Increase In Fibroblast Growth Factor 23 Research Articles

High Fibroblast Growth Factor 23, Sialic Acids, and Albumin Modulation in Alzheimer’s Patients

Background: Alzheimer’s disease (AD) is a prevalent form of dementia, posing significant health and societal burdens. Pathologically characterized by neurofibrillary tangles and senile plaques, it lacks definitive diagnostic markers. Fibroblast growth factor (FGF)23 and Sialic Acids (Sias) are implicated in cell signaling and antioxidative defense, while lipid peroxidation (LPO) is linked to neurodegeneration. The aim of this study was to assess serum levels of Fibroblast Growth Factor 23 (FGF23), Malondialdehyde (MDA) as a marker of lipid peroxidation, Sialic Acids (Sias), and albumin in Alzheimer's disease (AD) patients compared to age-matched healthy controls. Method: A case-control study involving 17 AD patients and 17 healthy controls investigated serum levels of FGF23, Sias, malondialdehyde (MDA), and albumin. Biochemical assays and statistical analyses were conducted. Results: Biochemical analyses revealed a significant increase in serum FGF23 and MDA levels in AD patients compared to controls (p < 0.05). Additionally, AD patients exhibited lower levels of serum Sias and albumin. Furthermore, in the patient group, serum MDA levels were inversely correlated with normalized global gray matter volume (GMV), adjusted for age, sex, and Child-Pugh class. Conclusion: This study underscores the potential of FGF23, MDA, Sias, and albumin as biomarkers for AD. Further research elucidating their roles in AD pathogenesis is warranted. Decreased FGF23 in AD may involve disrupted phosphate regulation and neuroprotection mechanisms. Elevated MDA suggests increased lipid peroxidation, contributing to neuronal damage. Reduced Sias may impair antioxidative defense, exacerbating oxidative stress. Low albumin levels correlate with cognitive decline and oxidative damage in AD.

Changes of FGF23 and hearing in chronic renal failure and their correlation analysis

BackgroundTo explore the association between fibroblast growth factor 23 (FGF23) and hearing in chronic renal failure (CRF). MethodsPure tone audiometry was used to detect the hearing of patients with CRF; the level of serum FGF23, creatinine, blood urea nitrogen (BUN), parathyroid hormone (PTH), and mean binaural hearing threshold were compared to the control group (people without kidney disease). The rat model of renal failure was established by 5/6 nephrectomy, and the auditory brainstem response (ABR) of rats after modeling was detected by the Tucker Davis Technologies (TDT) system; the expression level of FGF23 in the peripheral blood, renal and cochlear tissue was also detected. ResultsThe incidence of hearing loss (HL) and serum FGF23 were higher in CRF patients than the control group; the sFGF23 was positively correlated with the mean binaural hearing threshold. Animal studies showed that the ABR threshold, creatinine, FGF23, BUN, and PTH increased after modeling; although, an increase in FGF23 was observed earlier than other indicators. The HL of rats with renal failure was significantly correlated with BUN, phosphate, PTH, sFGF23, kFGF23/β-actin, eFGF23/β-actin, weight, and modeling cycle. ConclusionsBoth CRF patients and rat models showed high-frequency HL. FGF23 was highly expressed in the serum of HL renal failure patients and rats, as well as in the renal tissue and cochlea of renal failure rats. Therefore, FGF23 may be involved in the occurrence and development of HL caused by CRF.

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

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

Increased Bone Turnover and Decreased BCMA Levels in Patients with Response to Anti-BCMA CAR T Cell Therapy in Relapsed/Refractory Multiple Myeloma

Introduction For most patients (pts), multiple myeloma (MM) remains an incurable disease. Osteolytic lesions (OL) are present in 80% of pts at diagnosis and skeletal-related events are the most common cause for symptomatic relapse. Hence, myeloma bone disease (MBD) is a major cause of morbidity and mortality especially among pts with relapsed/refractory MM (RRMM). B cell maturation antigen (BCMA) targeted chimeric antigen receptor (CAR) T cells have revolutionized treatment of patients with RRMM. While remission rates are high and pts experience long-standing treatment free intervals after CAR T cell treatment, little is known about its effects on MBD and bone turnover. The latter can be determined in plasma by measuring markers of bone formation and resorption. We aimed to analyze the longitudinal development of bone turnover during and after anti-BCMA CAR T cell treatment in RRMM pts. Methods We analyzed 28 consecutive pts with RRMM who underwent treatment with either Idecabtagene-Vicleucel (n=27) or Ciltacabtagen-Autoleucel (n=1) at our center between December 2021 and February 2023. Median age at infusion was 63 (range 39-75) years. 57% of pts were male. All pts were triple-class exposed, 21% had penta-class refractory disease. Status prior to CAR T cell infusion was complete remission (CR, 11%), partial remission (PR, 21%), very good PR (14%), stable disease (4%), or progressive disease (PD, 50%). The impact of CAR T cell treatment on bone turnover was assessed by collecting plasma samples on the day of T cell apheresis, as well as days (d) 30 and 100 after CAR T cell infusion. Samples were analyzed by ELISA to evaluate plasma levels of bone formation marker Osteocalcin (OCN), bone resorption markers Tartrate-resistant acid phosphatase 5b (TRAcP5b) and fibroblast growth factor 23 (FGF23) as well as BCMA as a marker for the targeted myeloma cells. Median levels were compared between subgroups by Wilcoxon tests. Remission status after CAR T cell therapy was first evaluated at d 30 according to International Myeloma Working Group consensus criteria. Median follow-up was 6 months. Results Of the 28 pts treated with anti-BCMA CAR T cells, 64% achieved at least a PR (responders), while 36% had PD shortly (30 d) after. Within 14 d after infusion, 82% developed a cytokine release syndrome (CRS, °I or II), in 30% of which Tocilizumab was applied. Only 1 pt developed immune effector cell-associated neurotoxicity syndrome. In responders, BCMA levels in plasma decreased significantly between apheresis and d 30 ( P&amp;lt;.01) and between apheresis and d 100 ( P&amp;lt;.01), while pts with PD showed no significant change in BCMA levels at the same timepoints ( P=.6 and P=.8). Furthermore, BCMA levels were significantly higher in pts with PD at d 30 ( P&amp;lt;.01) and d 100 ( P=.02), compared to responders (Figure 1). Regarding bone resorption markers, TRAcP5b levels were significantly increased in responders ( P=.01) but not pts with PD ( P=.56) on d 30 after apheresis. Furthermore, we determined a significant increase of intact FGF23 between apheresis and d 30 ( P&amp;lt;.01) and a subsequent significant decrease of intact FGF23 ( P=.02) between d 30 and d 100 in responders. Since FGF23 and interleukin-6 (IL-6) are physiologically dependent, the observed FGF23 dynamics are likely to be an effect of increasing IL-6 in the context of CRS. Aptly, pts who received Tocilizumab because of full-blown CRS had higher intact FGF23 levels at d 30 ( P=.02) compared to pts without Tocilizumab treatment. The bone formation marker OCN showed a significant increase in responders between apheresis and d 100 ( P=.01), as well as between d30 and d100 ( P=.02), while there were no significant changes in OCN levels over the time in pts with PD (Figure 2). Conclusion Pts responding to treatment with anti-BCMA CAR T cells, showed an increased bone turnover shortly after infusion. The increase of bone resorption marker levels appeared to be a short-term trend and could possibly be related to inflammation and high interleukin levels during the first days after infusion. However, we also saw a steady increase of bone formation marker OCN, which remained significant till d 100 in responders. Our data implies, that response to anti-BCMA CAR T cells is accompanied by increasing bone formation. Further analyses are needed to evaluate, whether this treatment can have positive long-term effects on MBD.

Impaired Growth Plate Maturation in XLH Is due to Both Excess FGF23 and Decreased 1,25-Dihydroxyvitamin D Signaling.

X-linked hypophosphatemia (XLH) is the most common form of hereditary hypophosphatemic rickets. The genetic basis for XLH is loss of function mutations in the phosphate-regulating endopeptidase X-linked (PHEX), which leads to increased circulating fibroblast growth factor 23 (FGF23). This increase in FGF23 impairs activation of vitamin D and attenuates renal phosphate reabsorption, leading to rickets. Previous studies have demonstrated that ablating FGF23 in the Hyp mouse model of XLH leads to hyperphosphatemia, high levels of 1,25-dihydroxyvitamin D, and is not associated with the development of rickets. Studies were undertaken to define a role for the increase in 1,25-dihydroxyvitamin D levels in the prevention of rickets in Hyp mice lacking FGF23. These mice were mated to mice lacking Cyp27b1, the enzyme responsible for activating vitamin D metabolites, to generate Hyp mice lacking both FGF23 and 1,25-dihydroxyvitamin D (FCH mice). Mice were fed a special diet to maintain normal mineral ion homeostasis. Despite normal mineral ions, Hyp mice lacking both FGF23 and Cyp27b1 developed rickets, characterized by an interrupted, expanded hypertrophic chondrocyte layer and impaired hypertrophic chondrocyte apoptosis. This phenotype was prevented when mice were treated with 1,25-dihydroxyvitamin D from day 2 until sacrifice on day 30. Interestingly, mice lacking FGF23 and Cyp27b1 without the PHEX mutation did not exhibit rickets. These findings define an essential PHEX-dependent, FGF23-independent role for 1,25-dihydroxyvitamin D in XLH and have important therapeutic implications for the treatment of this genetic disorder.

Mild Chronic Kidney Disease Associated with Low Bone Formation and Decrease in Phosphate Transporters and Signaling Pathways Gene Expression.

The initial phases of molecular and cellular maladaptive bone responses in early chronic kidney disease (CKD) remain mostly unknown. We induced mild CKD in spontaneously hypertensive rats (SHR) by either causing arterial hypertension lasting six months (sham-operated rats, SO6) or in its' combination with 3/4 nephrectomy lasting two and six months (Nx2 and Nx6, respectively). Sham-operated SHRs (SO2) and Wistar Kyoto rats (WKY2) with a two-month follow-up served as controls. Animals were fed standard chow containing 0.6% phosphate. Upon follow-up completion in each animal, we measured creatinine clearance, urine albumin-to-creatinine ratio, renal interstitial fibrosis, inorganic phosphate (Pi) exchange, intact parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), Klotho, Dickkopf-1, sclerostin, and assessed bone response by static histomorphometry and gene expression profiles. The mild CKD groups had no increase in renal Pi excretion, FGF23, or PTH levels. Serum Pi, Dickkopf-1, and sclerostin were higher in Nx6. A decrease in trabecular bone area and osteocyte number was obvious in SO6. Nx2 and Nx6 had additionally lower osteoblast numbers. The decline in eroded perimeter, a resorption index, was only apparent in Nx6. Significant downregulation of genes related to Pi transport, MAPK, WNT, and BMP signaling accompanied histological alterations in Nx2 and Nx6. We found an association between mild CKD and histological and molecular features suggesting lower bone turnover, which occurred at normal levels of systemic Pi-regulating factors.

PS-B02-3: FGF23 EXACERBATES CARDIAC FIBROSIS IN DOCA-SALT HYPERTENSIVE MICE THROUGH LOCALLY ABNORMAL VITAMIN D METABOLISM

Backgrounds: Fibroblast growth factor 23 (FGF23) is associated with cardiovascular disease in patients with chronic kidney disease (CKD), but the mechanisms underlying the effect of FGF23 on cardiac function remain to be investigated. Herein, we studied the effect of continuous intravenous (CIV) FGF23 loading in a deoxycorticosterone acetate (DOCA)-salt mouse model that has mild CKD and hypertension, and heart failure with a preserved ejection fraction (HFpEF). Design and method: Wild type male mice (n = 16) were allocated randomly to four groups: normal control (NC), vehicle-treated DOCA-salt mice (V), FGF23-treated DOCA-salt mice (F), and FGF23 and calcitriol-treated DOCA-salt mice (C). The DOCA-salt mice received agents by CIV for ten days via an infusion mini-pump, uninephrectomized, and cardiac changes were evaluated in these mice. Results: DOCA-salt mice that received FGF23 showed a marked increase in serum FGF23 (249 pg/mL in V, 1416 pg/mL in F, and 1261 pg/mL in C) than NC (51 pg/mL). Echocardiography in these DOCA-salt mice revealed HFpEF. These mice also showed exacerbation of myocardial fibrosis area (7.0% in V, 13.2% in F, and 3.8% in C) concomitant with an inverse and significant correlation with Cyp27b1 expression (r = -0.79, P &lt; 0.01). Calcitriol treatment attenuated the FGF23-induced cardiac fibrosis (F vs. C, P &lt; 0.01) and improved diastolic function (early-to-atrial wave ratio in doppler echocardiography, 0.7 in F vs. 2.0 in C; P &lt; 0.01) via inhibition of transforming growth factor (TGF)-beta signaling. Protein expression levels of TGF-beta was significantly higher in F (1.32-fold to NC; P &lt; 0.01) than in NC, and significantly lower in C (0.96-fold to NC; P &lt; 0.05) than in F. This effect was independent of systemic and local FGF23 levels. Conclusions: These results suggest that CIV FGF23 loading induced cardiac fibrosis concomitantly with locally abnormal vitamin D metabolism, and this might have contributed to HFpEF progression in the DOCA-salt mice model. Thus, cardiac toxicity of FGF23 may be partly due to vitamin D inactivation in cardiac tissue. Calcitriol has cardioprotective effects by mediating TGF-beta signaling, independently of local and systemic FGF23 levels.

Fetuin A is assessing of developing bone mineral disorders and cardiovascular calcifi cation formation risk marker in patients with stage 5 chronic kidney disease

INTRODUCTION. Recent years clinical studies have shown that bone mineral disorders in chronic kidney disease (CKD) increase the risk of cardiovascular mortality . Factors involved in mineral metabolism , dysregulation of the synthesis of which increases the risk of cardiovascular calcification in CKD S5D include fetuin A. A decrease in the level of fetuin A can lead to the development and progression of processes of extraossal calcification and increased cardiovascular mortality in patients with CKD S5D. THE AIM: to determination of Fetuin A level n and assessment of its relationship with factors involved in mineral metabolism to identify the risk of cardiovascular calcification in patients with CKD S5D. PATIENTS AND METHODS. 84 patients with stage 5 CKD receiving hemodialysis treatment were examined , of which 40 are female and 44 are male . The average age of patients was 55.6±14.9 years . All patients underwent routine examinations , as well as echocardioscopy with an assessment of calcification of the heart valves , radiography of the abdominal organs in a lateral projection with aortic calcification assessment , an analysis of indicators characterizing phosphorus-calcium metabolism was carried out . The level of serum fetuin A was determined , along with the level of calcitriol (1.25 (OH)D), fibroblast growth factor -23 (FGF-23), parathyroid hormone (PTH), alpha-klotho (A- klotho ), phosphorus (P) and calcium ( Ca ) of blood . Statistical analysis was carried out using the program «STATISTICA 12.6» (« StatSoft Inc.», USA). RESULTS. It was found that the level of fetuin A in the blood of patients is 0.78± 0.11 ng / ml and ranges from 0.45 to 0.95 ng / ml , signs of calcification of the heart valves and / or aortic wall were noted in 51.2 % of patients . It was revealed that fetuin A has a positive correlation with albumin , its level decreases in patients with age , in patients with low values of " dry weight ", indicating the presence of protein-energy deficiency in this category of patients . It has been shown that a decrease in fetuin A level is associated with an increase in FGF-23 and a decrease in A- klotho and indicates an increase in the potential of vascular calcification . The effect of a decrease in the level of fetuin A on the risk of detection of calcification of the aortic wall and heart valves was confirmed . It was revealed that a low level of fetuin A not only increases the p robability of calcification itself , but also its severity . We have established that fetuin A is able to do this in conjunction with A- klotho . Since both factors have protective properties against calcification , their friendly reduction also contributes to its development . CONCLUSION. A decrease in the level of fetuin A in patients blood with CKD S5D contributes to an increased risk of calcification of the heart valves and the aortic wall , both independently and in combination with a decrease in the level of A- klotho . Low fetuin A values increase the severity of cardiovascular calcification .

Mineral and Bone Disease After Kidney Transplantation: Risk of Fracture, Graft Dysfunction and Mortality - a Review

The mineral and bone disease of chronic kidney disease (CKD-MBD) is a combination of three components: abnormalities in calcium, phosphorus, PTH, fibroblast growth factor 23 (FGF23) and vitamin D metabolism; abnormalities of bone metabolism, mineralization, volume, growth and strength; and vascular and other soft tissue calcification. During the natural course of kidney disease, there is an increase in FGF23 levels, inhibition of calcitriol production, secondary hyperparathyroidism, hypocalcemia and hyperphosphatemia. These changes have consequences on the cardiovascular and bone systems. Regarding cardiovascular disease, left ventricular hypertrophy is highlighted, associated with an increase in FGF23 and vascular calcification, directly related to hyperphosphatemia. The main types of bone disease are cystic fibrous osteitis (high turnover) and adynamic bone disease (low turnover), both of which are associated with a high risk of fracture in this population. Successful kidney transplantation (KT) does not fully correct the mineral, bone and cardiovascular abnormalities generated by CKD-MBD. In the first months after transplantation, PTH and FGF23 levels remain elevated in most patients. There is an increase in the production of calcitriol by the graft. These are the main alterations responsible for a mineral phenotype that resembles primary hyperparathyroidism, with hypercalcemia, hypophosphatemia and elevated PTH levels. Cardiovascular disease does not revert after KT and the transplant patient has a higher cardiovascular risk than the general population. In relation to bone disease, in addition to the pre-existing bone alteration, specific factors of the post-KT period add damage to the bone, especially the use of corticosteroids. The main types of bone disease in renal transplant patients are bone fracture, renal osteodystrophy, osteoporosis and osteonecrosis. CKD-MBD is a complex disease that affects patients with CKD, increasing their morbidity and mortality. KT does not fully reverse the disease and still adds other specific risk factors that make its approach challenging. This review sought to show the association between the bone mineral disease of chronic kidney disease and the risk of fractures, vascular and other tissue calcifications, graft dysfunction and kidney transplant patient mortality.

Growth-related skeletal changes and alterations in phosphate metabolism.

Serum inorganic phosphate (Pi) levels are higher in children than in adults; however, the underlying mechanisms remain unclear. Therefore, we herein attempted to elucidate the mechanisms altering Pi metabolism from youth to adulthood using 4-week-old (young) and 12-week-old (adult) mice. Despite higher serum Pi levels, serum fibroblast growth factor 23 (FGF23) levels were lower in young mice, and the amount of FGF23 in bone tended to increase from youth to adulthood. Increases in serum FGF23 levels during growth were associated with the up- and down-regulation of the renal expression of Cyp24a1 encoding vitamin D-24-hydroxylase and Slc34a3 encoding the type IIc sodium/phosphate (Na+/Pi) co-transporter, respectively, suggesting an enhancement in the FGF23-mediated bone-kidney axis from youth to adulthood. We then isolated osteoblasts and osteocytes from young and adult mice and compared the expression of genes involved in Pi metabolism and/or mineralization. In contrast to the growth-related increase in Fgf23 expression, the expression of some genes, including the dentin matrix protein 1 (Dmp1) and phosphate-regulating gene with homologies to endopeptidases on the X chromosome (Phex) markedly decreased from youth to adulthood. The down-regulation of Dmp1 and Phex may contribute to growth-related increases in FGF23. The responses of isolated osteoblasts and osteocytes to high Pi levels also markedly differed between young and adult mice. Treatment of isolated osteocytes with high Pi increased the production of FGF23 in adult mice but not in young mice. These results indicate a close relationship between skeletal changes from youth to adulthood and an alteration in Pi metabolism, and provide insights into the mechanisms by which osteoblasts and osteocytes maintain Pi homeostasis.

Changes in Serum Intact Fibroblast Growth Factor 23 Concentrations From Midlife to Late Life and Their Predictors in the Community: The ARIC Study.

ObjectiveTo investigate longitudinal changes in the blood concentration of fibroblast growth factor 23 (FGF23) from midlife to late life and their major predictors in the general population.Patients and MethodsIn 14,444 participants of the Atherosclerosis Risk in Communities Study, we analyzed the association of 31,095 measurements of serum intact FGF23 with age using data from 3 visits (visit 2 [N=13,460; mean age, 57 years]; visit 3 [N=12,323; mean age, 60 years]; and visit 5 [N=6122; mean age, 76 years]) and a linear mixed-effects model. Among 5804 participants who had FGF23 measurements at both visits 3 and 5, we explored predictors of FGF23 change from midlife to late life using linear regression models. Prespecified risk factors were estimated glomerular filtration rate, body mass index, ever smoking, ever drinker, diabetes, hypertension, history of cardiovascular disease, total cholesterol, and high-density lipoprotein cholesterol.ResultsMedian FGF23 concentrations were 41.9 pg/mL (interquartile interval [IQI], 33.9 to 51.8 pg/mL) at visit 2, 38.3 pg/mL (IQI, 30.6 to 48.3 pg/mL) at visit 3, and 55.0 pg/mL (IQI, 44.4 to 70.3 pg/mL) at visit 5. A linear mixed-effects model showed that the association of FGF23 with age was nonlinear, with a slight decline or no change in age 45-60 years and a monotonic increase in age greater than or equal to 65 years (FGF23, +10 to 15 pg/mL per 10 years of age). In a multivariable linear regression model, significantly greater increases in FGF23 were noted, with midlife estimated glomerular filtration rate less than 60 mL/min per 1.73 m2 vs more than or equal to 60 mL/min per 1.73 m2 (ΔFGF23, +4.4 pg/mL [95% CI, 0.9 to 8.0]), diabetes vs no diabetes (ΔFGF23, +6.2 pg/mL [95% CI, 4.1 to 8.3]), and hypertension vs no hypertension (ΔFGF23, +4.1 pg/mL [95% CI, 2.7 to 5.4]).ConclusionFGF23 did not show any major changes in midlife but increased linearly in late life. Reduced kidney function, diabetes, and hypertension were robustly associated with a greater increase in FGF23. Further investigations are needed to understand the potential mechanisms linking these conditions to an increase in FGF23 concentrations.

Correlation of glomerular filtration rate and fibroblast growth factor-23 levels in chronic kidney disease; sub analysis chronic kidney disease–mineral and bone disorder study

Introduction: One of the chronic kidney disease (CKD) manifestations is mineral disorder, such as phosphate and calcium. Phosphatonin levels are regulated by the hormone phosphatonin, which the most commonly associated with CKD is fibroblast growth factor-23 (FGF-23), mainly synthesized by bone cells. The increase in FGF-23 in CKD subjects is a physiological response to stabilize phosphate levels. Several conditions can increase FGF-23 levels including age, body mass index (BMI), diabetes mellitus (DM), and hypertension. Objectives: This study aims to test the correlation between FGF-23 levels at various stages of glomerular filtration rate (GFR) in CKD. Patients and Methods: This study is observational with a cross-sectional approach conducted at Wahidin Sudirohusodo and Unhas hospitals of Makassar. Subjects are CKD patients which meet inclusion criteria. Intact serum FGF-23 levels were measured using an ELISA (enzyme-linked immunosorbent assay) kit (Immutopics). Statistical analysis was conducted using ANOVA test, Mann-Whitney U, and Spearman’s correlation tests. Statistical results are considered significant if P&lt;0.05. Results: The research was conducted on 78 subjects with CKD stages 3, 4 and 5, which consisted of 40 men and 38 women. The correlation test showed that the lower the GFR, the higher the FGF-23 level (P&lt;0.05). No significant correlation between age, body mass index, diabetes mellitus, and hypertension with FGF-23 were detected (P&gt;0.05). Conclusion: We found that every increase in the CKD stages and decrease of GFR, would be associated with an increase in the plasma levels of FGF-23. However, FGF-23 plasma concentration had no significant correlation with age, BMI, DM, and hypertension.

Cinacalcet hydrochloride-nanoemulsion: preparation, characterization, enhanced bioavailability and pharmacodynamics.

The aim of the study was to improve the bioavailability of Cinacalcet hydrochloride (CLC) and enhance its efficacy by the nanoemulsion drug delivery system. First, cinacalcet hydrochloride-nanoemulsion (CLC-NE) was prepared and optimized through the pseudo ternary phase diagram and central composite design response surface methodology (CCD). The release of CLC-NE in vitro was investigated with four different dissolution media, and the bioavailability of CLC-NE in vivo was studied through beagle dogs. Finally, the pharmacodynamics of CLC-NE was evaluated by the rat model of uremia. Oleic acid, op-10, and PEG-200 were selected as oil phase, emulsifier, and co-emulsifier, respectively. The optimum ratio of oleic acid, op-10, PEG-200, and water was 9.87%, 38.33%, 12.78%, and 39.02%. CLC-NE has similar dissolution rates in different pH media, and the relative bioavailability of CLC-NE was 166.5%. The uremia model showed that CLC-NE could enhance renal function and reduce the excessive phosphorus (P), serum creatinine (Scr), and urea nitrogen (Urea) of model rats, as well as the inhibited increase of fibroblast growth factor-23 (FGF23) and parathyroid hormone (PTH). The solubility, bioavailability, and pharmacodynamics of CLC can be significantly improved through the nanoemulsion drug delivery system.

Effect of Oxidative Stress-Induced Apoptosis on Active FGF23 Levels in MLO-Y4 Cells: The Protective Role of 17-β-Estradiol.

The discovery that osteocytes secrete phosphaturic fibroblast growth factor 23 (FGF23) has defined bone as an endocrine organ. However, the autocrine and paracrine functions of FGF23 are still unknown. The present study focuses on the cellular and molecular mechanisms involved in the complex control of FGF23 production and local bone remodeling functions. FGF23 was assayed using ELISA kit in the presence or absence of 17β–estradiol in starved MLO-Y4 osteocytes. In these cells, a relationship between oxidative stress-induced apoptosis and up-regulation of active FGF23 levels due to MAP Kinases activation with involvement of the transcriptional factor (NF-kB) has been demonstrated. The active FGF23 increase can be due to up-regulation of its expression and post-transcriptional modifications. 17β–estradiol prevents the increase of FGF23 by inhibiting JNK and NF-kB activation, osteocyte apoptosis and by the down-regulation of osteoclastogenic factors, such as sclerostin. No alteration in the levels of dentin matrix protein 1, a FGF23 negative regulator, has been determined. The results of this study identify biological targets on which drugs and estrogen may act to control active FGF23 levels in oxidative stress-related bone and non-bone inflammatory diseases.

Decreased Concentration of Fibroblast Growth Factor 23 (FGF-23) as a Result of Supplementation with Selenium and Coenzyme Q10 in an Elderly Swedish Population: A Sub-Analysis.

There is a reduced intake of selenium in many countries due to low levels of selenium in the soil. This results in an increased cardiovascular risk. Fibroblast growth factor 23 (FGF-23) is active mainly in the metabolism of vitamin D and phosphorus. However, there are indications that FGF-23 may also provide information both on cardiovascular function and prognosis. The aim of the study was to evaluate the effect of supplementation with selenium and coenzyme Q10 on the FGF-23 concentration in an elderly population with low concentrations of both selenium and coenzyme Q10 and in which the supplementation improved cardiac function and mortality. In a randomised double-blind placebo-controlled trial, FGF-23 was measured in 219 individuals at the start and after 48 months. Selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/day) (n = 118) or placebo (n = 101) were given as a dietary supplement. The intervention time was 48 months. t-Tests, repeated measures of variance, and ANCOVA analyses were used to evaluate the differences in FGF-23 concentration. Following supplementation with selenium and coenzyme Q10, a significantly lower level of FGF-23 could be seen (p = 0.01). Applying 10 years of follow-up, those who later died a cardiovascular death had a significantly higher FGF-23 concentration after 48 months compared with those who survived (p = 0.036), and a significantly lower FGF-23 concentration could be seen in those with a normal renal function compared to those with an impaired renal function (p = 0.027). Supplementation with selenium and coenzyme Q10 to an elderly community-living population low in both substances prevented an increase of FGF-23 and also provided a reduced cardiovascular risk.

POS-259 THE DIFFERENCES OF SERUM CALCIUM-PHOSPHATE PRODUCT LEVELS AND IRON STATUS AMONG HIGH AND LOWER FIBROBLAST GROWTH FACTOR-23 LEVELS IN REGULAR HEMODIALYSIS PATIENTS

Fibroblast growth factor 23 (FGF-23), primarily produced by osteocytes, is a phosphate-regulating hormone. The levels of FGF-23 increase along with the decline in kidney function. This occurs as a physiologic response to maintain normal serum phosphate levels and help maintain the average phosphate balance. Dysregulation in iron balance and inflammation occurred in chronic kidney disease, including patients with hemodialysis. This study aimed to determine the difference in serum calcium phosphate levels and iron status between regular hemodialysis patients with high and lower FGF-23 serum levels.

POS-252 THE DIFFERENTIAL IMPACT OF TWO NOVEL INTRAVENOUS IRON AGENTS ON FIBROBLAST GROWTH FACTOR 23, PHOSPHATE AND OTHER CLINICAL AND FUNCTIONAL MARKERS: METHODOLOGY AND BASELINE DATA

Third generation intravenous (IV) iron preparations are increasingly used in the treatment of non-dialysis dependent chronic kidney disease (CKD) associated iron deficiency. Such compounds allow rapid delivery of large concentrations of iron safely at a single sitting. Evidence suggests that their use may lead to improved cardiovascular outcomes. Nonetheless, concerns exist regarding the potential induction of hypophosphatemia via fibroblast-growth-factor 23 (FGF-23) following the use of certain compounds. Raised FGF-23 has been associated with mineral bone and cardiac disorders, alongside prognostic implications. No prior study has provided a head-to-head comparison between iron preparations in CKD. This pilot study is designed to primarily investigate the differential impact of two different IV iron compounds on FGF-23 and phosphate in patients with CKD; secondarily we examine the impact of these compounds on bone markers and functional status, quality of life and cardiovascular function. This is a randomized controlled double-blinded pilot study recruiting patients with CKD stage 3a – 5 (non-dialysis) and iron deficiency +/- anemia. Patients are randomized to receive either ferric carboxymaltose or ferric derisomaltose over two infusions (one-month apart) to achieve full repletion. The initial dose administered is 1000 mg for both medications, with 500 mg or 1000 mg reserved for the second dose depending on weight and hematinics. Follow up is over a period of three months following the first infusion with measurements of intact FGF-23, phosphate, phosphaturia, vitamin D, parathyroid hormone, bone metabolism markers, functional status and quality of life and cardiac markers (figure 1). 168 patients were referred to the specialist renal anemia services for pre-screening. Ninety-nine were contacted for interest to participate, with 64 individuals declining to join. The commonest reason for not participating, was the COVID-19 pandemic (43.3%) with patients not keen to travel. Thirty-five patients were screened, and 27 patients enrolled in the study, of which 26 were randomized to receive iron (figure 2). One patient withdrew from the study, as they were unable to attend appointments following successful screening. In our baseline cohort the median age was 67.9 (12.4) and 17 participants were male. Mean hemoglobin was 100.3 (13.5) and hematinic markers consistent were consistent with iron deficiency. Median eGFR was 18.0 (11.3) ml/min/1.73 m2; the population as expected had a raised intact FGF-23 (212.1 (116.4) pg/ml). Serum calcium and phosphate were within normal parameters, while parathyroid hormone and 1,25 (OH)2 Vitamin D were deranged (Table 1). ExplorIRON-CKD, like a number of trials, experienced significant disruption in recruitment due to COVID-19. This study will provide further insight to the potential induction of FGF-23 following administration of specific intravenous iron compounds, and identify whether such a differential effect exists in patients with CKD. The effect of such induction in terms of phosphate and other markers of bone metabolism, functional status and cardiac functioning will be observed. The results will aid in hypothesis generation for further studies to identify the potential long-term impact of iatrogenic FGF-23 increase in patients with CKD.

Clinical progression of cats with early-stage chronic kidney disease fed diets with varying protein and phosphorus contents and calcium to phosphorus ratios.

BackgroundDietary protein and phosphorus (P) restriction is the mainstay for nutritional management of chronic kidney disease (CKD). However, adequate restriction levels for cats with early CKD remain unclear.ObjectivesTo investigate responses in cats with early CKD to varying dietary protein, P, and calcium (Ca) : P ratio.AnimalsNineteen research colony cats with International Renal Interest Society stages 1‐2 CKD.MethodsIn an opportunistic longitudinal case study, cats were fed a low protein (59 g/Mcal), low P (0.84 g/Mcal) dry diet (LP‐LP; Ca : P = 1.9) for 18 months and later transitioned onto a moderate protein (76‐98 g/Mcal), moderate P (1.4‐1.6 g/Mcal) dry‐wet diet regimen (MP‐MP; Ca : P = 1.4‐1.6) for 22 months. Fold‐changes in serum creatinine, total Ca (tCa) and P (primary outcomes) and fibroblast growth factor 23 (FGF23) were assessed by linear‐mixed models.ResultsWhile feeding LP‐LP, mean serum creatinine decreased (0.87‐fold, 95% confidence interval [CI] 0.81, 0.93, P < .001) to within reference range after 6 months, while increases in total Ca (tCa; 1.16‐fold, 95% CI 1.11, 1.22, P < .001) and FGF23 (2.72‐fold, 95% CI 1.72, 4.31, P < .001), but not in P (1.03‐fold, 95% CI 0.945, 1.124, P = .94), were observed after 17 months. On MP‐MP, mean creatinine, tCa and P remained within reference ranges and did not significantly change (P = .11, P = .98, and P = 1, respectively), while FGF23 significantly decreased (0.58‐fold, 95% CI 0.36, 0.95, P = .02) after 22 months.Conclusions and Clinical ImportanceCats with early CKD developed hypercalcemia after long‐term feeding of a highly P‐restricted diet. Increasing dietary P and reducing Ca : P ratio maintained renal markers, while improving Ca‐P balance. Cats with early CKD could benefit from moderately protein‐ and P‐restricted diets.

Serum Fibroblast Growth Factor 23 Level and Liver Fat Content in MAFLD: A Community-Based Cohort.

PurposeAlthough fibroblast growth factor-23 (FGF23) is involved in the development of metabolic diseases, its association with metabolic-associated fatty liver disease (MAFLD) remains unknown. We explored the relationship between serum fibroblast growth factor-23 level, metabolic associated fatty liver disease, and liver fat content.Patients and MethodsParticipants were enrolled from communities in Shanghai. Serum fibroblast growth factor-23 level was determined using two-side sandwich enzyme-linked immunosorbent assays. MAFLD was diagnosed using the international expert consensus (2020) criteria. Liver fat content was assessed using ultrasound.ResultsWe enrolled 1827 individuals aged 30–80 years (mean age, 59.4±7.3 years). MAFLD was diagnosed in 445/1393 (31.9%) non-diabetic participants and 245/434 (56.5%) diabetic participants. After adjusting for confounders, one standard deviation increase in serum FGF23 was associated with MAFLD in diabetic (odds ratio, 1.27; 95% confidence interval, 1.15–1.49; P<0.001) and non-diabetic (odds ratio, 1.28; 95% confidence interval, 1.07–1.74; P=0.030) groups. In a fully adjusted linear regression model, serum FGF23 emerged as a positive determinant of liver fat content in both diabetic and non-diabetic groups (P=0.039; P=0.034).ConclusionParticipants with MAFLD had higher serum fibroblast growth factor-23 level than those without MAFLD, regardless of diabetes status. Serum fibroblast growth factor-23 was independently related to MAFLD and liver fat content.

Effect of empagliflozin on phosphorus and calcium metabolism in patients with type 2 diabetes mellitus with preserved kidney function

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 /cm2 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&gt;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.