Serum γ-Klotho and Fibroblast Growth Factor-2 Levels in Patients with Pressure Ulcers

Fibroblast Growth Factor-2: An Endogenous Antidepressant and Anxiolytic Molecule?

Atherosclerosis is highly prevalent in CKD. The rate of progression of atherosclerosis is associated with cardiovascular events. Fibroblast growth factor 2 (FGF-2) is a member of the FGF family with potentially both protective and deleterious effects in the development of atherosclerosis. The role of circulating FGF-2 levels in the progression of atherosclerosis in CKD is unknown. We used a multicenter, prospective, observational cohorts study of 481 patients with CKD. We determined the presence of atheroma plaque in ten arterial territories by carotid and femoral ultrasounds. Progression of atheromatosis was defined as an increase in the number of territories with plaque after 24 months. Plasma levels of FGF-2 were measured by multiplex analysis. A multivariable logistic regression analysis was performed to determine whether plasma FGF-2 levels were associated with atheromatosis progression. Average age of the population was 61 years. The percentage of patients in each CKD stage was 51% in stage 3, 41% in stages 4-5, and 8% in dialysis. A total of 335 patients (70%) showed plaque at baseline. Atheromatosis progressed in 289 patients (67%). FGF-2 levels were similar between patients with or without plaque at baseline (79 versus 88 pg/ml), but lower in patients with atheromatosis progression after 2 years (78 versus 98 pg/ml; P<0.01). In adjusted analyses, higher plasma FGF-2 was associated with lower risk of atheromatosis progression (odds ratio [OR], 0.86; 95% confidence interval [95% CI], 0.76 to 0.96; per 50 pg/ml increment). Analysis of FGF-2 in tertiles showed that atheroma progression was observed for 102 participants in the lowest tertile of FGF-2 (reference group), 86 participants in the middle tertile of FGF-2 (adjusted OR, 0.70; 95% CI, 0.40 to 1.20), and 74 participants in the lowest tertile of FGF-2 (adjusted OR, 0.48; 95% CI, 0.28 to 0.82). Low FGF-2 levels are independently associated with atheromatosis progression in CKD.

Objective To analyze the influencing factors of serum fibroblast growth factor 23 (FGF23) level in maintenance hemodialysis (MHD) patients, and to explore its relationship with mineral bone metabolism disorders and vascular calcification. Methods From January to February of 2018, a total of 380 patients who had undergone MHD for more than 3 months in our hospital were enrolled for this study. Clinical parameters were recorded, including gender, age, dialysis age, dialysis adequacy, and use of phosphorus-reducing drugs. Before dialysis, blood was drawn for detection of serum calcium, phosphorus, intact parathyroid hormone (iPTH), and alkaline phosphatase as mineral bone metabolism indicators, as well as hemoglobin, albumin, blood glucose, blood lipids, high-sensitivity C-reactive protein (hs-CRP), and β2 microglobulin, etc. The serum level of FGF23 was determined with enzyme-linked immunosorbent assay (ELISA), while multislice spiral CT (MSCT) was used to evaluate coronary artery calcification scores. The t-test and chi-square test were applied to analyze the influencing factors of FGF23 in the MHD patients. Multivariate linear regression analysis was performed for multivariate analysis. The chi-square test was also used to analyze the correlation between parathyroid hormone and coronary artery calcification scores in the MHD patients with different FGF23 levels. Results The median level of serum FGF23 in the MHD was 8 905.3 pg/ml. According to 50% of the FGF23 median level, the patients were divided into high-level group and low-level group. Univariate analysis showed that dialysis age, dialysis duration, dialysis ultrafiltration volume, and dialysis frequency were the influencing factors of serum FGF23 level. The level of FGF23 was higher in patients with larger age, longer duration of dialysis, more frequent dialysis, and greater volume of dialysis ultrafiltration (P<0.05). In the FGF23 high-level group, blood urea nitrogen, serum creatinine, and serum β2 microglobulin levels were higher than in the FGF23 low-level group (P<0.05). Multivariate linear regression analysis showed that dialysis age and serum creatinine were risk factors for the increase of FGF23 (P<0.001). And high FGF23 level was associated with the levels of serum calcium, serum phosphorus, iPTH, and high coronary artery calcification scores. Conclusions Dialysis age, dialysis duration, dialysis ultrafiltration volume, dialysis frequency, blood urea nitrogen, serum creatinine, serum β2 microglobulin, were related to the maintenance of FGF23 elevation in MHD patients. Dialysis AGE and serum creatinine were risk factors for FGF23 elevation. FGF23 was significantly associated with mineral-bone metabolism and coronary artery calcification in MHD patients. Key words: Hemodialysis; Fibroblast growth factor 23; Vascular calcification; Mineral-bone metabolism disorder; Cardiovascular disease

Objective To explore the serum levels of fibroblast growth factor 23 (FGF23) in patients with rheumatoid arthritis (RA) and to investigate the relationship between FGF23 and RA disease activity and the occurrence of osteoporosis (OP). Methods Serum levels of FGF23 from 174 cases of patients with RA and 88 normal subjects were detected by enzyme linked immunosorbent assay (ELISA). Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry. All the clinical and laboratory indexes of RA patients were recorded in details, disease activity score (DAS28) and health assess questionnaire (HAQ) were also calculated in the meantime. Radiographic changes in both hands of RA patients were assessed by Sharp's method. T test, nonparametric test, χ2 test, correlation analysis and Logistic regressive analysis were used for statistical analysis. Results Serum levels of FGF3 [145.46(67.67, 245.93) pg/ml] in RA patients were higher than the control group [32.64(12.34, 44.70) pg/ml, Z=11.416, P<0.01]. The positive rate of serum levels of FGF23 (≥71.95 pg/ml) in RA was 74.7%(130/174), while the positive rate in control was 4.5%(4/88,χ2=115.16, P<0.01). The threshold of FGF23 serum levels for diagnosing RA was 48.56 pg/ml (AUC=0.932, Youden index=0.743, P<0.01, sensitivity 89.1%, specificity 85.2%). In RA patients with serum FGF23≥48.56 pg/ml, compared with negative FGF23 group, VAS, HAQ, number of joint swelling and BMD at femoral neck,Ward, GT, Total hip, L4 and L1-4 were significantly higher in FGF23 positive group (P<0.05). Linear correlation analysis found that in RA patients with serum FGF23≥48.56 pg/ml, anti-CCP was negatively correlated with serum FGF23 levels (r=-0.171, P=0.035). And DAS28 was positively correlated with serum FGF23 (r=0.163, P=0.045). BMD at femoral neck, Ward, GT, Total hip, L4 and L1-4 were negatively correlated with serum FGF23 (P<0.05). Results of logistic regression analysis showed that sex (OR=8.518, 95%CI (2.636, 27.522), P<0.01, age [OR=1.129, 95%CI (1.079, 1.180), P<0.01] and Sharp score [OR=1.008, 95%CI(1.003, 1.013), P=0.001] were risk factors for OP in RA patients. BMI[OR=0.801, 95%CI(0.707, 0.909), P=0.001] was a protective factor for OP in RA patients. Conclusion Serum FGF23 level is significantly higher in RA patients. Meanwhile, the serum FGF23 level correlates with RA disease activity and BMD. Key words: Arthritis, rheumatoid; Fibroblast growth factor 23; Osteoporosis

High levels of the phosphaturic hormone fibroblast growth factor 23 (FGF-23) predict mortality in haemodialysis patients. The prognostic relevance of increased plasma FGF-23 levels in patients with less advanced chronic kidney disease (CKD) who are not on dialysis therapy is presently unknown. We measured plasma c-terminal FGF-23 levels in 149 CKD patients not undergoing dialysis treatment. Patients were stratified by their baseline FGF-23 levels (>104 vs ≤ 104 rU/mL) and followed for a period of 4.8 ± 0.9 years. During the follow-up, the pre-specified combined clinical endpoint was the first occurrence of a cardiovascular event, e.g. myocardial infarction, coronary artery angioplasty/stenting/bypass surgery, stroke, carotid endarterectomy/stenting, non-traumatic lower extremity amputation, lower limb artery surgery/angioplasty/stenting or death. At baseline, elevated FGF-23 levels >104 rU/mL were associated with more advanced CKD. Traditional cardiovascular risk factors and prevalent cardiovascular disease did not differ between CKD patients with high vs low FGF-23 levels. Fifty patients experienced a cardiovascular event during follow-up. Compared with CKD patients with FGF-23 ≤104 rU/mL, CKD patients with FGF-23 levels above the cut-off had worse event-free survival at univariate (log-rank test P = 0.012) and multivariate analysis [hazard ratio 2.49 (95% CI 1.40-4.39); P = 0.002]. Elevated FGF-23 plasma levels predict cardiovascular events in CKD patients not on dialysis therapy. This finding complements two recent cohort studies in which incident and prevalent haemodialysis patients with highest FGF-23 levels had worst survival. Lowering FGF-23 levels (e.g. by oral phosphate binder medication) could emerge as a promising new therapeutic option to reduce cardiovascular morbidity in CKD patients.

The present investigation was conducted to determine serum levels of basic fibroblast growth factor (FGF) by enzyme immunoassay in patients with various urogenital tumors. Renal cell carcinoma had a higher tendency (28 of 52, 53.8%) toward increased serum levels of basic FGF than any of the other urogenital tumors, and increased serum basic FGF was detected more frequently in patients with advanced renal cell carcinoma. Analysis of histological pattern indicated that renal cell carcinoma with a solid or tubular component is more likely to produce basic FGF. However, no significant difference was seen between the percentage of clear cell type tumor patients with increased serum basic FGF (50.0%) and the percentage of granular cell type tumor patients with increased serum basic FGF (66.7%). Five of 8 patients with renal cell carcinoma who underwent selective renal venous sampling before nephrectomy showed increased serum basic FGF in the renal vein from the affected kidney. After resection of the affected kidney to remove the cancer, serum basic FGF disappeared within 2 weeks. However, residual huge tumor or postoperative disease prolonged the increased levels of basic FGF in 2 patients, indicating that basic FGF is produced from and secreted by tumor tissue itself. These findings suggest that serum basic FGF can be useful in the diagnosis, and in evaluating the prognosis, of patients with renal cell carcinoma.

To characterise the magnitude and distribution of fibroblast growth factor-2 (FGF-2) following topical application in hypromellose gel and film formulations or a solution in an animal wound model, in order to assess the potential of this route for treatment of chronic wounds. Topical formulations of FGF-2 were applied to punch biopsy wounds, and FGF-2 levels within the wound measured. Each 12 mm diameter wound received 0.3 microg FGF-2 in solution, a 7% (w/w) hypromellose gel, a dried hypromellose film on Melolin-backing or a saline control. After 2, 5 or 8 h the wounds were horizontally dissected into four sections (surface granulation, subcutaneous fat, superficial muscle and deep muscle) which were then analysed for FGF-2 concentration using ELISA. Confocal microscopy was used to evaluate the distribution of FGF-2 within the wound. There were significant differences in the mean FGF-2 levels with respect to formulation and time following application (P < 0.05). FGF-2 penetrated faster into tissue when formulated as a solution than as a gel or a film. There did not appear to be a significant difference between the gel and the film with respect to total concentrations achieved in the tissue, although confocal microscopy showed differences in FGF-2 distribution within the wound. Delivery of FGF-2 to wounds in a solution gave the greatest increase in tissue FGF-2 concentration when measured by ELISA and visualised using confocal microscopy. Gel and film formulations prolonged the release of FGF-2 into the wound, although FGF-2 levels were not significantly different from controls when measured by ELISA. Confocal microscopy highlighted the differences in the penetration and distribution of the FGF-2 within the wound when released from different formulations.

TNF alpha-stimulated gene 6 (TSG6) is chondroprotective in vivo but overexpression cannot compensate for loss of FGF2

To observe the effect of Ronghuang granule on serum fibroblast growth factor 23 (FGF23), fibroblast growth factor receptor (FGFRs) and Klotho protein levels in non-dialysis patients with chronic kidney disease-mineral and bone disorder (CKD-MBD) and kidney deficiency and damp heat syndrome. Seventy non-dialysis CKD-MBD patients with kidney deficiency and dampness-heat syndrome were randomized into control group (n=35) and treatment group (n=35). All the patients were given routine treatment combined with traditional Chinese medicine retention enema, and the patients in the treatment group received additional Ronghuang granule treatment (3 times a day). After the 12-week treatments, the patients were examined for changes of TCM syndromes. Serum levels of Ca, P, parathyroid hormone (iPTH), FGF23, FGFRs and Klotho proteins were detected before and after treatment. These parameters were also examined in 20 healthy volunteers. Sixty-five patients completed the study, including 33 in the control group and 32 in the treatment group. The patients in the treatment group showed significantly better treatment responses than those in the control group (P &lt; 0.05 or 0.01). At 4, 8, and 12 weeks of treatment, the patients in the treatment group had significantly lowered scores of TCM syndromes compared with the score before treatment (P &lt; 0.05 or 0.01), while in the control group, significant reduction of the scores occurred only at 12 weeks (P &lt; 0.05); at each of the time points, the treatment group had significantly greater reductions in the score than the control group (P &lt; 0.01). Significant improvements in serum Ca, P and iPTH levels were observed at 4, 8, and 12 weeks in the treatment group (P &lt; 0.05) but only at 12 weeks in the control group (P &lt; 0.05). The patients in the control and treatment groups all showed elevated serum levels of FGF23, FGFRs and Klotho protein compared with the normal subjects (P &lt; 0.01); FGF23, FGFRs and Klotho levels were significantly reduced in the treatment group (P &lt; 0.05) but remained unchanged in the control group (P&gt;0.05), showing significant differences between the two groups. Ronghuang granule improves the clinical symptoms of non-dialysis CKD-MBD patients with kidney deficiency and dampness heat syndrome by reducing serum levels of FGF23, FGFRs and Klotho, improving calcium and phosphorus metabolism disorder, and inhibiting secondary hyperparathyroidism.

Is angiogenic potential of follicular fluid (FF) and granulosa-lutein cells (GLCs) altered in polycystic ovary syndrome (PCOS) and does it play a role in corpus luteum (CL) defect observed in them? FF and GLCs of women with PCOS show reduced expression of pro-angiogenic factors compared to controls and exhibit a diminished capacity to induce angiogenesis. In women with PCOS, CL insufficiency and frequent miscarriage are reported, which may be due to defect in CL. The development of new blood vessels is essential to promote ovarian folliculogenesis and functional CL formation. The vasculature formation in CL which is important for its function is still unexplored in these women. This case-control study was conducted in 30 healthy control women and 30 women with PCOS undergoing controlled ovarian hyperstimulation for IVF. The FF, GLCs and serum were collected from all participants during ovum pick up. The capacity of FF to induce angiogenesis was assessed by measuring levels of pro-angiogenic factors vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) and its tube formation and wound healing potential using human umbilical vein endothelial cells (HUVECs). We investigated the angiogenic potential and endothelial cell-like nature of GLCs using several approaches such as the expression of angiogenic genes by quantitative PCR, DiI-conjugated acetylated low-density lipoproteins (Dil-Ac-LDL) internalization assay, tube formation assay, expression of endothelial cell markers by immunofluorescence analysis. In addition, correlation of transcript levels of angiogenic genes with oocyte parameters was studied. FF and serum levels of VEGF and FGF2 were significantly higher and lower, respectively, in PCOS compared to controls. The tube formation and wound healing capacity of HUVECs was found to be reduced when measured after supplementation with FF of women with PCOS compared to controls. This suggests a decreased angiogenic capacity of FF in women with PCOS. Tube formation (P = 0.003) and Dil-Ac-LDL internalization (P = 0.03) ability of GLCs were significantly reduced in women with PCOS compared to controls. Protein expression levels of endothelial markers, vascular endothelial growth factor A (VEGFA) (P = 0.004), vascular endothelial growth factor receptor 2 (VEGFR2) (P = 0.011), TEK Receptor Tyrosine Kinase (Tie-2) (P = 0.026), fibroblast growth factor receptor 1 (FGFR1) (P = 0.026) and CD31 (P = 0.035) and transcript levels of angiogenic genes VEGFA (P = 0.042), hypoxia inducing factor 1A (HIF1A) (P = 0.025), FGF2 (P = 0.038), angiopoietin 1 (ANGPT1) (P = 0.028), heparin sulfate proteoglycan 2 (HSPG2) (P = 0.016), ADAM metallopeptidase with thrombospondin type1 motif, 1 (ADAMTS1) (P = 0.027) and fibronectin 1 (FN1) (P = 0.016) were found to be low in GLCs of PCOS compared to controls. Thus, the findings of this study indicate that endothelial cell-like characteristics of GLCs were significantly decreased in PCOS. Furthermore, transcript levels of VEGFA (r = 0.46, P = 0.009), ADAMTS1 (r = 0.55, P = 0.001), FGF2 (r = 0.42, P = 0.022) and ANGPT2 (r = 0.47, P = 0.008) showed a positive correlation with oocyte fertilization rate. The vasculature formation in CL is not possible to study in women, but we explored the angiogenic characteristics of FF and GLC obtained from women with PCOS to speculate any vascularization defect of CL in these women. The FF and GLCs were obtained from the stimulated cycle during oocyte retrieval, which may not exactly mimic the in-vivo condition. The small sample size is another limitation of this study. Larger sample size and support by color Doppler studies on CL blood flow would help to strengthen our findings. Our findings suggest that the altered angiogenic potential of FF and GLCs may affect vasculature development required for CL formation and function in PCOS. These findings pave the way to devise therapeutic strategies to support angiogenesis process in follicle of women with PCOS, which may improve CL insufficiency, progesterone levels and prevent frequent miscarriages in these women. Furthermore, our study also hypothesizes that the vascularization around the ovarian follicles is also compromised which may lead to the growth arrest of the follicles in PCOS, however, this needs thorough investigations. This work was supported by Grant BT/PR16524/MED/97/346/2016 from the Department of Biotechnology, Government of India. The authors have no conflicts of interest to disclose. N/A.

Left ventricular hypertrophy (LVH) is a common feature of cardiovascular disease in chronic kidney disease (CKD) and affects up to 90% of patients by the time they reach dialysis. Serum levels of fibroblast growth factor (FGF) 23 continuously rise as patients progress to renal failure. We have previously shown that FGF23 can activate FGF receptor (FGFR) 4 and the PLCgamma/calcineurin/NFAT signaling cascade in cardiac myocytes and induce hypertrophy in vitro and in vivo. Administration of an isoform-specific FGFR4 blocking antibody in the 5/6 nephrectomy rat model of CKD immediately after surgery protects rats from developing LVH, and delivery of a pan-FGFR blocker in CKD rats two weeks after surgery reverses LVH. To further study the reversibility of cardiac FGF23 effects, we elevated serum FGF23 levels in mice by administration of a high phosphate (2%) diet for three months. Animals developed LVH, as evident by significantly increased LV wall thickness and myocyte cross sectional area. When mice were switch from high phosphate to normal chow, the LVH phenotype resolved and cardiac parameters were comparable to those of mice that constantly received a normal diet. Furthermore, isolated cardiac myocytes recovered within 24 hours from FGF23-induced hypertrophy upon removal of FGF23. Finally, the FGFR4 blocking antibody was capable of reversing FGF23-induced hypertrophy in vitro. Our data indicate that FGF23-induced LVH is reversible and treatable. Interfering with FGF23/FGFR4 signaling in the heart might provide a novel therapeutic strategy to tackle cardiac injury in CKD. We propose that progression and reversibility of cardiac injury might depend on the duration of cardiac FGF23/FGFR4 activation.

In-stent restenosis (ISR) after vertebral artery stenting (VAS) affects 20-35% of patients, yet current risk stratification lacks sensitivity for early intervention. We propose the first combined biomarker model integrating endothelin-1 (ET-1) and fibroblast growth factor 23 (FGF23) to address this gap. A prospective cohort study was conducted involving 148 patients who underwent VAS between 2020 and 2024. Blood samples were collected preoperatively to measure ET-1 and FGF23 levels. ISR was defined as a stenosis of at least 50% on follow-up imaging. Statistical analyses included multivariable logistic regression and receiver operating characteristic (ROC) curve evaluations to assess the biomarkers' performance. ISR occurred in 34 patients (23%). Both ET-1 and FGF23 levels were significantly higher in the ISR group. Multivariate analysis identified ET-1, FGF23, stent length, and LDL-C levels as independent predictors of ISR. The combined model using both biomarkers demonstrated superior discriminative performance (AUC = 0.96) compared to individual markers (AUC = 0.73 for ET-1 and AUC = 0.77 for FGF23). The model achieved sensitivity and specificity of 92.3% and 89.7%, respectively. The combined assessment of serum ET-1 and FGF23 exhibits a synergistic predictive role for ISR after VAS. The ET-1/FGF23 model enables personalized risk stratification, guiding targeted therapies to reduce recurrent ischemic events and healthcare costs.

Fibroblast growth factor 23 (FGF23), a bone-derived phosphaturic hormone, is elevated in chronic kidney disease (CKD). There are scarce data on the levels of its essential co-receptor klotho, and longitudinal changes in FGF23 levels are also unknown. We examined FGF23 and soluble klotho (s-klotho) levels over 1 year in 154 children with CKD Stages 1-5 (CKD1-5), were on dialysis or who have received a transplantation. In children with CKD1-5 and who were receiving dialysis, FGF23 correlated inversely with the estimated glomerular filtration rate (eGFR) (P < 0.001), whereas a decrease in s-klotho was observed with a lower eGFR (P = 0.01). There was no correlation between FGF23 and serum phosphate (P) or parathyroid hormone (PTH) in our cohort wherein 89 and 66%, respectively, had normal levels. FGF23 increased by 6-fold over a 12-month period in children with eGFR of 15-29 mL/min/1.73 m(2), with an overall 5% annual increase in the CKD1-5 and dialysis cohort. High FGF23 levels were seen with high calcium (Ca) levels (P < 0.001). FGF23 levels were high when 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] were deficient (P = 0.05 and P < 0.001, respectively). s-klotho levels correlated positively with 25(OH)D (P < 0.001) and negatively with PTH (P = 0.04) and age (P = 0.03). Multivariate regression analysis demonstrated a strong relationship between FGF23 and eGFR, whereas the association between s-klotho and eGFR as observed in univariate analysis was lost following the adjustment of confounders. In transplanted patients, FGF23 correlated with eGFR (P = 0.02) and 25(OH)D (P = 0.05). This study shows increasing FGF23 and reduced s-klotho levels with progressive renal failure even in a population of children with well-controlled P levels. Novel associations between FGF23 and serum Ca as well as 25(OH)D warrant further investigation.

The relationship between soluble Klotho (s-Klotho) levels, fibroblast growth factor 23 (FGF23) levels, and albuminuria in patients with diabetic chronic kidney disease (CKD) remains unclear. A total of 109 patients...

Recently, fibroblast growth factor 23 (FGF23), a phosphate-regulating hormone, has been linked to the pathophysiology of heart failure (HF), thus encouraging us to examine which hemodynamic abnormalities of HF are linked to either serum FGF23 or plasma B-type natriuretic peptide (BNP) levels. We measured both the serum FGF23 and plasma BNP levels in 154 consecutive prospectively enrolled hospitalized HF patients, with an estimated glomerular filtration rate >40 ml min-1 1.73 m-2, who underwent heart catheterizations and an echocardiogram. The serum FGF23 levels correlated with the diameter of the inferior vena cava and its respiratory changes, whereas the plasma BNP levels did not. Both the plasma BNP and serum FGF23 levels were moderately correlated with the mean pulmonary artery (PA) pressure and pulmonary capillary wedge (PCW) pressure. Interestingly, in patients with an above-median right-atrial (RA) pressure (4 mm Hg), FGF23 levels were correlated with both PA and PCW pressures, but the levels were not correlated in patients with a below-median RA pressure. In contrast, the plasma BNP levels were correlated with both PA and PCW pressures. Finally, serum FGF23 levels, compared with the plasma BNP levels, were more strongly associated with the clinical outcomes in patients with above-median RA pressure. These findings suggested that serum FGF23 levels are predominantly correlated with clinical outcomes, may serve as a biomarker for HF in patients with higher RA pressure, may provide beneficial information for patients with right-sided HF and may represent different clinical information than that provided only by plasma BNP levels.