Increase In Fibroblast Growth Factor 23 Research Articles

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.

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

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

A phosphate and calcium-enriched diet promotes progression of 5/6-nephrectomy-induced chronic kidney disease in C57BL/6 mice

C57BL/6 mice are known to be rather resistant to the induction of experimental chronic kidney disease (CKD) by 5/6-nephrectomy (5/6-Nx). Here, we sought to characterize the development of CKD and its cardiac and skeletal sequelae during the first three months after 5/6-Nx in C57BL/6 mice fed a calcium- and phosphate enriched diet (CPD) with a balanced calcium/phosphate ratio. 5/6-NX mice on CPD showed increased renal fibrosis and a more pronounced decrease in glomerular filtration rate when compared to 5/6-Nx mice on normal diet (ND). Interestingly, despite comparable levels of serum calcium, phosphate, and parathyroid hormone (PTH), circulating intact fibroblast growth factor-23 (FGF23) was 5 times higher in 5/6-Nx mice on CPD, relative to 5/6-Nx mice on ND. A time course experiment revealed that 5/6-Nx mice on CPD developed progressive renal functional decline, renal fibrosis, cortical bone loss, impaired bone mineralization as well as hypertension, but not left ventricular hypertrophy. Collectively, our data show that the resistance of C57BL/6 mice to 5/6-Nx can be partially overcome by feeding the CPD, and that the CPD induces a profound, PTH-independent increase in FGF23 in 5/6-Nx mice, making it an interesting tool to assess the pathophysiological significance of FGF23 in CKD.

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

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

Successful Medical Management of a Non-Localising Case of Tumour-Induced Osteomalacia

Introduction: TIO is a rare paraneoplastic syndrome characterised by renal phosphate wasting due to fibroblast growth factor-23 (FGF23) over-secretion from a phosphaturic mesenchymal tumour (PMT). While surgery is potentially curative, localisation is often challenging. Clinical Case: A 53 year old lady presented with recurrent fragility fractures in the spine (T10-L1, L4, S1-2), right femoral neck fracture and pelvic fractures at the bilateral superior and inferior pubic rami, associated with a 2 year onset of lower limb pain and proximal myopathy. Power was 2/5 proximally, rendering her progressively chairbound. She had no family history of fragility fractures. Biochemistry revealed hypophosphatemia of 0.48 mmol/l (NR 0.86–1.45 mmol/l), normal adjusted calcium of 2.32 mmol/l (NR 2.15–2.55 mmol/l), hyperphosphaturia (TmP/GFR 0.39 mmol/l, NR 0.88–1.42 mmol/l), mildly insufficient 25(OH)D level of 25 μg/l, inappropriately suppressed 1,25(OH)2D at 13 pg/ml (NR 18–78 pg/ml) and raised FGF23 at 484 RU/ml (NR<180 RU/ml). Localisation of the PMT was unsuccessful, despite multiple investigations including 68-Gallium-DOTANOC PET-CT, bilateral lower limb MRI for non-specific inguinal lymph nodes and various ultrasonographic evaluation of soft tissue lesions including biopsy of a benign breast tumour. Surgical removal of the breast papilloma did not affect FGF23 levels. In the absence of any suspicious lesion, selective venous sampling was not performed due to uncertain utility. She was treated medically, requiring 16mmol oral phosphate, 1000 IU cholecalciferol and 0.5mcg calcitriol daily, with a view to perform interval DOTA-peptide scan. Despite an increase in FGF23 to 760 RU/ml over 29 months, phosphate level was maintained in the low-normal range and alkaline phosphatase, as a marker of disease activity, normalised from 370 U/l to 92 U/l (NR 40-130U/l). Development of secondary hyperparathyroidism improved with uptitration of calcitriol. There was no hypercalciuria on monitoring of urinary calcium. Symptoms of generalised body pain resolved, and her bone mineral density (BMD) improved over 47 months of medical therapy. Power improved to 4/5, and she was able to ambulate with assistance. BMD at the femoral neck, total hip and lumbar spine increased by 68.2%, 44.6% and 65.2% respectively. Conclusion: This is a challenging case of TIO which has failed to localise despite best efforts. One must consider FGF23-independent and dependent causes of osteomalacia when patients present with severe frailty and hypophosphatemia as substantial morbidity results from delayed diagnosis and treatment. TIO-related PMTs can be difficult to localise, even with a combination of functional and anatomical imaging. With medical therapy, bone mineralisation and symptoms can improve significantly. Patients need to be monitored for complications of long-term phosphate and calcitriol replacement.

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

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

Vitamin D Supplementation for Patients with Chronic Kidney Disease: A Systematic Review and Meta-analyses of Trials Investigating the Response to Supplementation and an Overview of Guidelines

A large proportion of patients with chronic kidney disease (CKD) are vitamin D deficient (plasma 25-hydroxyvitamin D (25(OH)D) < 25 or 30 nmol/L per UK and US population guidelines) and this contributes to the development of CKD–mineral bone disease (CKD–MBD). Gaps in the evidence-base for the management of vitamin D status in relation to CKD–MBD are hindering the formulation of comprehensive guidelines. We conducted a systemic review of 22 RCTs with different forms of vitamin D or analogues with CKD–MBD related outcomes and meta-analyses for parathyroid hormone (PTH). We provide a comprehensive overview of current guidelines for the management of vitamin D status for pre-dialysis CKD patients. Vitamin D supplementation had an inconsistent effect on PTH concentrations and meta-analysis showed non- significant reduction (P = 0.08) whereas calcifediol, calcitriol and paricalcitol consistently reduced PTH. An increase in Fibroblast Growth Factor 23 (FGF23) with analogue administration was found in all 3 studies reporting FGF23, but was unaltered in 4 studies with vitamin D or calcifediol. Few RCTS reported markers of bone metabolism and variations in the range of markers prevented direct comparisons. Guidelines for CKD stages G1–G3a follow general population recommendations. For the correction of deficiency general or CKD-specific patient guidelines provide recommendations. Calcitriol or analogues administration is restricted to stages G3b–G5 and depends on patient characteristics. In conclusion, the effect of vitamin D supplementation in CKD patients was inconsistent between studies. Calcifediol and analogues consistently suppressed PTH, but the increase in FGF23 with calcitriol analogues warrants caution.

Hypophosphatémie et fer injectable : à propos d’un cas et revue de la littérature

Iron deficiency and iron-deficiency anemia are common medical conditions. Management of the etiology and iron supplementation are both necessary to treat this condition. Use of intravenous iron preparations is increasing due to its advantages over oral iron. Indeed, the total dose required can be provided in a single infusion, and it is more effective and increases hemoglobin levels more quickly than oral iron. Hypophosphatemia, sometimes severe, following intravenous iron administration, has been described in literature these past years, in particular with ferric carboxymaltose. We report here a case of severe hypophosphatemia with ferric carboxymaltose and carry out a literature review to determine the incidence of hypophosphatemia and to precise its clinical presentation, its pathophysiological mechanisms and its treatment. We found that hypophosphatemia is frequent with ferric carboxymaltose. Most of the time, there are no clinical manifestations, but cases of symptomatic osteomalacia have been described. Duration of hypophosphatemia is variable, from a few weeks to several months in case of prolonged administration. Hypophosphatemia owing to renal phosphate wasting is caused by an increase in intact fibroblast growth factor 23 (FGF-23) levels. However, the mechanism of ferric carboxymaltose- induced increase in intact FGF-23 is still unknown.

Persistent Hypophosphatemia after Ferric Carboxymaltose Is Associated with Persistent Changes in Biomarkers of Bone Metabolism

Introduction High-dose intravenous (IV) iron formulations are used to correct iron-deficiency anemia in patients when there is a clinical need to deliver iron rapidly or to treat patients who do not tolerate or fail to respond to oral iron. Hypophosphatemia is an important adverse effect of some IV iron formulations. Persistent hypophosphatemia is associated with bone complications, including osteomalacia. In two recent head-to-head trials, ferric carboxymaltose (FCM) induced marked increases in the phosphaturic hormone fibroblast growth factor 23 (FGF23), which led to significantly higher rates of incident and persistent hypophosphatemia than in patients treated with ferric derisomaltose (FDI) (Wolf et al. JAMA. 2020;323:432-43). Here, we present a post hoc analysis of patients with incident hypophosphatemia in which we investigated predictors of persistent hypophosphatemia and tested whether persistent hypophosphatemia was associated with persistent changes in biomarkers of bone metabolism, which could help explain bone complications that have been linked to FCM in numerous case reports. Methods We analyzed pooled data from two open-label, randomized clinical trials that compared the US dosing of FCM (2 doses of 750mg administered 1 week apart; N=117) to FDI (1 dose of 1000mg; N=125). In this analysis only patients who developed incident hypophosphatemia (serum phosphate &amp;lt;2.0 mg/dL) after treatment were included. This subgroup was then classified according to their serum phosphate at the end of the trials' observation period on day 35 as either 'recovered' (≥2.0 mg/dL) or 'persistent' (&amp;lt;2.0 mg/dL). We used multivariate logistic regression analyses with forward stepwise selection to identify baseline predictors of persistent hypophosphatemia. To better understand the effects of persistent hypophosphatemia on bone health, we compared changes in biomarkers of bone metabolism in patients who developed persistent hypophosphatemia with those who recovered from hypophosphatemia. Results Overall, 90 patients (FDI, n=8; FCM, n=82) who developed incident hypophosphatemia were classified as 'recovered' or 'persistent'. All 8 patients who developed hypophosphatemia after FDI recovered. In the FCM group, hypophosphatemia recovered in 43% of patients (n=35) and persisted in 57% (n=47). Besides FCM use, no baseline predictor could independently distinguish patients who developed hypophosphatemia and recovered from patients who experienced persistent hypophosphatemia. Within the FCM group, patients who developed persistent hypophosphatemia had greater increases in intact FGF23 on day 8 compared to patients who recovered (mean change from baseline to day 8 [95% CI]: 471.3 pg/mL [402.7 to 539.9] vs 228.3 pg/mL [186.8 to 269.9]). Compared to patients who recovered from hypophosphatemia, patients in whom hypophosphatemia persisted also had significant and persistent differences in multiple biomarkers at study end on day 35 (mean change from baseline to day 35 [95% CI]): increased intact FGF23 (58.7 pg/mL [40.8 to 76.5] vs -0.1 pg/mL [-6.7 to 6.5); increased parathyroid hormone (38.6 pg/mL [26.6 to 50.5] vs 14.5 pg/mL [4.5 to 24.5]); decreased 1,25-(OH)2-vitamin D (-35.1 pg/mL [-39.1 to -30.9] vs -3.4 pg/mL [-8.5 to 1.7]); and decreased N-terminal pro-peptide of type 1 collagen (-22.5 ng/mL [-26.3 to -18.6] vs -6.1 ng/mL [-11.1 to -1.1]). Conclusion Persistent hypophosphatemia developed only in patients who received FCM. Baseline characteristics could not discern whether patients with incident hypophosphatemia would remain persistently hypophosphatemic or go on to recover by study end. Persistent hypophosphatemia resulted in similarly persistent changes in biomarkers of bone metabolism. These findings suggest that treatment with FCM may affect bone health, especially in patients with persistent hypophosphatemia, and may help explain the association of FCM with osteomalacia and fractures that has been described in several case reports. Disclosures Wolf: Akebia: Consultancy, Honoraria; Amag: Consultancy, Honoraria; Ardelyx: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Pharmacosmos: Consultancy, Honoraria; Bayer: Consultancy. Schaefer:Vifor Pharma: Honoraria; Pharmacosmos A/S: Honoraria, Research Funding. Zoller:Pharmacosmos A/S: Consultancy, Honoraria, Research Funding; Vifor Pharma: Consultancy, Honoraria.

Serum Klotho is correlated to cardiovascular complications of chronic kidney disease in children.

Aim of the study was to investigate soluble Klotho (sKl), fibroblast growth factor 23 (FGF23) concentrations, and their correlations with cardiovascular complications in children with CKD. 38 children with CKD stages 2-5 were compared to 38 healthy controls in terms of: plasma FGF23, serum sKl, peripheral and central blood pressure, arterial stiffness (pulse wave velocity - (PWV)), carotid intima media thickness (cIMT), left ventricular mass index (LVMI), and diastolic function. Correlations between FGF23, sKl, and cardiovascular parameters were investigated. The CKD group was characterized by higher FGF23, lower sKl concentrations, higher peripheral and central blood pressure, arterial stiffness, cIMT, left ventricular mass index, and decreased E/A ratio compared to the control group. In CKD children, sKl correlated negatively with diastolic blood pressure (DBP), mean arterial pressure (MAP), central systolic, diastolic, and mean blood pressure, PWV, and LVMI. In multivariate analysis, higher sKl was a significant predictor of lower peripheral and central DBP and lower LVMI and E/A, whereas higher FGF23 was a predictor of higher of LVMI. (1) In children with CKD, decreased sKl might be a marker of elevated central blood pressure. (2) Both sKl decrease and FGF23 increase could possibly contribute to left ventricular hypertrophy in this group of patients.

Simultaneous management of disordered phosphate and iron homeostasis to correct fibroblast growth factor 23 and associated outcomes in chronic kidney disease.

Hyperphosphatemia, iron deficiency, and anemia are powerful stimuli of fibroblast growth factor 23 (FGF23) production and are highly prevalent complications of chronic kidney disease (CKD). In this manuscript, we put in perspective the newest insights on FGF23 regulation by iron and phosphate and their effects on CKD progression and associated outcomes. We especially focus on new studies aiming to reduce FGF23 levels, and we present new data that suggest major benefits of combined corrections of iron, phosphate, and FGF23 in CKD. New studies show that simultaneously correcting iron deficiency and hyperphosphatemia in CKD reduces the magnitude of FGF23 increase. Promising therapies using iron-based phosphate binders in CKD might mitigate cardiac and renal injury and improve survival. New strategies to lower FGF23 have emerged, and we discuss their benefits and risks in the context of CKD. Novel clinical and preclinical studies highlight the effects of phosphate restriction and iron repletion on FGF23 regulation.

P0094KLOTHO DECLINE IS ASSOCIATED WITH PRO-HYPERTROPHIC SIGNALING IN MYOCARDIUM OF NEPHRECTOMIZED SPONTANEOUSELY HYPERTENSIVE RATS (PILOT SYUDY)

Abstract Background and Aims Klotho deficiency is suggested to be involved in cardiac complications in chronic kidney disease (CKD) through modulation of intracellular pro-hypertrophic signaling pathways. The aim of this study was to investigate the molecular mechanisms of myocardial remodeling in the settings of Klotho decline in experimental CKD. Method Systolic blood pressure (BP), myocardial mass index (MMI), serum and urinary creatinine (Cr), serum urea (Ur), inorganic phosphate (Pi), 25-hydroxyvitamin D (25OHD), parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), Klotho, myocardial Klotho, calcineurin/ NFAT and beta-catenin expression (IHC), quantitative morphometry of cardiomyocite (CM) thickness and nuclei area (hematoxylin and eosin), myocardial perivascular (PF) and interstitial fibrosis (IF), renal fibrosis (RF) (Masson’s trichrome) and Klotho expression (rKl, IHC) were analyzed in spontaneously hypertensive rats with 3/4 or 5/6 nephrectomy (Nx) and duration of experimental exposure 1 and 2 mo (Nx1, n = 9; Nx2, n = 8). Controls were sham operated (SO) animals (SO1, n = 9; SO2, n = 9). Results The experimental model was corresponded to the initial stages of CKD (Ur level was between 6.64 and 13.36 mmol/L, serum Cr increased less than 50% vs SO, RF did not exceed 22 % FOV). Serum concentration of Klotho and rKl expression decreased, while MMI, CM thickness increased in both Nx1 and Nx2 (Table). There were no differences in serum Pi, FGF23 and PTH levels in Nx1 vs SO (Table). In Nx2 Klotho decline was accompanied by the development of IF and PF, serum 25OHD decrease, Pi and FGF23 increase vs SO2 (Table). In multiple regression analyzes including SO and Nx animals rKl was independently associated with MMI (β = -0.38 ± 0.16, p = 0.026), and CM thickness (β = -0.64 ± 0.14, p &amp;lt;0.001). Myocardial fibrosis was associated with rKl level (IF: β = -0.87 ± 0.19, p = 0.001) and serum 25OHD (PF: β =-0.34 ± 0.15, p=0.032). According to pilot data of IHC, in Nx rat myocardium Klotho protein expression decreased, cytoplasmic calcineurin and nuclear NFAT in CM were observed (Figure), suggesting an increase in the activity of the calcineurin / NFAT signaling pathway. An intracellular redistribution of β-catenin from the cytoskeleton to the cytoplasm and nuclei were observed in CM of Nx rats (Figure), likely corresponding to increase in the activity of Wnt signaling. Conclusion Associations of CM hypertrophy, myocardial fibrosis and Klotho decline in CKD may be mediated by calcineurin / NFAT and Wnt signaling in myocardium.

P0904EFFECT OF EMPAGLIFLOZIN ON SERUM MARKERS OF OSTEOCYTE AND OSTEOBLAST FUNCTION AND ALBUMINURIA IN DIABETIC AND NON-DIABETIC PATIENTS WITH CHRONIC KIDNEY DISEASE

Abstract Background and Aims Sodium-glucose co-transporter 2 (SGLT2) inhibitors are new class of oral antidiabetic drugs that show potent cardio- and nephroprotective actions. Despite having a favorable safety profile the treatment with SGLT2 inhibitors has been associated with several side-effects including increased risk of fractures. Although the pathomechanism of this complication has not been elucidated these drugs may inhibit tubular reabsorption of phosphate which may stimulate a secretion of fibroblast growth factor 23 (FGF23). The study was designed to assess the effect of SGLT2 inhibitor on markers of calcium-phosphate metabolism, bone turnover and early glomerular injury in diabetic and non-diabetic patients with stage 3 chronic kidney disease (CKD). Method 41 patients with chronic kidney disease including 23 without diabetes (13 M, 11F, age 52.9±0.7 years, estimated glomerular filtration rate (eGFR) 38.6±10.8 ml/min/1.73 m2) and 18 with type 2 diabetes (12 M, 6F, age 58.8±1.4 years, eGFR 38.8±7.7 ml/min/1.73 m2) were recruited. Main inclusion criteria were CKD stage 3 and urine albumin secretion &amp;gt;100 mg/g creatinine. All subjects received oral empagliflozin 10 mg once daily for 7 days. Serum calcium, phosphorus, parathormone (PTH), calcitriol, bone alkaline phosphatase (BAP), FGF23 and urine calcium, phosphate and albumin were measured at baseline and after 7 days of empagliflozin treatment. Results Plasma calcitriol, serum and urine calcium, phosphorus and BAP did not change significantly during the administration of empagliflozin. Urine phosphate/creatinine ratio was similar in both subgroups at baseline and did not change during empagliflozin administration. Plasma PTH was higher in non-diabetics than in diabetics both at baseline and after empagliflozin. The increase of PTH after empagliflozin tended to be higher in diabetic patients (p=0.07). There was only a trend towards an increase of serum FGF23 in both non-diabetic and diabetic subgroup (by 4.2±0.2 vs. 9.3±1.1 pg/mL, ns). BAP was significantly higher at baseline in diabetic patients but did not significantly change after empagliflozin in the subgroups. Albumin/creatinine ratio decrease after empagliflozin administration was significant only in non-diabetic patients (-62±17 vs. -2±8 mg/g in diabetic patients, p=0.03 for difference). Conclusion Our study showed no effect of short-time administration of empagliflozin on calcium-phosphate and bone metabolism markers in patients with both diabetic and non-diabetic CKD. Empagliflozin decreased albuminuria significantly only in non-diabetic CKD that may suggest a potentially greater nephroprotective effect of this SGLT2 inhibitor in non-diabetic than in diabetic nephropathy.

Oral vitamin D3 supplementation increases serum fibroblast growth factor 23 concentration in vitamin D-deficient patients: a systematic review and meta-analysis.

Studies have suggested that vitamin D supplementation may increase serum fibroblast growth factor 23 (FGF23) among vitamin D-deficient patients although the results were inconsistent across the studies. This systematic review and meta-analysis was conducted to summarize all available data. A systematic review was conducted using MEDLINE and EMBASE database from inception to February 2019 to identify studies that provided oral vitamin D3 supplement to vitamin D-deficient participants (25-hydroxyvitamin D < 20ng/mL). Mean serum FGF23 concentration and standard deviation of participants at baseline and after vitamin D3 supplementation were extracted to calculate standard mean difference (SMD). Pooled SMD was calculated by combining SMDs of each study using random effects model. Nine studies were eligible for the meta-analyses. Seven studies measured serum intact FGF23, and two studies measured serum C-terminal FGF23. The meta-analyses found that serum intact FGF23 increased significantly after oral vitamin D3 supplementation in vitamin D-deficient participants with the pooled SMD of 0.36 (95%CI, 0.14, 0.57; p = 0.001; I2 of 36%). Serum C-terminal FGF23 also increased after vitamin D3 supplementation in vitamin D-deficient participants with the pooled SMD of 0.28 although without reaching statistical significance (95%CI, - 0.08, 0.65; p = 0.13; I2 of 0%). Funnel plot of the meta-analysis of serum intact FGF23 did not provide a suggestive evidence for publication bias. Vitamin D supplementation leads to a significant increase in serum intact FGF23 among vitamin D-deficient patients. An increase in serum C-terminal FGF23 was also observed although the number of included studies was too small to demonstrate statistical significance. The present systematic review and meta-analysis revealed that serum intact FGF23 concentration increased significantly after oral vitamin D3 supplementation in vitamin D-deficient participants. An increase in serum C-terminal FGF23 concentration was also observed although the number of included studies was too small to demonstrate statistical significance.

Osteokines and the vasculature: a review of the in vitro effects of osteocalcin, fibroblast growth factor-23 andlipocalin-2.

Bone-derived factors that demonstrate extra-skeletal functions, also termed osteokines, are fast becoming a highly interesting and focused area of cross-disciplinary endocrine research. Osteocalcin (OCN), fibroblast growth factor-23 (FGF23) and lipocalin-2 (LCN-2), produced in bone, comprise an important endocrine system that is finely tuned with other organs to ensure homeostatic balance and health. This review aims to evaluate in vitro evidence of the direct involvement of these proteins in vascular cells and whether any causal roles in cardiovascular disease or inflammation can be supported. PubMed, Medline, Embase and Google Scholar were searched for relevant research articles investigating the exogenous addition of OCN, FGF23 or LCN-2 to vascular smooth muscle or endothelial cells. Overall, these osteokines are directly vasoactive across a range of human and animal vascular cells. Both OCN and FGF23 have anti-apoptotic properties and increase eNOS phosphorylation and nitric oxide production through Akt signalling in human endothelial cells. OCN improves intracellular insulin signalling and demonstrates protective effects against endoplasmic reticulum stress in murine and human endothelial cells. OCN may be involved in calcification but further research is warranted, while there is no evidence for a pro-calcific effect of FGF23 in vitro. FGF23 and LCN-2 increase proliferation in some cell types and increase and decrease reactive oxygen species generation, respectively. LCN-2 also has anti-apoptotic effects but may increase endoplasmic reticulum stress as well as have pro-inflammatory and pro-angiogenic properties in human vascular endothelial and smooth muscle cells. There is no strong evidence to support a pathological role of OCN or FGF23 in the vasculature based on these findings. In contrast, they may in fact support normal endothelial functioning, vascular homeostasis and vasodilation. No studies examined whether OCN or FGF23 may have a role in vascular inflammation. Limited studies with LCN-2 indicate a pro-inflammatory and possible pathological role in the vasculature but further mechanistic data is required. Overall, these osteokines pose intriguing functions which should be investigated comprehensively to assess their relevance to cardiovascular disease and health in humans.

Fibroblast Growth Factor 23 and Cardiovascular Outcome in Acute Kidney Injury

Even though the identification of Fibroblast Growth Factor 23 (FGF23) has been the breakthrough of the last decades in understanding mineral homeostasis, it is clear that it could have only been the starting point of an outstanding biomarker. This article focuses on available literature data concerning the increase of FGF23 in AKI and its potential influence upon associated or future to be cardiovascular disease.

Attenuated Dentin Matrix Protein 1 Enhances Fibroblast Growth Factor 23 in Calvaria in a Primary Hyperparathyroidism Model.

Fibroblast growth factor 23 (FGF23) secretion is facilitated by the PTH, particularly in hyperparathyroidism. The PTH also attenuates dentin matrix protein 1 (DMP1), which is produced by osteocytes to contribute to bone mineralization and suppress FGF23 expression. Nevertheless, it remains unknown whether attenuated DMP1 affects FGF23 expression in hyperparathyroidism. We examined their expression in bone tissue using a mouse model of primary hyperparathyroidism (PHPT). PHPT mice increased serum FGF23 levels, along with a high level of serum PTH. Fgf23 expression increased, and Dmp1 decreased significantly in the calvaria of PHPT mice compared with wild-type mice and primary osteoblasts treated with PTH. In UMR106 mature osteoblasts, PTH increased Fgf23 expression and decreased Dmp1 expression, and stimulation of protein kinase A (PKA) signaling by forskolin also increased Fgf23 expression and decreased Dmp1 expression in a dose-dependent manner, whereas inhibition of PKA signaling with 10-5 M H89 reversed the changes in Fgf23 and Dmp1 expression when cells were stimulated with PTH. Silencing Dmp1 along with PTH treatment led to an additive increase in Fgf23 expression, accompanied by additive phosphorylation of the cAMP-response element-binding protein. These results indicate that persistent and high levels of PTH lead to the continuous activation of PKA signaling in osteoblasts/osteocytes, resulting in an increase in FGF23 and a decrease in DMP1 in bone. Moreover, suppression of DMP1 enhanced FGF23 expression in PHPT, besides having a direct effect on PTH. These mechanisms may describe one of the pathogeneses behind the increase in FGF23 transcription in bone tissue in patients with PHPT.

Impact of fibroblast growth factor-23 on blood pressure and pulse pressure in hemodialysis patients; a multicenter study

Introduction: Hypertension seems to be a major problem in dialysis patients. Fibroblast growth factor-23 (FGF-23) appears to be a risk factor for mortality in patients with end-stage renal disease (ESRD). Objectives: This study aims to investigate FGF-23 and its association with blood pressure and pulse pressure among hemodialysis patients. Patients and Methods: This cross-sectional multicenter study was performed on 135 patients aged 18 years and over with ESRD treated with hemodialysis. Systolic and diastolic blood pressure of all patients was measured. FGF-23, uric acid, Na and K were measured using blood test and fasting. We used univariate and multivariate linear and non-linear regression. Results: The mean age of patients was 56.45±13.64 years. Around 60% of patients were male. The mean and median FGF-23 in patients was 855.07±43.33 pg/mL and 762.6 pg/mL (IQR=456.6-1430.3) respectively. After adjustment for age, gender, dialysis time, uric acid, Na, K and kt/V, FGF-23 had quadratic association with pulse pressure. We found, each 10-unit (pg/mL) increase in FGF-23 was significantly associated with 0.50 mm Hg decrease in minimum pulse pressure (P=0.002) and 0.42 mm Hg decrease in mean pulse pressure (P= 0.009). Conclusions: FGF23 had a significant association with dialysis vintage and a significant reverse association with minimum and mean pulse pressure.

Renal and extrarenal effects of fibroblast growth factor 23

Fibroblast growth factor 23 (FGF23) is a hormone with a central role in the regulation of phosphate homeostasis. This regulation is accomplished by the coordinated modulation of renal phosphate handling, vitamin D metabolism and parathyroid hormone secretion. Patients with kidney disease have increased circulating levels of FGF23 and in other patient populations and in healthy individuals, FGF23 levels also rise following an increase in dietary phosphate intake. Maladaptive increases in FGF23 have a detrimental effect on several organs and tissues and, importantly, these pathological changes most likely contribute to increased morbidity and mortality. For example, in the context of heart disease, FGF23 is involved in the development of pathological hypertrophy that can lead to congestive heart failure. Increased FGF23 concentrations can also lead to microcirculatory changes, in particular reduced vasodilatory capacity, and collectively these cardiovascular changes can compromise tissue perfusion. In addition, FGF23 is associated with inflammation and an increased risk of infection; other potentially detrimental effects of FGF23 are likely to emerge in the future. Most importantly, recent insights demonstrate that FGF23 can be therapeutically targeted, which holds promise for the treatment of many patients in a variety of clinical settings.