factors in young Japanese women: a cross-sectional study.

Phosphorus homeostasis is determined by dietary intake, intestinal absorption, and renal tubular reabsorption of phosphorus. Serum fibroblast growth factor-23 (FGF-23) is considered to be a sensitive early biomarker of disordered phosphorus metabolism in both patients with chronic kidney diseases and healthy subjects. However, the number of studies evaluating serum FGF-23 concentrations in healthy subjects is limited. The objective of this cross-sectional study was to examine the relationship between serum FGF-23 concentrations and phosphorus related factors in 182 young Japanese women (mean age, 19.5±0.4 years). We found that higher serum concentrations of inorganic phosphorus and lower serum concentrations of 1,25-dihydroxy vitamin D as well as lower fat but higher phosphorus and calcium intake were weakly but significantly associated with high serum concentrations of FGF-23, adjusted for postmenarcheal age and body weight. These results suggested that in young Japanese women, serum FGF-23 might be indicative of phosphorus nutrition status. However, it is worthy of note that maturity factors, including postmenarcheal age and physical attributes, such as body weight, might be related to serum FGF-23 concentrations.

Serum Fibroblast Growth Factor 23 (FGF23) in Patients with Rheumatoid Arthritis.

Objective Rheumatoid arthritis (RA) is a chronic inflammatory disease accompanied by periarticular and systemic osteoporosis. Fibroblast growth factor 23 (FGF23), which is mainly produced by osteocytes, circulates to the kidneys and regulates bone metabolism. We herein assessed serum FGF23 and its relationship to inflammation and osteoporosis in patients with RA. Methods Sixty-one patients with RA were included. Serum concentrations of FGF23 were determined using a sandwich enzyme-linked immunosorbent assay. Results The mean (± standard deviation) serum FGF23 concentration was 34.9±9.2 (range, 21.0-61.0) pg/mL. The serum FGF23 level was significantly and positively correlated with the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels, disease activity score-28 based on the ESR (DAS-28 ESR) and DAS-28 CRP (r=0.261, p=0.044, r=0.280, p=0.029, r=0.409, p=0.001 and r=0.421, p=0.001, respectively). The serum matrix metalloproteinase-3 level was also significantly and positively correlated with the serum FGF23 level (r=0.331, p=0.015). Concentrations of type I collagen cross-linked N-telopeptide in the serum was significantly correlated with the serum FGF23 level (r=0.272, p=0.034). Neither the bone mineral density in the femoral neck nor lumbar was significantly correlated with the serum FGF23 level. Serum phosphate, calcium, 25-hydroxy vitamin D, and intact parathyroid hormone were not related to the serum FGF23 level. Conclusion In patients with RA, serum FGF23 is correlated with inflammation, the disease activity of RA, and bone absorption markers. Serum FGF23 may be associated with abnormal bone absorption related to RA inflammation. Further studies are necessary to clarify the mechanism underlying this association.

SERUM LEVELS OF FIBROBLAST GROWTH FACTOR 21 IN TYPE 2 DIABETIC PATIENTS.

Fibroblast growth factor 21 (FGF21) has recently been identified as a metabolic regulator, but its physiological role is still not completely known. The aim of this study was to evaluate serum FGF21 levels in an Iranian population with type 2 diabetes. This cross-sectional study was conducted in patients with type 2 diabetes. All patients were evaluated for fasting serum levels of glucose, glycated hemoglobin (HbA1c), lipids, urea and creatinine. Participants were divided into two groups with poorly-controlled and well-controlled diabetes based on their HbA1c levels. Healthy non-diabetic subjects (matched with patients in terms of age, sex and body mass index [BMI]) were also recruited as control group. Serum FGF21 concentrations were determined in all subjects using ELISA. Of the evaluated 141 subjects, 49 (34.8%) were categorized as having well-controlled diabetes, 66 (46.8%) had poorly-controlled diabetes, and there were 26 subjects in the normal control group. Mean serum FGF-21 concentration was 337.89±283.67 ng/L in the diabetic group and 237.25±43.22 ng/mL in the non-diabetic group (p<0.001). Mean serum FGF21 level was 237.25 ± 43.22 ng/mL in the control group, 309.81 ± 301.68 ng/mL in the well-controlled diabetic group, and 358.73 ± 269.98 ng/mL in the poorly controlled diabetic group. Serum FGF21 level in the poorly controlled diabetic group was significantly higher than that in the well-controlled diabetic and the healthy control groups (p=0.02) but there was no significant difference between the well-controlled and healthy groups. There was no significant association between serum FGF21 levels with lipid levels, presence of diabetic complications and BMI (p > 0.05). The present results suggested an association between elevated serum levels of FGF21 and poor control of diabetes. Future studies are warranted to elucidate the prognostic role of these elevated levels of FGF21 in diabetic subjects.

The serum level of the morphogenetic protein fibroblast growth factor 23 (FGF-23) as a marker for the efficiency of hyperphosphatemia therapy with phosphate-binding agents in chronic kidney disease

To study whether the excessive production of serum fibroblast growth factor 23 (FGF-23) may be reduced with phosphate-binding agents to treat hyperphosphatemia in patients with Stage VD chronic kidney disease (CKD). The investigation enrolled 25 patients with Stage VD CKD on regular hemodialysis (HD) (12 patients with chronic glomerulonephritis, 8 with tubulointerstitial nephritis, and 5 with hypertensive nephrosclerosis); among them there were 15 men and 10 women at the age of 21 to 65 years; their mean age at inclusion in the study was 43±4.5 years. The clinical, laboratory, and instrumental examination similar to that in patients with the early stages of CKD was done. Serum FGF-23 levels (Human FGF-23 ELISA kit using monoclonal antibodies to the full FGF-23 molecule) were investigated in all the 25 patients. A whole blood sample was taken 2 days after the last session of HD before initiation of its regular procedure. The elevated serum FGF-23 concentrations in the patients on regular HD correlated with their HD duration (r=0.508; p<0.001). Along with this, a strong direct correlation (r=0.522; p<0.001) was found between the concentration of FGF-23 in the serum and inorganic phosphorus; at the same time hyperphosphatemia was less significantly associated with higher serum intact parathyroid hormone (PTH) levels (r=0.398; p<0.05). Lower FGF-23 and PHT levels were noted in a group of patients who could achieve and maintain the target serum inorganic phosphorus level (0.9-1.45 mmol/l) compared to that of patients with uncorrected hyperphosphatemia (>1.45 mmol/l) (p<0.01). A decrease in FGF-23 and PHT levels was achieved chiefly in the patients who had used phosphate-binders that contained no calcium (sevelamer hydrochloride). Lower FGF-23 levels were observed in the patients with CHD on regular HD who can achieve and maintain the target serum inorganic phosphorus level when using phosphate-binders that do not contain calcium than in those with uncorrected hyperphosphatemia (p<0.01).

Administration of Ferric Citrate Hydrate Decreases Circulating FGF23 Levels Independently of Serum Phosphate Levels in Hemodialysis Patients with Iron Deficiency

Background/Aim: Dietary phosphate intake and vitamin D receptor activator (VDRA) regulate fibroblast growth factor 23 (FGF23); iron may modulate FGF23 metabolism. We aimed to determine whether oral iron supplementation influences serum FGF23 concentration in hemodialysis (HD) patients, while excluding the effect of dietary phosphate intake. Methods: This prospective study enrolled 27 maintenance HD patients with iron deficiency and hyperphosphatemia treated with sevelamer-HCl. The phosphate binder was changed from sevelamer-HCl to ferric citrate hydrate (FCH) to maintain constant phosphate levels. VDRA, other phosphate binders, and cinacalcet HCl were not changed. Serum intact FGF23, C-terminal FGF23 (C-term FGF23), intact parathyroid hormone (PTH), 1,25(OH)₂D and other parameters were monitored for 12 weeks. Results: Serum phosphate levels (5.89 ± 1.45 mg/dl at baseline, 5.54 ± 1.35 mg/dl at 12 weeks) and 1,25(OH)₂D levels were unchanged. Serum ferritin levels increased from 25.6 ± 24.3 ng/ml at baseline to 55.8 ± 33.5 ng/ml at 12 weeks with FCH administration. Serum intact FGF23 and C-term FGF23 levels significantly decreased at 12 weeks compared with baseline (2,000 (1,300.0-3,471.4) to 1,771.4 (1,142.9-2,342.9) pg/ml, p = 0.01, and 1,608.7 (634.8-2,308.7) to 1,165.2 (626.1-1,547.8) RU/ml, p = 0.007, respectively); serum intact PTH levels significantly increased (96 (65-125) to 173 (114-283) pg/ml, p < 0.001). Conclusions: Oral FCH administration decreased serum intact FGF23 and C-term FGF23 levels and increased intact PTH levels; phosphate and 1,25(OH)₂D levels were unchanged. Oral FCH administration to treat iron deficiency is a possible strategy for reducing serum FGF23 levels independent of phosphate and VDRA.

The relationship between Fibroblast Growth Factor-21 and characteristic parameters related to energy balance in dairy cows.

BackgroundNegative energy balance (NEB) is a common pathological foundation of ketosis and fatty liver. Liver and fat tissue are the major organs of lipid metabolism and take part in modulating lipid oxidative capacity and energy demands, which is also a key metabolic pathway that regulates NEB develop during perinatal period. Fibroblast growth factor-21 (FGF-21) is a recently discovered protein hormone that plays an important and specific regulating role in adipose lipid metabolism and liver gluconeogenesis for human and mouse. Our aim is to investigate the variation and relationship between serum FGF-21 concentration and characteristic parameters related to negative energy balance in different energy metabolism state.MethodsIn this research, five non-pregnant, non-lactating Holstein–Friesian dairy cows were randomly allocated into two groups. The interventions were a controlled-energy diet (30 % of maintenance energy requirements) and a moderate-energy diet (120 % of predicted energy requirements) that lasted for the duration of the experiment. We measured biochemical parameters, serum FGF-21, leptin and insulin levels by commercial ELISA kits.ResultsThe results showed that serum FGF-21 levels were significantly higher in both groups treated with a controlled-energy diet, while FGF-21 levels in both groups treated with moderate-energy diet were low. FGF-21 levels exhibited a significant positive correlation with serum leptin levels, while an inverse relationship was found between FGF-21 and blood glucose and β-hydroxybutyrate acid (BHBA) levels.ConclusionAn increase in FGF-21 levels after a controlled-energy diet treatment may contribute to a positive metabolic effect which could result in a new theoretical and practical basis for the preventive strategy of dairy cows with NEB.

Alterations in Hepatic FGF21, Co-Regulated Genes, and Upstream Metabolic Genes in Response to Nutrition, Ketosis and Inflammation in Peripartal Holstein Cows.

In rodents, fibroblast growth factor 21 (FGF21) has emerged as a key metabolic regulator produced by liver. To gather preliminary data on the potential importance of FGF1, co-regulated genes, and upstream metabolic genes, we examined the hepatic mRNA expression in response to nutrition and inflammation in dairy cows. In experiment 1, induction of ketosis through feed restriction on d 5 postpartum upregulated FGF21, its co-receptor KLB, and PPARA but only elicited a numerical increase in serum FGF21 concentration. In experiment 2, cows in control (CON) or receiving 50 g/d of L-carnitine (C50) from -14 through 21 d had increased FGF21, PPARA, and NFIL3 on d 10 compared with d 2 postpartum. In contrast, compared with CON and C50, 100 g/d L-carnitine (C100) resulted in lower FGF21, KLB, ANGPTL4, and ARNTL expression on d 10. In experiment 3, cows were fed during the dry period either a higher-energy (OVE; 1.62 Mcal/kg DM) or lower-energy (CON; 1.34 Mcal/kg DM) diet and received 0 (OVE:N, CON:N) or 200 μg of LPS (OVE:Y, CON:Y) into the mammary gland at d 7 postpartum. For FGF21 mRNA expression in CON, the LPS challenge (CON:Y) prevented a decrease in expression between d 7 and 14 postpartum such that cows in CON:N had a 4-fold lower expression on d 14 compared with d 7. The inflammatory stimulus induced by LPS in CON:Y resulted in upregulation of PPARA on d 14 to a similar level as cows in OVE:N. In OVE:Y, expression of PPARA was lower than CON:N on d 7 and remained unchanged on d 14. On d 7, LPS led to a 4-fold greater serum FGF21 only in OVE but not in CON cows. In fact, OVE:Y reached the same serum FGF21 concentration as CON:N, suggesting a carryover effect of dietary energy level on signaling mechanisms within liver. Overall, results indicate that nutrition, ketosis, and inflammation during the peripartal period can alter hepatic FGF21, co-regulated genes, and upstream metabolic genes to various extents. The functional outcome of these changes merits further study, and in particular the mechanisms regulating transcription in response to changes in energy balance and feed intake.

Altered Calcium and Vitamin D Homeostasis in First-Time Calcium Kidney Stone-Formers.

BackgroundElevated serum 1,25-dihydroxyvitamin D (1,25(OH)2D) concentrations have been reported among cohorts of recurrent calcium (Ca) kidney stone-formers and implicated in the pathogenesis of hypercalciuria. Variations in Ca and vitamin D metabolism, and excretion of urinary solutes among first-time male and female Ca stone-formers in the community, however, have not been defined.MethodsIn a 4-year community-based study we measured serum Ca, phosphorus (P), 25-hydroxyvitamin D (25(OH)D), 1,25(OH)2D, 24,25-dihydroxyvitamin D (24,25(OH)2D), parathyroid hormone (PTH), and fibroblast growth factor-23 (FGF-23) concentrations in first-time Ca stone-formers and age- and gender frequency-matched controls.ResultsSerum Ca and 1,25(OH)2D were increased in Ca stone-formers compared to controls (P = 0.01 and P = 0.001). Stone-formers had a lower serum 24,25(OH)2D/25(OH)D ratio compared to controls (P = 0.008). Serum PTH and FGF-23 concentrations were similar in the groups. Urine Ca excretion was similar in the two groups (P = 0.82). In controls, positive associations between serum 25(OH)D and 24,25(OH)2D, FGF-23 and fractional phosphate excretion, and negative associations between serum Ca and PTH, and FGF-23 and 1,25(OH)2D were observed. In SF associations between FGF-23 and fractional phosphate excretion, and FGF-23 and 1,25(OH)2D, were not observed. 1,25(OH)2D concentrations associated more weakly with FGF-23 in SF compared with C (P <0.05).ConclusionsQuantitative differences in serum Ca and 1,25(OH)2D and reductions in 24-hydroxylation of vitamin D metabolites are present in first-time SF and might contribute to first-time stone risk.

FGF21 Response to Critical Illness: Effect of Blood Glucose Control and Relation With Cellular Stress and Survival.

Critical illness is hallmarked by mitochondrial damage, which is attenuated by targeting normoglycemia. Mitochondrial dysfunction induces fibroblast growth factor-21 (FGF21) via the integrated stress response (ISR). We evaluated whether critical illness elevates serum FGF21 concentrations and whether targeting normoglycemia (80-110 mg/dL) with insulin vs tolerating hyperglycemia may lower serum FGF21 by attenuating mitochondrial dysfunction and the ISR. We quantified serum FGF21 concentrations in critically ill patients. To allow tissue analyses, including hepatic fgf21 expression in relation with mitochondrial function and ISR markers, we studied critically ill rabbits. Patients and rabbits were randomized to hyper- or normoglycemia. Patients/Other Participants: We studied 405 fed critically ill patients vs 20 matched non-critically ill control subjects as well as 26 critically ill rabbits vs 13 healthy rabbits. Insulin was infused to control blood glucose. Serum FGF21 concentrations upon intensive care unit admission were 8-fold higher than in control subjects (P < .0001), decreased with time, but always remained higher in nonsurvivors than survivors (P ≤ .006). Maintaining normoglycemia lowered serum FGF21 (P = .01), statistically explaining at least part of its mortality benefit. In ill rabbits, hepatic fgf21 expression was substantially increased (P < .0001) and was tightly correlated with mitochondrial dysfunction (all R(2) ≥ 0.49; all P ≤ .0006 for complex I and V) and ISR markers on day 3 (R(2) ≥ 0.73; P ≤ .0001), all lowered by targeting normoglycemia. Critical illness is a potent inducer of serum FGF21 and of liver fgf21 expression, possibly driven at least in part by mitochondrial damage and the ISR, which were all attenuated by targeting normoglycemia.

Fish Oil Supplements Lower Serum Lipids and Glucose in Correlation with a Reduction in Plasma Fibroblast Growth Factor 21 and Prostaglandin E2 in Nonalcoholic Fatty Liver Disease Associated with Hyperlipidemia: A Randomized Clinical Trial.

Fish oil has been used effectively in the treatment of cardiovascular disease via triglyceride reduction and inflammation modulation. This study aimed to assess the effects of fish oil on patients with nonalcoholic fatty liver disease (NAFLD) associated with hyperlipidemia. Eighty participants with NAFLD associated with hyperlipidemia were randomly assigned to consume fish oil (n=40, 4 g/d) or corn oil capsules (n=40, 4 g/d) for 3 months in a double-blind, randomized clinical trial. Blood levels of lipids, glucose and insulin, liver enzymes, kidney parameters and cytokines at baseline and the end of the study were measured. Seventy people finished the trial. Plasma concentrations of eicosapentaenoic acid and docosahexaenoic acid significantly increased in the fish oil group after intervention. After adjustment for age, gender and BMI, fish oil significantly decreased fasting serum concentrations of total cholesterol, triglyceride, apolipoprotein B and glucose (by (mean±SD) 0.49±0.43 mmol/L, 0.58±0.89 mmol/L, 0.28±0.33 g/L and 0.76±0.56 mmol/L, respectively, P<0.05), as well as alanine aminotransferase and γ-glutamyl transpeptidase levels (by (median (interquartile)) 9.0(0.5, 21.5) and 7.0(2.2, 20.0) IU/L, respectively, P<0.05), significantly increased serum adiponectin levels (by 1.29±0.62 μg/mL, P<0.001), and reduced serum levels of tumor necrosis factor α, leukotrienes B4, fibroblast growth factor 21 (FGF21), cytokeratin 18 fragment M30 and prostaglandin E2 (by 1.70±1.18 pg/mL, 0.59±0.28 ng/mL, 121±31 pg/mL, 83±60 IU/L and 10.9±2.3 pg/mL, respectively, P<0.001). Corn oil had no effect except for increasing serum creatinine concentrations by 7.7±8.9 μmol/L (P=0.008). The effects of fish oil on lipids, glucose and γ-glutamyl transpeptidase were positively correlated with the reductions of serum FGF21 and prostaglandin E2 concentrations after adjustment for age, gender and BMI (r = 0.275 to 0.360 and 0.261 to 0.375, respectively, P<0.05). In conclusion, our findings suggest that fish oil can benefit metabolic abnormalities associated with NAFLD treatment.Trial Registration ChiCTR-TRC-12002380

Associations of Fibroblast Growth Factor 23 and Fetuin-A With Coronary Plaque Burden and Plaque Composition in Young Adults

ObjectiveThe total burden of subclinical coronary artery disease (CAD) is significant among young adults. Serum fibroblast growth factor 23 (FGF-23) and fetuin-A are established predictors of morbidity and mortality because...

Serum fibroblast growth factor 21 levels is associated with lower extremity atherosclerotic disease in Chinese female diabetic patients.

BackgroundFibroblast growth factor 21 (FGF21) is an emerging metabolic regulator associated with glucose and lipid metabolism, and it is still unclear whether FGF21 is related to atherosclerosis. Here, we explored the potential link between FGF21 and lower extremity atherosclerotic disease (LEAD) in type 2 diabetic patients.MethodsA cross-sectional study was conducted on 504 type 2 diabetic patients (283 men, 221 women). LEAD was defined by Ankle-brachial index (ABI) <0.9 and lower extremity arterial plaque evaluated by color Doppler ultrasound. Serum FGF21 concentrations were quantified by a sandwich enzyme-linked immunosorbent assay.ResultsThe total FGF21 levels of male and female patients had no significant differenence ((299.14(177.31-534.49) vs 362.50(214.01-578.73), P=0.516). Serum FGF21 levels in LEAD group were significantly higher than non-LEAD group in females (385.34(243.89-661.54) vs 313.13(156.38-485.79), P=0.006), while not in male patients (295.52(177.09-549.64) vs 342.09 (198.70-549.87), P=0.613). In diabetic women, subjects with LEAD had significantly higher serum FGF21 regardless of non-alcoholic fatty liver disease (NAFLD) (P < 0.05). And serum FGF21 levels were positively correlated with waist circumference and systolic blood pressure after adjusted for age and BMI (r=0.198, P=0.004; r=0.152, P=0.027; respectively). Moreover, FGF21 was independently tied to femoral intima-media thickness (FIMT) (β=0.208, P=0.031). After adjusted for other LEAD risk factors, FGF21 was demonstrated to be an independent risk factor for LEAD in type 2 diabetic women (OR, 1.106; 95%CI 1.008-1.223; P=0.028). In addition, FGF21 was negatively correlated with estradiol in premenopausal diabetic women (r=−0.368, P=0.009). After adjusted for estradiol, serum FGF21 levels were still positively associated with FIMT in premenopausal diabetic women (r=0.381, P=0.007). In diabetic men, serum FGF21 levels were correlated with triglyceride and C-reactive protein even after adjusted for age and BMI (r=0.204, P=0.001; r=0.312, P < 0.001; respectively). However, serum FGF21 was not an independent impact factor for LEAD in men (P > 0.05).ConclusionsSerum FGF21 level independently and positively links LEAD in Chinese women with type 2 diabetes. The gender difference may be due to different estrogen levels.

Relationship of fibroblast growth factor 23 and fetuin-A to coronary atherosclerosis

BackgroundSerum fibroblast growth factor 23 (FGF-23) and fetuin-A are established predictors of morbidity and mortality due to cardiovascular disease. The objective of the present study is to evaluate the relationship between coronary artery disease (CAD) and serum concentrations of FGF-23 and fetuin-A. MethodsA total of 383 subjects who underwent coronary computed tomography angiography (CCTA) were included in the study. CCTA detected CAD in 208 patients; the rest of the patients had no detectable CAD. ResultsSerum FGF-23 and fetuin-A levels were significantly increased in CAD patients compared to non-CAD patients (26.6±21.1pg/mL vs. 17.9±16.1pg/mL, p=0.001 and 826±350mg/L vs. 595±300mg/L, p<0.001, respectively). Serum FGF-23, fetuin-A, low-density lipoprotein (LDL)-cholesterol, and uric acid values were elevated in non-diabetic patients with CAD when compared to those without CAD. FGF-23, and fetuin-A were not significantly different in diabetic patients with CAD when compared to those without CAD. Using multivariate logistic regression analysis, we found that age, hypertension, LDL-Cholesterol, high-density lipoprotein (HDL)-Cholesterol, hs-CRP, uric acid, FGF-23 and fetuin-A levels were independently associated with the presence of CAD. ConclusionFGF-23 and fetuin-A were positively correlated with coronary atherosclerosis Similar trends were seen among diabetic patients, but this did not reach statistical significance. FGF-23 and fetuin-A could be used as novel risk markers of cardiovascular disease.

Effects of omega-3 fatty acids and pioglitazone combination on insulin resistance through fibroblast growth factor 21 in type 2 diabetes mellitus

Fibroblast growth factor 21 (FGF21) is an effective regulator of glucose and lipid metabolism. It is mainly regulated by peroxisome proliferator activated receptors, and is widely associated with cases of insulin resistance as obesity and type 2 diabetes (T2D). Our study aimed to investigate the potential effects of omega-3 fatty acids, pioglitazone, and their combination on serum and liver FGF21 concentrations, and its hepatic gene expression in a rat model of T2D. We also studied the modulating effects of these treatments on blood glucose, lipid profile, and insulin resistance. T2D was induced in male Sprague–Dawley rats by combination of high fat diet and low dose streptozotocin (35 mg/kg). Diabetic rats were treated with omega-3 fatty acids (10%W/W diet), pioglitazone (20 mg/kg), and their combination for a period of 4 weeks. Serum FGF21 concentration was significantly increased in diabetic rats. In contrast, hepatic FGF21 concentration, and gene expression were significantly decreased. Omega-3 fatty acids, pioglitazone, and their combination significantly decreased serum FGF21. Omega-3 fatty acids and combination therapy significantly decreased liver FGF21 concentration, with non-significant changes in gene expression. On the other hand, pioglitazone significantly increased hepatic FGF21 concentration and gene expression. Omega-3 fatty acids, pioglitazone and their combination significantly improved lipid profile. Pioglitazone and combination significantly decreased blood glucose levels and improved insulin resistance. In conclusion, this study introduces the first evidence regarding the antidiabetic effects of omega-3 fatty acids and pioglitazone combination, such effects are mediated through FGF21.

Role of the morphogenetic proteins FGF-23 and Klotho and the glycoprotein sclerostin in the assessment of the risk of cardiovascular diseases and the prognosis of chronic kidney disease

AIM. To analyze changes in the serum concentrations of the morphogenetic proteins fibroblast growth factor 23 (FGF-23) and Klotho, as well as sclerostin, an osteocyte-secreted glycoprotein, in relation to the degree of hypertension, left ventricular (LV) hypertrophy, and arterial stiffness in patients with chronic kidney disease (CKD) at its different stages. Sixty-five patients (33 men and 32 women) aged 20-65 years, including 25 with chronic glomerulonephritis, 15 with tubulointerstitial nephritis, and 25 with hypertensive nephrosclerosis, were examined. A control group consisted of 15 healthy volunteers matched to the study group patients for age and gender. Serum FGF-23 concentrations and blood pressure (BP) were measured in the all subjects. Patients with BPs > 140/80 mm Hg underwent echocardiography, followed by determination of LV mass (LVM) and calculation of LVM index. Vascular circulation, pulse wave velocity, cardiac and vascular calcifications, and vascular functional properties were estimated. There was a strong direct Correlation between the serum concentration of FGF-23 and the stage of CKD and an inverse correlation between the levels of Klotho and sclerostin and the stage of CKD. As the glomerular filtration rate became lower, the concentration of FGF-23 increased and that of Klotho and sclerostin decreased just in Stage III CKD while hyperphosphatemia and elevated parathyroid hormone levels were noted in Stages IV-V CKD. As CKD progressed, the serum concentrations of Klotho and sclerostin were inversely correlated with the levels of phosphorus and parathyroid hormone. The degree of blood pressure elevation correlated positively with serum FGF-23 concentrations and inversely with Klotho levels. There was no significant correlation of the level of sclerostin with the degree of BP increase. The direct correlation between higher FGF-23 level and higher VLM is most pronounced in hypertensive patients. There was a strong direct relationship between FGF-23 and Klotho levels and a strong inverse relationship between sclerostin levels and pulse wave velocity. Lower Klotho concentrations were associated with the detection rate of calcifications in the heart valves and large arteries (the abdominal aorta). The reduced serum levels of Klotho and sclerostin were also correlated with concentric LV remodeling. It was demonstrated that there was a clear link between increased serum FGF-23 and decreased Klotho concentration as CKD progressed, and that between arterial stiffness and calcification and myocardial remodelling regardless of traditional risk factors. More experimental and clinical studies are required to clarify the role of sclerostin in CKD.

The relationship of fibroblast growth factors 21 and 23 and α-Klotho with platelet activity measured by platelet volume indices.

Subjects with high fibroblast growth factor 21(FGF21) and 23 (FGF23), endocrine hormones that regulate insulin sensitivity and phosphate metabolism, respectively, are reported to have a higher risk for adverse cardiovascular outcome. Therefore, the relationship of FGF21, FGF23, and α-Klotho (co-receptor for FGF23 signaling) with mean platelet volume (MPV) and platelet distribution width (PDW), two platelet volume indices that reflect platelet activity, was investigated. Data from 156 patients admitted to the cardiology department were analyzed. MPV and PDW were measured by an automatic blood counter, and serum FGF21, FGF23, and α-Klotho concentrations were measured by an enzyme-linked immunoassay. Log(FGF21) was significantly correlated with serum triglycerides but did not differ according to the use of non-use of antidiabetic or lipid-lowering drugs. MPV and PDW were significantly correlated (R=0.475, p<0.001). MPV was significantly correlated with log(FGF21) (R=-0.167, p<0.05) and log(FGF23) (R=0.351, p<0.001) but not with log(α-Klotho). Linear regression analysis showed a negative and positive association of log(FGF21) and log(FGF23), respectively, with MPV that was independent of possible confounders including sex, age, renal function, and antithrombotic drug use. In addition, log(FGF23) was found to have a significant independent positive association with PDW. Among cardiac patients, FGF21 had a negative association with MPV, whereas FGF23 had a positive association. Future studies of serum FGF23/FGF21 concentrations and the incidence of thromboembolic disorders are warranted.

Abstract 9902: Serum FGF23 Concentration is Associated With Cardiac Hypertrophy and Decreased Systolic Function Among Both CKD and Non-CKD Cardiac Patients

Introduction: Purpose: Serum concentrations of fibroblast growth factor-23 (FGF23) are increased in response to elevated serum phosphate levels among patients with renal dysfunction. Besides regulating circulating phosphate levels, FGF23 may induce cardiac hypertrophy; thus, enhanced FGF23 excretion may underlie the heart failure observed among patients with chronic kidney disease (CKD). Here we examined whether FGF23 concentrations are associated with cardiac hypertrophy among cardiac patients regardless of the presence or absence of CKD. Methods: The present study enrolled 480 cardiac patients admitted to our cardiology department between January 2012 and December 2012. Serum FGF23 level was measured by an ELISA method. Left ventricular mass index (LVMI) was used as a marker of cardiac hypertrophy. Results: Of the 480 patients, 132 (27.5%) had an estimated glomerular filtration rate (eGFR) of &lt;60 mL/min/m2 (no-CKD group) and the remaining 348 (72.5%) had an eGFR of 60 or greater (CKD group). FGF23 was correlated with eGFR in the CKD group, but not in the no-CKD group. Stepwise multivariate linear regression analysis was performed using LVMI as a dependent variable, and sex, age, eGFR, serum calcium and phosphate, and log(FGF23) as independent variables. Log(FGF23) was selected as an independent variable that had a significant association with LVMI with a standardized correlation coefficient of 0.26 in the no-CKD group (P&lt;0.01) and 0.25 in the CKD group (P&lt;0.01). When left ventricular ejection fraction was used as an independent variable in this model, log(FGF23) was selected as significant predictor with a standardized correlation coefficient of -0.20 in the no-CKD group (P&lt;0.05) and -0.18 in the CKD group (P&lt;0.01). Conclusions: Among cardiac patients, serum FGF23 concentration was associated positively with left ventricular mass and negatively with left ventricular ejection fraction not only in patients with CKD, but also in those without CKD.